40 years
> 50 years
> 50 years
-
> 50 years
Anamnestic malignancies
X
X
-
X
-
Diabetes mellitus
-
-
-
-
X
Inflammatory diseases
Inflammation of the intestine
-
Prostatitis
-
-
Unbalanced diet, heavy on meat, low in fiber
X
-
X
-
-
Nutrition (more than 1 liter milk per day)
X
-
X
-
-
Genetics
Familial Polyposis
approx. 5% (mainly BRCA-1, BRCA-2)
approx. 5-10 %
X
approx. 5-10% (e.g.HNPCC syndrome)
Sex
-
X
X
-
X
Infections
-
-
-
-
Sexually transmitted HPV
immunosuppression
-
-
-
-
X
Childlessness
-
-
-
-
X
Medications
-
hormone replacement therapy, calcium antagonist
-
-
estrogens, tamoxifen, aromatase inhibitors
early menarche,late menopause
-
-
-
-
X
Nicotine abuse
X
X
-
XX
X
polyps, cysts
intestinal polyps
-
-
-
ovarian cysts
race
-
-
Black
-
-
pollution load
-
-
-
e.g. Asbestos
-
Shift work (especially with night work)
X
X
X
X
-
Sexual partner alternating
-
-
-
-
X
radiation exposure (e.g.through diagnostic or therapeutic medicine, profession)
-
X
-
X
X
Overweight
X
X
X
-
X
Factor
urinary bladder
Malignant melanoma (skin)
head neck tumors
pancreas
Non Hodgkin lymphoma
Leukemia
Frequency in % (Ø)
4w, 8m
1w, 3m
3
3
3
3
Alcohol abuse
-
-
X
-
-
-
Anamnestic malignancies
-
X
-
-
-
-
Diabetes mellitus
-
-
-
X
-
-
Inflammatory diseases
Inflammation of the bladder
-
-
Inflammation of the pancreas
-
-
Unbalanced diet, heavy on meat, low in fiber
X
-
-
-
-
-
Genetics
-
X
-
X
-
-
Skin nevi
-
X
-
-
-
-
immunosuppression
-
X
-
-
-
-
Infections
-
-
Eppstein Barr
-
Eppstein Barr
HTLV
Medications
cyclophosphamide, phenacetin
Arsenic
-
-
-
cytostatics, immunosuppressants
mouth hygiene lacking
-
-
X
-
-
-
Nicotine abuse
X
-
X
X
-
X
race
-
fairness
-
-
-
-
pollution load
e.g. aromatic amines
-
X
-
-
X
shift work (especially with night work)
X
-
-
X
X
X
radiation exposure (eg.through diagnostic or therapeutic medicine, profession)
-
UV light
X
-
-
X
Radiation exposure (living within 5 km to nuclear power plant)
X
Factor
Ovaries
Testicles
Liver
stomach
kidney
Frequency in % (Ø)
5w
2m
4
4
Alcohol abuse
-
-
X
X
X
age
X
-
-
-
-
Anamnestic malignancies
-
X
-
-
-
Cystic kidney disease
-
-
-
-
X
Iron storage disease
-
-
X
-
-
Inflammatory diseases
-
-
-
stomach lining
-
Unbalanced diet, heavy on meat, low in fiber
-
-
-
-
X
birth weight low
-
X
-
-
-
Genetics
X
X
-
X
X
Sex
-
X
-
-
-
undescended testicles
-
X
-
-
-
Infections
-
-
hepatitis, moulds
Helicobacter pylori
-
Childlessness
X
-
-
-
-
Cirrhosis of the liver
-
-
X
-
-
Medications
-
-
-
-
painkillers
Nicotine abuse
-
-
-
X
X
Estrogen levels ↑ (mother or man)
-
X
-
-
-
reflux esophagitis
-
-
-
X
-
pollution load
-
-
X
X
X
Overweight
-
-
-
-
X
Factor
pharynx larynx
thyroid
Esophagus
Penis
Frequency in % (Ø)
1-2
2w, 1m
1w, 2m
Alcohol abuse
X
-
X
-
Diabetes mellitus
-
-
-
-
Unbalanced diet, heavy on meat, low in fiber
X
-
-
-
Genetics
-
X
X
-
Infections
-
X
-
HPV
Oral hygiene lacking
X
-
-
-
Nicotine abuse
X
-
X
-
reflux esophagitis
-
-
X
-
pollution load
X
-
-
-
SD node cold
-
X
-
-
radiation exposure (e.gB by diagnostic or therapeutic medicine, profession)
-
X
-
-
Overweight
-
-
X
-
Cancer risk factors and types of cancer that trigger these factors preferentially
If, after knowing the basic data, we want to decide in the direction of "early cancer therapy" at a point in time when the tumor is still too small to be generally visible, tumor markers, ultrasound examinations or whole-body CT scans bring this at a very early stage Tumor stage often no reliable results. However, the laboratories in particular offer a large number of further diagnostic parameters, which are tables are listed.
measure
Parameters
Use
General laboratory screening
BKS, blood count, creatinine, BG, uric acid, protein electrophoresis, LDH, GOT, GPT, y-GT, AP, SP, TSH, K, Na, calcium, Fe, HDL, LDL, triglycerides, urinary status
General information and screening for organ disorders and tissue breakdown
Immune screening (initial, tumor phase I)
Differential blood count with granulocytes, monocytes, lymphocytes (cellular), immunoglobulins IgA, IgG, IgM, IgE (humoral), TH1/TH2 balance
Primarily measures the quality of the defense, says little about tumor-specific defense (since tumor cells are mostly camouflaged, at least initially)
Immune system advanced (tumour phase II)
lymphocyte differentiation, B cells, T cells, T helper cells, naive helper cells, memory cells, IL-2 expressing helper cells, T suppressor cells, NK cells, T-cytotoxic suppressor cells, activated killer cells, neopterin, CD 25, CD 69, TGFβ
Indication of tumor-associated changes in immune competence and help in therapy decisions, therapy monitoring
Inflammation screening
hsCRP, TNFα, histamine, IP-10 IL-1, IL-6, NFkB
Indications of acute or chronic inflammation
Detox Screening Detox advanced
GSH (intracellular) Paracetamol, caffeine metabolite test GSH/GSSG
Indications of the quality of the detoxification function
Screening of oxidative-nitrosative stress Oxidative-nitrosative stress advanced
MDA-LDL, nitrotyrosine, Antioxidant capacity (TAS), hydroperoxides, antioxidants, lactate pyruvate, methylmalonic acid, 8-OH-deoxyguanosine
Indications of exposure to radicals and antioxidant capacity
Acid-base screening Acid-base advanced
Daily urine pH profile with test strips Sander titration
Indications of acidosis
Intestinal function screening Intestinal function advanced
Intestinal flora determination, zonulin (serum marker for intestinal permeability) antitrypsin (inflammatory marker in stool)
Indications of the function of the intestine
Neuro-endocrine screening Neuro-endocrine function advanced
Daily cortisol profile (saliva), noradrenaline, serotonin tryptophan, tyrosine, dopamine, DHEA
Indications of the function of the neurotransmitter metabolism
Mitochondrial screening Mitochondria advanced
ATP L-carnitine, coenzyme Q10
Indications of the function of mitochondria
Nutrition of the tumor
TKTL1
Indication of energy production in the tumor
Micronutrient diagnostics
e.g.Zinc and iron (low levels indicate tumor activity), copper and ferritin (high levels indicate tumor activity), selenium, Vit B12, Vit B2, glutathione, homocysteine , folic acid
Indications of undersupply and imbalance as well as tumor activity
Bleeding diagnostics
hemoglobin-haptoglobin in stool erythrocytes in urine
Indications of microbleeds
What can make sense for graded oncologically oriented laboratory diagnostics in practice
measure
Use
TPA (tissue polypeptide antigen) Tumor associated proliferation antigen
Non-specific tumor marker, Independent of the primary tumor and generally applicable
mutation of the gene p53
capacity for apoptosis unspecific (prognostic factor for various tumors)
p53 autoantibody
Non-specific tumor marker positive in 10-30% of tumors (healthy cells are p53 autoantibody negative)
Apo10 antigen
Non-specific tumor marker (healthy cells are Apo10-negative), which indicates disturbances in apoptosis of tumor cells
Cyp1B1 enzyme (from the cytochrome p450 family)
Non-specific tumor marker (according to Dr. Dan Burke, healthy cells are Cyp1B1 negative)
Chemosensitivity test
Tumor tissue is treated with medication in order to find the most suitable substance for the tumor in question
CEA (carcinoembrional antigen) tumor associated antigen
Highly specific, especially for colon-Ca (80%) and less specific for pancreatic-Ca (60%), mamma-Ca (55%) and bile-duct and bronchial-Ca (50%) or similar tumors
PSA (prostate specific antigen) Tissue specific antigen
In suspected prostate Ca
TG (thyroglobulin), hCT (human calcitonin)
In suspected thyroid Ca
AFP (α1-fetoprotein)
In suspected liver Ca, teratoma
AFP and HCG (human chorionic gonadotropin)
In suspected germ cell tumors (testicles, ovary)
CA 72-4
In case of suspected stomach-Ca, breast-Ca
Monoclonal immunoglobulins and Bence Jones proteins
In suspected multiple fibroids
CA 19-9, CA 195, TPA
In suspected pancreas-.Ca
CA 15-3, CA 549, MCA (Mucin-like Carcinoma Associated Antigen)
In suspected mammary ca
CA 24, CA 50
In suspected intestinal Ca, pancreatic Ca
CA 125
In suspected gastric Ca
NSE (neuron-specific enolase)
In suspected bronchial Ca, neuroblastoma
CYFRA 21-1 (cytokeratin fragment)
In suspected bronchial Ca
Skeletal alkaline phosphatase (ostasis, bone AP)
In suspected bone metastasis11
SCC (squamous cell carcinoma antigen)
In V.a.Cervical Ca
Bence Jones proteins and beta-2 microglobulin
In suspected plasmacytoma
5-S-cysteinyldopa
In suspected malignant melanoma
neopterine, ß2-microglobulin
In suspected leukemia, lymphoma
BTA (bladder tumor antigen)
In suspected bladder Ca
M2-PK
In suspected renal cell carcinoma, colon and rectal carcinoma
5-HIES (5-hydroxyindoleacetic acid)
In suspected carcinoid (especially in the gastrointestinal tract)
protein S100
Prognostic factor in malignant melanoma
HER2-neu oncogene
Prognostic factor in mamma-Ca
BRCA 1+2 gene mutations
Indication of breast cancer risk
Approaches for meaningful backup diagnostics in practice (including common tumor markers)
Sample questionnaire for a "cancer check"
The below Of course, questionnaires do not replace medical diagnostics, but serve to raise awareness of one's own cancer risk by asking about some relevant cancer risk factors. Even if all questions are answered in the negative, this is of course not to be understood as meaning that there is no risk of cancer.
YES
Has one or more relatives in your family had any of the following cancers: breast cancer, colon cancer, ovarian cancer, uterine cancer, stomach cancer?
Have there been periods of prolonged alcohol abuse in your life?
Have you ever had cancer in the past?
Do you have diabetes mellitus?
Have you ever had an inflammatory disease (e.g. of the intestines, prostate, bladder, pancreas, gastric mucosa, reflux oesophagitis)?
Have or do you have colon polyps?
Have or do you have ovarian cysts (valid only for women)?
Are you childless (valid only for women)?
Did you or your mother have elevated estrogen levels (valid only for men)?
Have or do you have birthmarks?
Have or do you have cold thyroid nodules?
Have you had or do you have an iron storage disease?
Do you have cystic kidney disease?
Did you have a low birth weight?
Did you have or do you have undescended testicles?
Would you be able to say that your oral hygiene is inadequate?
Is your diet rather unbalanced, heavy on meat, low in fibre?
Do you drink more than 1 liter of milk per day?
Have or do you have conspicuous infectious diseases (e.g.STDs, HPV, Eppstein-Barr, HTLV, AIDS, hepatitis, mold, Helicobacter pylori)
Do you have a known weakness of the immune system or immunosuppression?
Is there childlessness (valid only for women)?
Did you take or do you take medication over a longer period of time, such as calcium antagonists, contraceptives, estrogens, tamoxifen, phenacetin, painkillers, cyclophosphamide, arsenic, cytostatics, immunosuppressants or so-called aromatase inhibitors?
Did your menarche occur rather early (valid only for women)?
If you have already had menopause, did it come on late (valid only for women)?
Do you smoke or have you smoked regularly for a long time?
Have you been or are you exposed to pollutants over a longer period of time (e.g. asbestos, mercury, aromatic amines)?
Shift work (particularly with night work)
Do you have frequently changing sexual partners?
Are you or were you exposed to increased radiation (e.g. from UV light, job, diagnostic or therapeutic medicine)?
Do you live - or have you lived - within a 5 km radius of a nuclear power plant?
Are you overweight?
If you answered "yes" to one or more of these questions, it is likely that you are at increased risk of cancer. In this case, be sure to discuss with your therapist what further steps should be taken.
Important micronutrient groups for general cancer prevention
micronutrient
Special features (general effects)
Antioxidants (e.g. Vit. C, Vit E, glutathione)
have an antioxidant effect (protect cells from damage caused by radicals), support detoxification, reduce the overall risk of cancer
polyphenols (e.g. isoflavonoids) carotenoids (e.g. β-carotene, lycopene)
have an antioxidant and anti-inflammatory effect, support detoxification, reduce the overall risk of cancer
zinc
Balances the immune system, activates lymphocytes, controls apoptosis,Zinc deficiency increases cancer incidence
selenium
activates DNA repair enzymes, induces tumor cell apoptosis, reduces overall cancer risk
magnesium, calcium
Deficiency increases cancer incidence
iron
Deficiency increases cancer incidence
folic acid, Vit B6
Deficiency increases cancer risk (especially in women > 65 years)
Vit B12
Caution: different statements regarding cancer protection or cancer promotion by B12, but: deficiency increases cancer incidence
fatty acids (e.g.γ-linolenic acid, omega-3 fatty acids)
Reduce overall cancer risk
vitamin D
Reduces overall cancer risk
vitamin K2
Reduces overall cancer risk
Key micronutrients for primary prevention of cancer and their characteristics
micronutrient
Special features
vitamin C standard substance
Antioxidant, cytotoxic, anti-inflammatory, antiangiogenic, detoxification phase I cofactor, promotes collagen formation
Cave: Distance to inorganic selenium and in late therapy distance to free-radical-forming cytostatics and to radiation
Vitamin E (most effective as natural Vit E with all tocopherols)
Antioxidant, anti-inflammatory, has anticancer activity in its own right and inhibits growth and mitosis of cancer cells, probably only in high pharmacological doses
glutathione
Antioxidant, detoxifying, strengthens repair and apoptosis mechanisms, reduces cancer cell and tumor growth, improves tolerability of the basic therapy without damaging healthy cells In late therapy, possibly tumor cell protection factor (protection from therapeutic radicals) and possibly Multi-drug resistance (when levels ↑)
α-lipoic acid
Antioxidant, detoxifying (chelating agent)
Secondary plant substances (polyphenols, carotenoids)
Antioxidant, anti-inflammatory, antiproliferative, Cave high-dose phytoestrogens in Re+ breast cancer (KI under hormone therapy)
selenium (inorganic) standard substance
reduces resistance and angiogenesis caveat: distance to Vit C
iron
Iron deficiency is common in cancer patients and must be optimally treated
zinc
Immune balancing, possibly inhibits tumor cell apoptosis (administration after basic therapy and in case of deficiency)
B vitamins
poss. B12 administration only after basic therapy and in case of deficiency as well as combined with Vit C (high doses of B12 may increase tumor cell growth), other B vitamins unproblematic
vitamin D
Anti-inflammatory, inhibits cell proliferation and angiogenesis, promotes apoptosis and cell differentiation, reduces tumor growth and metastasis
Vitamin A
Antioxidant, promotes cell differentiation, reduces tumor cell transformation
proteases
Anti-inflammatory, immunotherapy, anti-carcinogenic
Omega 3 fatty acids
Anti-inflammatory
probiotics
immunotherapy
Lead substances in early cancer therapy and late cancer therapy
micronutrient
Study results on the effect of individual micronutrients on certain types of cancer
antioxidants (e.g. Vit.C, glutathione)
Prostate, breast, uterus, ovaries, intestines, lungs, pancreas, glioblastoma, melanoma
polyphenols (e.g. resveratrol, isoflavonoids), carotenoids (e.g. lycopene)
breast, ovaries, prostate, gastrointestinal, leukemia, pancreas, liver
selenium
Melanoma, thyroid, non-Hodgkin's lymphoma, bladder, gastrointestinal, esophagus, leukemia, prostate, liver, lung, breast
zinc
Acute lymphocytic leukemia (ALL), malignant lymphoma, pancreas, bladder
calcium
intestines
magnesium
Acute lymphocytic leukemia (ALL), malignant lymphoma
Omega-3 fatty acids
prostate, pancreas
vitamin D
breast, bowel, Hodgkin's disease, melanoma, thyroid, bladder, pancreas, B-CLL, myeloma
Vitamin A
bubble
Lead substances in cancer therapy and a proven effect on certain types of cancer
Effect
substance
cytotoxic activity
Vit C (increases cytotoxicity in general, especially of doxorubicin, cisplatin, docetaxel, paclitaxel, dacarbazine, epirubicin, irinotecan, 5-FU, bleomycin, carboplastin and gemcitabine as well as that of arsenic trioxide in hematological diseases) selenium (increases cytotoxicity of taxol, doxorubicin, does not reduce cytotoxicity of radiation on cancer cells) quercetin (enhances cytotoxicity of cisplatin, busulfan) β-carotene (enhances cytotoxicity of 5-FU, adriamycin, etoposide, melphalan, cyclophosphamide) γ-linolenic acid and oleic acid (enhance cytotoxic effect of docetaxel, paclitaxel) Vit E (enhance cytotoxic effect of cisplatin)
apoptosis
selenium, α-tocopherol, resveratrol
inhibition of angiogenesis
selenium, α-tocopherol, resveratrol, coenzyme Q10 (with tamoxifen)
Inhibition of proliferation
Antioxidants, Genistein, Quercetin, Vit D
inflammation inhibition
Omega-3 fatty acids
Increase in response rate and prolongation of survival time
Vit C, Vit E and β-carotene (with paclitaxel, carboplatin), antioxidants (general), omega-3 fatty acids
Enhancement of tamoxifen effect
Genistein (in Re-neg breast cancer), Vit D, γ-linolenic acid, coenzyme Q10,Vit B2 and Vit B3
Increase in the number of therapy cycles
glutathione
Improvement of the operation success (e.g.Improvement of wound healing, reduction of infection risk and organ failure)
Antioxidants (such as Vit C, Vit E, glutathione) Selenium Zinc L-arginine, L-glutamine Omega-3 fatty acids Probiotics
improvement of radiation success
resveratrol, proteases, selenium
synergistic effects of micronutrients on the university basic therapy
The benefits of the above Micronutrients can be explained from their biochemical effects and from a large number of positive study results:
Antioxidant and detoxifying substances:
The various synergistically complementary antioxidants fulfill important functions in the primary prevention of cancer by detoxifying harmful radicals and other pollutants and make a significant contribution to preventing their fatal carcinogenic effects. The antioxidants that make sense here include vitamin C, vitamin E, vitamin A, glutathione, α-lipoic acid, coenzyme Q10 and phytochemicals (polyphenols, carotenoids) as well as cofactors of enzymatic antioxidants such as selenium, manganese, zinc or iron.
Anti-inflammatory and immune-modulating substances: Omega-3 fatty acids and vitamin D as well as zinc, selenium and secondary plant substances have proven their worth in this function. In addition to anti-inflammatory tasks, vitamin D, for example, has important functions for a balanced immune system (acts as a regulator in the immune system, activates macrophages and the formation of endogenous antibiotics) and for calcium metabolism.
In addition to these substances, other substances described in the above table are directly or indirectly involved in the optimization of metabolism, energy balance and repair mechanisms - such as Resveratrol:
Resveratrol
Using the example of the secondary plant substance resveratrol, some mechanisms of action of micronutrients for prevention (and possibly unavoidable later tumor therapy) will be described in more detail: Secondary plant substances such as resveratrol are active in all three phases of cancer formation and cancer development and can be used as a chemopreventive substances against cancer initiation, but also against cancer promotion and cancer progression for a wide use, which is why they can also be used in a complementary manner in the basic treatment of the disease.
Resveratrol initially has a primary preventive effect as a potent antioxidant and anti-inflammatory agent and has a positive effect on mitochondrial function and transcription factors. It blocks the activation of carcinogens and affects cancer initiation (phase I). It protects DNA from oxidative damage through its antioxidant effects and the promotion of the formation of antioxidant enzymes (e.g. catalase, superoxide dismutase and hemoxygenase-1). In connection with its anti-inflammatory effect, it alters gene expression and signal transduction pathways, e.g. by inhibiting transcription factors such as EGR-1, AP-1 and NFkB including a reduction in phosphorylation and degradation of the NFkB inhibitor IκBα. In addition, it probably prevents the activation of the aryl hydrocarbon receptor (AhR), which controls cell differentiation and cell growth.
Resveratrol influences numerous other transcription factors such as multi-drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and FlATPase as well as NFKB, STAT3, HIF-1α, β-catenin and PPAR-y.It blocks the transcription of the Cyp1A1 gene and reacts with the enzymes Cyp-1A1 and Cyp-1B1 (from the cytochrome p450 family) produced by mutant cells. These enzymes can have a pro-carcinogenic effect and create therapy resistance because they inactivate chemotherapeutic agents such as tamoxifen or docetaxel. The reaction of resveratrol with Cyp 1B1 also produces the resveratrol metabolite and tyrosine kinase inhibitor piceatannol, which activates apoptosis of tumor cells. The hypoxia-inducible transcription factor-1α (HIF-1α) is overexpressed in many human tumors and their metastases and is closely associated with an aggressive tumor phenotype. Resveratrol inhibits both basal levels and accumulation of the HIF-1α protein in cancer cells. It reduces the activities of the hypoxia-induced VEGF promoter and the release of VEGF as well as the activity of various protein kinases in cancer diseases, which also leads to a significant decrease in the accumulation of the HIF-1α protein and the activation of the VEGF transcription.
Resveratrol also significantly inhibits the invasiveness of cancer cells. In its role in detoxification processes, it inhibits phase I enzymes that can activate procarcinogens and promotes the formation of phase II enzymes that contribute to detoxification of carcinogens. It thereby improves DNA stability, influences cell differentiation and cell transformation and prevents the development of preneoplastic lesions and tumor formation in the mouse cancer model.
Resveratrol acts in secondary prevention or early therapy on various factors involved in tumor promotion and tumor progression and thereby inhibits tumor cell count, tumor growth and tumor spread. Here, too, it is initially involved in the downregulation of inflammatory processes in several ways. It inhibits synthesis and release of pro-inflammatory and carcinogenic substances such as TNF, COX-2, ornithine decarboxylase (key enzyme in polyamine biosynthesis), 5-LOX, VEGF, IL-1, IL-6, IL-8, AR, PSA, iNOS and CRP. It blocks activated immune cells, as well as nuclear factor B (NF-B) and AP-1, and it blocks AP-1-mediated gene expression.
Furthermore, resveratrol inhibits division and growth of tumor cells. It induces cell cycle arrest in S, G or M phase. It modulates cell cycle regulatory genes such as p53, Rb, PTEN, cyclin A, cyclin B1, cyclin E, Stat3-regulated cyclin D1 and CDK, while inducing p53-independent and p21 expression-mediated cell cycle inhibition.
Resveratrol suppresses angiogenesis, which is important for tumor growth by reducing the expression of VEGF and other angiogenic and pro-metastatic gene products (e.g. MMP's, cathepsin D and ICAM-1) . It inhibits DNA synthesis by blocking ribonucleotide reductase or DNA polymerase and altering biomarker expression.
Resveratrol promotes pro-apoptotic factors and induces programmed cell death (see figure), which is essential for protection against cancer and in which two main forms can be distinguished: "deadly" autophagy (programmed cell death type II ) and apoptosis (programmed cell death type I).
Factors affecting programmed cell death in cancer
Apoptosis is the better known form of programmed cell death and can be initiated either extrinsically or intrinsically.
The extrinsic pathway begins with the binding of a ligand (e.g. TNF or similar cytokines) to a receptor of the TNF receptor family (e.g. CD95), which triggers the caspase cascade and leads to apoptosis.
In the intrinsic pathway, DNA damage activates tumor suppressors such as p53.P53 stimulates substances of the pro-apoptotic Bcl-2 family (Bax, Bad), which release cytochrome C from mitochondria and thereby in turn trigger the caspase cascade and subsequent apoptosis
Apoptosis can be suppressed by anti-apoptotic substances of the Bcl-2 family (Bcl-2, Bcl-xL) and by protein kinase B and IAP (inhibitor of the apoptosis protein). The induction of programmed cell death by resveratrol occurs through expression of the pro-apoptotic proteins Bax, p53 and p21 as well as through depolarization of mitochondrial membranes and activation of CD95 independently Caspases (e.g. caspase-9, caspase-3).
Resveratrol also inhibits anti-apoptotic influences and inhibits various protein kinases in cancer cells such as IκBα kinase, src, JN kinase, MAP kinase, protein kinase B, protein kinase D as well as the COX-2 mRNA and TPA-induced protein kinase C and casein kinase 2. It represses the expression of anti-apoptotic genes and gene products such as Clap-2, Bcl-2, Bcl-xL and XIAP. It blocks the release of survivin by inhibiting survivin mRNA and activating sirtuin deacetylase. Survivin is produced by cancer cells and is one of the inhibitors of the apoptosis proteins that are secreted in most human cancers. It can inhibit mitochondria-dependent apoptosis and facilitate aberrant mitotic progression by inactivating the cell death protease caspase-9.
Resveratrol can also be used to support late cancer therapy . It sensitizes tumor cells to other therapies and shows its own cytotoxic activity. It can synergistically improve the effects of chemotherapy and radiation and can reduce both side effects and resistance to chemotherapy drugs.
In addition to resveratrol, a similar effect has been described for many other secondary plant substances, such as the epigallocatechin-3-gallate (EGCG) in green tea , which blocks an important enzyme in the proliferation of cancer cells. The less well-known phytochemicals include the protease inhibitors, which are mainly found in soybeans, legumes and various grains. They are also said to have a good anti-cancer effect, which is also reflected in the fact that synthetic protease inhibitors such as bortezomib are now being used in university oncology. Particularly interesting is the approach that resveratrol has a positive synergistic effect with other phytochemicals (e.g. quercetin) and that none of the processes influenced by resveratrol have any significant cytotoxicity towards healthy cells.
Selected studies on resveratrol in oncology
Resveratrol acts as a cancer chemopreventive agent. Here we discovered a new function of resveratrol: resveratrol is a potent sensitizer of tumor cells to tumor necrosis factor-dependent apoptosis-inducing ligand (TRAIL)-induced apoptosis through a p53-independent induction of p21 and linked to p21-mediated cell cycle inhibition with a depletion of survivin. Simultaneous analysis of cell cycle, survivin expression and apoptosis showed that resveratro-induced G(1) inhibition was associated with down-regulation of survivin expression and sensitization to TRAIL-induced apoptosis. Accordingly, G(1) inhibition by the cell cycle inhibitor mimosine or by overexpression of p21 t reduced survivin expression and sensitized cells to TRAIL treatment.Resveratrol-mediated cell cycle inhibition with subsequent survivin depletion and sensitization to TRAIL was impaired in p21-deficient cells. Down-regulation of survivin with survivin antisense oligonucleotides also sensitized cells to TRAIL-induced apoptosis. Importantly, resveratrol sensitizes various tumor cell lines, but not normal human fibroblasts, to dead receptor ligation or anticancer drug-induced apoptosis. This combined sensitizer (resveratrol) and inducer (e.g. TRAIL) strategy may be a new approach to improve the efficacy of TRAIL-based therapies in a variety of cancers. (Fulda S, Debatin KM ; Sensitization for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by the chemopreventive agent resveratrol; Cancer Res 2004; 64; 337-346)
Resveratrol is a chemopreventive agent against cancer. It has been shown to be anti-oxidant and anti-mutagenic, and thus an anti-initiation agent. Resveratrol selectively represses the activation of cytochrome P-450 1A1 transcription and inhibits the formation of carcinogen-induced preneoplastic lesions in the mouse model. It also inhibits the formation of 12-OTetradecanoylphorbol-13-Acetate (TPA) promoted skin tumors in the two-phase model. The enzymatic activity of COX-1 and -2 is inhibited in cell-free models and the COX-2 mRNA- and TPA-induced activation of protein kinase C and the AP-1-mediated gene expression are suppressed by resveratrol in mammary epithelial cells. In addition, resveratrol strongly inhibits the generation of nitric oxide and the expression of the iNOS protein. NFκB is closely associated with inflammatory and immune responses, and with oncogenesis in some models of carcinogenesis. Resveratrol suppresses the induction of this transcription factor. The mechanism also involves a decrease in phosphorylation and degradation of IκBα. At the cellular level, resveratrol induces apoptosis, cell cycle delay, or blockage of the G1→S transition phase in a variety of cell lines. (Bhat K, Pezzuto JM; Cancer Chemopreventive Activity of Resveratrol, Annals of the New York Academy of Sciences 2006; 957; 210-229)
Resveratrol works against inflammation and disease by modulating many different pathways. It binds to numerous cell signaling molecules such as multi-drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and Fl-ATPase. It activates various transcription factors (e.g. NFKB, STAT3, HIF-1α, β-catenin and PPAR-y), suppresses the expression of anti-apoptotic gene products (e.g. Bcl-2, Bcl-XL, XIAP and survivin) and of protein kinases ( e.g. src, PI3K, JNK and AKT), induces antioxidant enzymes (e.g. catalase, superoxide dismutase and hemoxygenase-1), suppresses the expression of inflammatory biomarkers (e.g. TNF, COX-2, iNOS and CRP), inhibits the expression of angiogenic and metastatic gene products (e.g. MMPs, VEGF, cathepsin D and ICAM-1) and modulates cell cycle regulatory genes (e.g. p53, Rb, PTEN, cyclins and CDK). Numerous animal studies have shown that resveratrol is effective against numerous age-related diseases including cancer, diabetes, Alzheimer's, cardiovascular and lung diseases. Efforts are also underway to improve its effects in vivo through structural modification and reformulation. (Harikumar KB et al.; Resveratrol: a multitargeted agent for age-associated chronic diseases; Cell Cycle 2008; 7; 1020 -1035)
Compelling evidence shows the positive effects of resveratrol on the nervous system, liver, cardiovascular system and cancer chemoprevention.In doing so, it blocks the different phases of carcinogenesis (tumor initiation, promotion and progression). One of the possible mechanisms for its biological activities includes downregulation of inflammatory responses by inhibiting the synthesis and release of pro-inflammatory mediators, altering eicosanoid synthesis, inhibition of activated immune cells of inducible nitric oxide synthase (iNOS) and of cyclooxygenase-2 (COX-2) via its inhibitory effect on nuclear factor B (NF-B) or activator protein-1 (AP-1). Recent data offer interesting insights into the effects of resveratrol on the lifespan of yeast and flies, demonstrating the potential of resveratrol as an anti-aging agent in the treatment of age-related diseases in humans. It must be mentioned that resveratrol has low bioavailability and rapid clearance from plasma. This article considers its potent anti-inflammatory activity and the plausibility of these mechanisms, and provides an update on resveratrol's bioavailability, pharmacokinetics and effects on lifespan. (De la Lastra CA, Villegas I; Resveratrol as an anti -inflammatory and anti-aging agent: mechanism and clinical implications; Molecular Nutrition and Food Research 2005; 49; 405-430)
Resveratrol inhibits growth, S-phase cell cycle arrest and changes in biomarker expression in human cancer cell lines. It differentially reduces the expression of cyclin B1, cyclin A, cyclin D1 and beta-catenin. It induces apoptosis. (Joe AK et al.; Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines. Cancer Res .2002;8, 893-903)
Resveratrol inhibits the growth of leukemia cells in culture. It induces leukemia cell differentiation, apoptosis, cell cycle arrest in S phase, inhibition of DNA synthesis by blocking ribonucleotide reductase or DNA polymerase. (Tsan MF et al.; Anti-leukemia effect of resveratrol.Leuk.Lymphoma 2002;43, 983-987)
Resveratrol reduces human colon cancer cell growth by 70%. The cells accumulated in the S/G2 phase transition of the cell cycle. Resveratrol significantly reduces the activity of ornithine decarboxylase (a key enzyme in polyamine biosynthesis involved in cancer growth). (Schneider Y et al.; Anti-proliferative effect of resveratrol, a natural component of grapes and wine , on human colonic cancer cells.Cancer Lett. 2000; 158, 85-91)
Resveratrol significantly reduces tumor growth in rapidly growing rat tumors and leads to an increase in the number of cells in the G2/M cell cycle phase. It induces apoptosis and leads to a decrease in cell numbers. (Carbo N et al; Resveratrol, a natural product present in wine, decreases tumor growth in a rat tumor model. Biophys. Res Commun 1999;254, 739-743)
Resveratrol induces apoptosis in more than 80% of CD95-sensitive and CD95-resistant acute lymphoblastic leukemia (ALL) cells by depolarizing mitochondrial membranes and by activating caspase-9, independent of CD-95 signaling. There is no significant cytotoxicity to normal peripheral blood cells. (Dorrie J et al.; Resveratrol induces extensive apoptosis by depolarizing mitochondrial membranes and activating caspase-9 in acute lymphoblastic leukemia cells. Cancer Res. 2001; 61, 4731-4739 )
Resveratrol (200 mcg/kg) significantly reduces carcinogenesis of colon cancer in rats. It significantly reduces cell number and alters bax and p21 expression. (Tessitore L et al.; Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21 (CIP) expression Carcinogenesis 2000; 21, 1619-1622)
Resveratrol develops antiproliferative activity. It inhibits proliferation and induces cytotoxicity and apoptosis in cells of Waldenstrom's macroglobulinemia (WM). Peripheral blood cells are not affected. Resveratrol shows synergistic cytotoxicity when combined with dexamethasone, fludarabine and bortzomib. (Roccaro AM et al.; Resveratrol Exerts Antiproliferative Activity and Induces Apoptosis in Waldenstrom's Macroglobulinemia; Clin. Cancer Res 2008; 14: 1849-1858)
Resveratrol acts on all three stages of carcinogenesis (initiation, promotion and progression) by altering signal transduction pathways that control cell division, cell growth, apoptosis, inflammation, angiogenesis and metastasis. Resveratrol's anti-cancer properties are supported by its ability to inhibit the proliferation of a variety of human tumor cells in vitro and in animal studies. In this review, data from preclinical in vivo studies and interventional studies on cancer and associated mechanisms of action are presented. In addition, bioavailability, pharmacokinetics and potential toxicity of resveratrol as well as its usefulness in cancer are discussed. (Bishayee A; Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials; Cancer Prev Res (Phila Pa) 2009; 2: 409-418)
Resveratrol significantly inhibits cell growth in pancreatic carcinoma cell lines (PANC-1 and AsPC-1) in a concentration- and time-dependent manner and induces cell apoptosis. (Ding XZ et al.; Resveratrol inhibits proliferation and induces apoptosis in human pancreatic cancer cells; Pancreas 2002; 25: e71-76)
Resveratrol has anti-cancer properties and suppresses the proliferation of a variety of tumor cells. The growth inhibitory effect is mediated by cell cycle inhibition with upregulation of p21(CIP1/WAF1), p53 and Bax and downregulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs and activation of caspases. Resveratrol suppresses the activation of transcription factors such as NFkB, AP-1 and EGR-1 and inhibits protein kinases including IkBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II. It downregulates COX2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities are responsible for the suppression of angiogenesis. Resveratrol also enhances the apoptotic effects of cytokines, chemotherapy drugs and radiation. It blocks carcinogen activation by inhibiting CYP1A1 expression and activity and suppresses tumor initiation, promotion and promotion. In addition to chemopreventive effects, resveratrol appears to have therapeutic effects against cancer. (Aggarwal BB et al.; Role of Resveratrol in prevention and therapy of cancer: preclinical and clinical studies; Anti-cancer Res 2004; 24; 2783-2840 )
Resveratrol influences (in addition to its protective function on the cardiovascular system) all three stages of cancer development (tumor initiation, promotion and progression). It also suppresses angiogenesis and metastasis. The anti-cancer effects of resveratrol appear to be closely related to its ability to interact with several molecular parameters involved in carcinogenesis while minimizing toxicity in healthy tissues. Therefore, resveratrol should be used in human cancer chemoprevention in combination with chemotherapeutic agents or cytotoxic factors for highly efficient treatment of drug-refractory tumor cells.The anti-carcinogenic potential of resveratrol for cancer chemoprevention and anti-cancer therapy represents, so to speak, a new explanation of the French paradox (Liu BL et al.; New enlightenment of French Paradox: resveratrol's potential for cancer chemoprevention and anti-cancer therapy; Cancer Biol Ther 2007;6:1833-1836)
Several studies have demonstrated the modulating effect of resveratrol on a variety of cell signaling and gene expression pathways. This article summarizes the effects of resveratrol in chemoprevention. (Goswami SK, Das DK; Resveratrol and chemoprevention; Cancer Lett 2009; 284: 1-6)
Resveratrol has a strong growth-inhibiting effect against various human cancer cells. Here, the inhibitory effect of resveratrol on experimental liver cancer is examined using a two-stage model in rats. Resveratrol 50-300 mg/kg body weight reduces the incidence, number, volume and multiplicity of visible hepatocyte nodules in a dose-dependent manner. It leads to a decrease in cell proliferation and an increase in apoptotic cells in the liver. It also induces expression of the pro-apoptotic protein Bax, reduces expression of the anti-apoptotic Bcl-2, and at the same time increases the Bax/Bcl-2 ratio. Due to its favorable toxicity profile, resveratrol has the potential to be developed as a chemopreventive drug against human hepatocellular carcinoma. (Bishayee A, Dhir N; Resveratrol-mediated chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis: inhibition of cell proliferation and induction of apoptosis; Chem Biol Interact 2009;179:131-44)
The aim of this study was to demonstrate interactions of ellagic acid and quercetin with resveratrol (polyphenols) in inducing apoptosis and reducing cell growth in human leukemia cells (MOLT-4). The combination of ellagic acid with resveratrol has a synergistic effect more than additive. Both substances alone and together induce significant changes in cell cycle kinetics. There are positive synergistic interactions between ellagic acid and resveratrol and between quercetin and resveratrol in inducing caspase-3 activity. The anticarcinogenic potential of foods with polyphenols can be enhanced through synergistic effects. (Mertens-Talcott SU, Percival SS; Ellagic acid and quercetin interact synergistically with resveratrol in the induction of apoptosis and cause translent cell cycle arrest in human lekemia cells; Cancer Lett 2005;218;141-151)
Resveratrol has a cancer-preventive effect and, in physiological doses, induces Bax-mediated and Bax-independent mitochondrial apoptosis in human HCT116 colon carcinoma cells. Both pathways limit the cells' ability to form colonies. (Mahyar-Roemer M et al.; Role of Bax in resveratrol-induced apoptosis of colorectal carcinoma cells; BMC Cancer 2002; 2; 27-36)
Interfering with multistep carcinogenesis by modulating intracellular signaling pathways may provide a molecular basis for phytochemical chemoprevention. Resveratrol has been extensively studied for its chemopreventive activity related to its ability to intervene in multistage carcinogenesis. Numerous intracellular signaling cascades converge with the activation of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), which act independently or coordinately to regulate expression of target genes. These ubiquitous eukaryotic transcription factors mediate pleiotropic effects on cellular transformation and tumor promotion.The aim of this review is to update the molecular mechanisms of resveratrol chemoprevention with particular attention to its effect on cellular signaling cascades mediated by NF-kappaB and AP-1.Resveratroldownregulates Survivin significantly in a dose- and time-dependent manner and the cell cycle, induces apoptosis and enhances the effects of chemotherapeutic agents in multidrug-resistant non-small cell lung cancer cells. (Zhao W et al.; Resveratrol down-regulates surviving and induces apoptosis in human multidrug-resistant SPC -A-1/CDDP cells; Oncology Reports 2010;23;279-286)
Resveratrol has antineoplastic activity. It inhibits the growth and induces the death of ovarian carcinoma cells (more via autophagy than via apoptosis), inter alia associated with caspase activation. It thus induces cell death via 2 different pathways: non-apoptotic and apoptotic (via release of the anti-apoptotic proteins Bcl-xL and Bcl-2) (Opipari AW et al.; Resveratrol-induced autophagy in the ovary Cancer Cells; Cancer Research 2004; 64, 696-703)
Resveratrol inhibits Src tyrosine kinase activity, thereby blocking activation of the constitutive signaling and transcription activator-3 (Stat3) protein in malignant cells. Analyzes of resveratrol-treated malignant cells harboring constitutively active Stat3 show irreversible cell cycle arrest of v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), human mammary (MDAMB-231), pancreatic (Panc-1 ) and prostate carcinoma (DU145) cell lines in G0-G1 or S phase human breast cancer (MDA-MB-468) and pancreatic cancer (Colo-357) cells, and loss of viability due to apoptosis. In contrast, cells treated with resveratrol but lacking aberrant Stat3 activity show reversible growth arrest and minimal loss of viability. Furthermore, in malignant cells that harbor constitutively active Stat3, including human prostate cancer DU145 cells and v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), resveratrol represses Stat3-regulated cyclin D1 as well as Bcl-xL and Mcl-1 genes, suggesting that resveratrol's anti-tumor cell activity is due in part to blockade of Stat3-mediated dysregulation of growth and survival pathways. Our study is among the first to identify Src-Stat3 signaling as a target of resveratrol, define the mechanism of resveratrol's antitumor cell activity, and demonstrate its potential for application to tumors with an activated Stat3 profile. (Kotha A et al.; Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein; Mol. Cancer Ther 2006; 5: 621 – 629)
Hypoxia-inducible factor-1α (HIF-1α) is overexpressed in many human tumors and their metastases and is closely associated with an aggressive tumor phenotype. In this study we investigated the effect of resveratrol on the accumulation of the hypoxia-induced HIF-1α protein and the expression of vascular endothelial growth factor (VEGF) in squamous cell carcinoma of the tongue and in hepatoma cells. Resveratrol markedly inhibits both basal levels and accumulation of hypoxia-induced HIF-1α protein in cancer cells, but not HIF-1α mRNA levels. Pretreatment of the cells with resveratrol markedly reduced the activities of the hypoxia-induced VEGF promoter and the release of VEGF at both the mRNA and protein level.The mechanism of resveratrol's inhibition of hypoxia-induced HIF-1α accumulation appears to involve a shortened HIF-1α protein half-life caused by increased degradation of proteins by the 26S proteasome system. In addition, resveratrol inhibits hypoxia-mediated HIF-1α accumulation Activation of extracellular signal-regulated kinase 1/2 and Akt, resulting in a marked decrease in accumulation of the hypoxia-induced HIF-1α protein and activation of VEGF transcription. Resveratrol also markedly inhibits the hypoxia-stimulated invasiveness of cancer cells. These data indicate that HIF-1α/VEGF could represent a promising target for resveratrol in the development of effective chemoprevention and therapy for human cancers. (Zhang Q et al.; Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1{alpha} and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells; Mol
Many recent studies have shown promising health benefits of red wine. This article provides an overview of some of the most important studies and the mechanisms for these beneficial effects. It has been shown that these positive effects are due to polyphenols in red wine, especially resveratrol in grape skins. These effects include a reduction of approximately 30% to 50%, 57%, and 50% in cardiovascular morbidity and mortality, lung cancer, and prostate cancer. Polyphenols possess antioxidant, superoxide scavenging, ischemia preconditioning, and angiogenesis properties. Some of these properties of polyphenols may explain their protective effects on the cardiovascular system and other organs of the body. Therefore, the United States Department of Health and Human Services recommended moderate alcohol consumption in their national health promotion and prevention initiative, Healthy People 2010. (Review; Vidavalur R et al.; Significance of wine and resveratrol in cardiovascular disease: French paradox revisited;Exp Clin Cardiol.2006;11:217-225)
Vitamin C
Vitamin C in particular plays an outstanding role in cancer therapy (see figure). Several different mechanisms of action of the substance come into play:
The antioxidant effect, for which there is sufficient evidence for use in supportive oncological therapy. In this way, vitamin C protects healthy cells and leads to a reduction in side effects as well as an improvement in the effect of usual therapy and an improvement in the quality of life
The cytotoxic effect on cancer cells especially with high-dose parenteral administration. As with radiation and some chemotherapeutic agents, it is mediated by the formation of H2O2 via anti-proliferative, but especially via pro-oxidative effects . With oral vitamin C administration, a cytotoxic effect was only found in early therapy, where it can also reduce the level of tumor markers, for example, but not in late therapy (e.g. Creagan, Moertel et al.; 1979) . This can be explained by the fact that with oral intake, the absorbed amounts of vitamin C are too low to achieve sufficiently high plasma levels over a longer period of time for a cytotoxic effect in the sense of apoptosis and autophagy in tumors that are already visible. On the other hand, there is sufficient evidence that parenteral vitamin C in pharmacological doses in late therapy achieves sufficient effective levels from approx. 25-30 mmol/l and, above all, in combination with other active substances, taking into account any possibleInteractions with chemotherapeutic agents and radiation in a wide variety of tumor forms in first-line chemotherapy is useful - without fear of systemic toxicity or damage to healthy cells
Vitamin C also has an anti-inflammatory effect, activates collagen formation, increases the cytotoxic potency of chemotherapeutic agents, reduces side effects such as pain, fatigue, vomiting or loss of appetite and contributes to improving the quality of life of tumor patients.
Antioxidant and prooxidative effects of vitamin C in oncology
selenium
Similar to vitamin C, selenium also plays a key role in the early and late treatment of malignant tumors.
It has antineoplastic and tumor-selective cytotoxic effects, inhibits tumor growth, invasion and angiogenesis and improves the detectability of tumor tissue
It promotes apoptosis of non-repairable cells (e.g. via activation of p53, p21, BAX and cytochrome C)
It increases the expression of selenium-dependent enzymatic antioxidants
It activates NK cells and potentiates the antitumor cytotoxicity of NK cell-based immunotherapies
It protects healthy cells and reduces side effects of basic therapy without loss of effectiveness
It has a prophylactic effect against lymphedema and erysipelas
It reduces the risk of resistance and sensitizes resistant tumor cells to therapy again
It reduces the risk of metastasis and recurrence as well as mortality
A selenium undersupply reduces the chances of success of basic university therapy, a good selenium supply and additional selenium doses increase it
Selected studies on selenium in oncology
CD94/NKG2A controls the activity of NK cells. Selenite reduces the expression of HLA-E on tumor cells and can potentiate the antitumor cytotoxicity of NK cell-based immunotherapies. (Enquist M et al.; Selenite induces posttranscriptional blockade of HLA-E expression and sensitizes tumor cells to CD94/NKG2A-positive N cells; J Immunol 2011; 187; 3546-3554)
Selenite oxidizes polythiols to corresponding disulfides and does not react with monothiols. It makes cancer cells more vulnerable to immune system surveillance and destruction. It activates NK cells and inhibits angiogenesis. (Lipinski B; Rationale for the treatment of cancer with sodium selenite; Med Hypotheses 2005; 64; 806-810)
Redox-active selenium inhibits the growth of cancer cells and has tumor-selective cytotoxic effects without resistance development. (Wallenberg M et al.; Selenium cytotoxicity in cancer; Basic & Clinical Pharmacology & Taxocology 2014; 1-10)
Low doses of selenium promote cell growth, high concentrations inhibit it. Selenium induces apoptosis of malignant cells and does not affect normal cells. (Björnstedt M, Fernandes AP; Selenium in the prevention of human cancers. EPMA J 2010;1: 389-95)
Low seleniumconcentrations are essential for cell growth, high concentrations selectively induce cell death in tumor cells. (Selenius M et al.; Selenium and the selenoprotein thioredoxin reductase in the prevention, treatment and diagnostics of cancer. Antioxid Redox Signal 2010;12:867-80) Selenium can reduce cancer risk as well as progression and metastasis in all cancer types (and specifically in prostate, liver, gastrointestinal and lung cancer), especially in people with a low selenium status (there is a reduction in DNA damage and oxidative stress, among other things). (Rayman MP; Selenium in cancer prevention: a review of the evidence and mechanism of action; Proc Nutr Soc 2005; 64; 527-542)
Seleniumsupplementation increases antioxidant protection through increased expression of selenium-dependent GSHPeroxidase and thioredoxin reductase Selenium protects against cancer: it affects tumor metabolism, the immune system, cell cycle regulation and apoptosis. (Combs GF Jr; Chemopreventive mechanism of selenium; Med Klin 199; 94 Suppl 3; 18-24)
Enzymes
There are basically three main groups of enzymes to be distinguished in therapeutic use in cancer:
the antioxidant enzymes (see under antioxidants)
the detoxifying enzymes (see under detoxification)
the proteolytic enzymes (proteases)
Many of these enzymes require cofactors, coenzymes or co-substrates for their activities, such as B vitamins, iron, zinc, selenium, manganese, magnesium or polyphenols, which belong to the closest group of micronutrients.
The proteases belong to the hydrolases. In complementary oncology, the substances bromelain and papain as well as trypsin and chymotrypsin are mostly used in combination in enteric-coated preparations.
The proteases have an anti-inflammatory effect, for example, improve phagocytosis, stimulate the body's own defences, reduce immune and cytokine complexes as well as adhesion molecules and TGFβ, absorb edema and hematomas and contribute to the unmasking of tumor cells. They are mainly used in late cancer therapy, where they have a synergistic effect with basic university therapy and improve the quality of life. However, they can also be used in early therapy and to prevent metastases, as palliative treatment and in the case of malignant effusions.
Examples of studies and articles on the use of micronutrients in tumor diseases
PREVENTION
i) Risk of cancer in general
Chronic inflammation
Different effects of inflammatory processes on cancer have been described. Acute inflammation usually reduces the development of cancer, while chronic inflammation promotes it. For example, while IL-6 inhibits apoptosis and can promote cancer development, interferons can promote DNA repair and stabilize p53. They have an anti-oncogenic effect. (Philip M et al.; Inflammation as a tumor promoter in cancer induction; Semin Cancer Biol 2004; 14; 433-439)
Chronic inflammation is responsible for up to 20% of all cancers, e.g. inflammatory bowel diseases (Crohn's disease, ulcerative colitis), viral infections, bacterial infections (e.g. caused by Helicobacter pylori), parasitosis, exposure to asbestos , alcohol and nicotine abuse or overweight. They lead to radical overproduction and lipid peroxidation. These are responsible for DNA damage, tumor cell growth, tumor spread and activation of cancer genes. (Deutsches Ärzteblatt; how chronic inflammation leads to cancer; international expert meeting at the German Cancer Research Institute in Heidelberg; March 10, 2006)
Inflammation contributes to the development of about 15% of all cancers. Inflammation and inflammation-induced NFkB protein contribute to uncontrolled cancer cell growth, and macrophages produce substances that stimulate tumor growth, including TNFalpha, which boosts NFkB activity. Tumor cells produce substances such as CSF-1 (colony stimulating factor 1) and COX-2, which in turn promote inflammation. NSAIDs reduce the risk of cancer by reducing inflammation. Components of red wine and green tea act as NFkB inhibitors. (Marx J; Cancer research.Inflammation and cancer: the link goes stronger; Science 2004; 306; 966-968)
Antioxidants
Apples have a high antioxidant capacity, suppress cancer cell proliferation, reduce lipid oxidation and cholesterol. They contain various phytochemicals including quercetin, catechin or phloridzin. The content of phytochemicals varies greatly between different apples and there are also differences in phytochemical content during the ripening process. (Review; Boyer J et al.; Apple phytochemicals and their health benefits; Nutr J 2004; 3; 5)
After 7.5 years, antioxidants (beta-carotene 6 mg, zinc 20 mg, selenium 100 mcg, vitamin C 100 mg, vitamin E 30 mg) significantly reduce the risk of cancer (relative risk 0.69, 95% CI ) and all-cause mortality (risk ratio, 0.63, 95% CI) in males. Note: In women, the results were not available: men had lower blood levels of antioxidants. (Randomized, double-blind, placebo-controlled; 13017 participants; SU.VI.MAX; 2004; Serge Hercberg et al.; Arch Intern Med .2004;164;2335-2342)
All-cause mortality is associated with low levels of carotene and vitamin C (and retinol). Low vitamin E levels are associated with an increased risk of lung cancer and in smokers with an increased risk of prostate cancer. (2974 participants over 17 years; Eichholzer M et al.; Prediction of male cancer Mortality by plasma levels of interacting vitamins; 17-year follow-up of the prospective Basel Study; Int J of Can 1996; 66; 145-150; Stahelin HB et al.; Plasma antioxidant vitamins and subsequent cancer mortality in twelve-year follow-up of the prospective Basel Study. Amer J of Epidem 1991; 133; 766-775)
Vitamin and mineral supplementation (particularly with the combination of beta-carotene, vitamin E, and selenium) reduces the risk of cancer in the Linxian population (RR 0.91; 95% CI). (Randomized, 29584 participants; Blot W et al.; Nutrition intervention trials in Linxian, China: Supplementation with specific vitamin/mineral combinations, cancer incidences and disease-specific mortality in the general population. J of the Nat Can Inst; 1993; 85; 1483-1492)
Low alpha-tocopherol levels increase cancer risk 1.5-fold for various types of cancer, the correlation being strongest for gastrointestinal tumors and for cancers independent of nicotine abuse and for non-smokers with low selenium levels . (36265 participants over 8 years; Knekt P et al.; Vitamin E and cancer prevention; The Amer J of Clin Nutr 1991; 53; 283S-286S)
The risk of malignant melanoma is reduced at the highest versus lowest plasma levels of β-carotene (OR 0.9; 95% CI) and for total vitamin E ( OR 0.7; 95% CI). (452 participants; Stryker WS et al.; Diet, plasma levels of beta-carotene and alpha-tocopherol, and risk of malignant melanoma; Am J Epidemiol 1990; 131: 597-611)
Resveratrol
The inhibition of tumor initiation by resveratrol probably occurs by preventing the activation of the Ah receptor. Resveratrol also affects several factors involved in tumor promotion and progression. Because tumor-promoting agents alter the expression of genes whose products are implicated in inflammation, chemoprevention of cardiovascular disease, and cancer, common mechanisms may exist. This includes, above all, the modulation of the expression of growth factors and cytokines. Recently, chemopreventive properties of resveratrol have been linked to inhibition of NF-kappaB.This transcription factor is closely linked to inflammatory and immune responses and to the regulation of cell proliferation and apoptosis. It is therefore important for tumorigenesis and many other diseases such as atherosclerosis. Although the mechanisms by which resveratrol interferes with NF-κB activation are not clear, it appears that inhibition of its degradation, which is necessary for its cellular activation, is the most important target. Based on the amount and variety of data available on the biological activity of resveratrol, it must be considered as a very promising chemoprotectant and chemotherapeutic agent. (Ignatowicz E et al.; Resveratrol, a natural chemopreventive agent against degenerative diseases; Pol J; Pharmacol 2001; 53; 557-569)
Resveratrol has cancer chemopreventive activity at three key stages of carcinogenesis. It has antioxidant, antimutagenic and induces phase II drug-metabolizing enzymes (anti-initiation activity). It mediates anti-inflammatory effects and inhibits cyclooxygenase and hydroperoxidase functions (anti-promotional activity) and induces differentiation of human promyelocytic leukemia cells (anti-progressive activity). In addition, it prevents the development of preneoplastic lesions in carcinogen-treated mice and inhibits tumorigenesis in the mouse skin cancer model. These data suggest that resveratrol is a potential chemopreventive agent for human use. (Jang MS et al.; Cancer chemopreventive activity of reseveratrol, a natural product derived from grapes; Science; 1997; 275 ; 218-220)
Resveratrol is a chemoprotective substance against skin cancer and activates sirtuin deacetylase. It extends the lifespan of lower organisms and has protective effects against stress and disease. (Baur JA, Sinclair DA; Therapeutic potential of resveratrol: the in vivo evidence; Nature Reviews Drug Discovery 2006; 5, 493 -506)
selenium
In patients with a history of skin cancer, selenium 200 mcg versus placebo did not significantly affect the incidence of basal cell carcinoma and squamous cell carcinoma (RR 1.10 and RR 1.14, respectively; 95% CI). The patients receiving selenium had a non-significant reduction in all-cause mortality (RR 0.83; 95% CI) and a significant reduction in all-cause mortality (RR 0.50; 95% CI) and all-cause incidence (RR 0.63; 95% CI). (Double-blind, rendomized, placebo-controlled; 1312 participants over 8 years (1983-1991); Clark LC et al.; Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group; JAMA 1996; 276; 1957-1963)
Vitamin D
Low vitamin D levels are associated with an increased risk of cancer incidence and mortality in men, particularly in the gastrointestinal system. A 25 nmol/L increase in vitamin D levels is associated with a 17% reduction in overall cancer risk and a 45% reduction in gastrointestinal cancer mortality. (Prospective Cohort Study; Health Professionals Follow-Up Study with 47,800 participants over the age of 14. Giovannucci E et al.; Prospective Study of Predictors of Vitamin D Status and Cancer Incidence and Mortality in Men; JNCI Journal of the National Cancer Institute 2006 98(7):451 -459)
There is a clear association between vitamin D status and the risk of colon, breast, prostate and ovarian cancer. (30 colon, 13 breast, 26 prostate and 7 ovarian carcinomas from 63 clinical studies Garland CF et al.; The role of vitamin D in cancer prevention; Am J Public Health 2006; 96; 252-261)
Calcium
Calcium generally protects women from cancer With doses of more than 1300 mg, there is no increasing risk reduction. Dairy products (eg, 3 cups of low-fat or non-fat dairy products) and calcium dose-dependently protect men (RR 0.84) and women (RR 0.77) from gastrointestinal and especially colorectal cancer. Calcium intake does not correlate with the risk of breast, endometrial, ovarian, and prostate cancer. (Prospective National Institutes of Health-AARP Diet and Health Study (cohort study) over 7 years Park Y et al .; Dairy Food, Calcium, and Risk of Cancer in the NIH-AARP Diet and Health Study; Arch Intern Med 2009; 169; 391-401)
Calcium intake is associated with the overall cancer risk in women and decreases up to a calcium intake of 1300 mg/d. Higher doses do not lower the risk any further. Calcium intake is inversely associated with the risk of gastrointestinal cancer in males and females (RR 0.84; 95 CI in males and RR 0.77; 95% CI in females) and especially colorectal cancer. ( National Institutes of Health-AARP-Diet and Health Study Approximately 500,000 participants over the age of 7 Park Park et al Dairy Food, Calcium, and Risk of Cancer in the NIH-AARP Diet and Health Study Arch Intern Med 2009 169(4):391-401)
selenium
Selenium can activate the p53 tumor suppressor protein (through redox mechanisms) and the DNA repair arm of p53 in cancer prevention (Seo YR et al.; selenomethionine regulation of p53 by a ref1-dependent redox mechanism; Proc Natl Acad Sci USA 2002;99;14548-14553)
Selenium can reduce the risk of cancer as well as the progression and metastasis of all types of cancer (and especially prostate, liver, gastrointestinal and lung cancer), especially in people with low selenium status (there is a reduction DNA damage and oxidative stress). (Rayman MP; Selenium in cancer prevention: a review of the evidence and mechanism of action; Proc Nutr Soc 2005; 64; 527-542)
Low seleniumlevels increase cancer incidence compared to high levels (OR 1.95) cohort study with 4857 participants (Ujiie S et al.; Serum Selenium contents and the risk of cancer; Gan To Kagaku Ryoho 1998;25;1891-1897)
Selenium supplementation increases antioxidant protection through increased expression of selenium-dependent GSHPeroxidase and thioredoxin reductase. Selenium protects against cancer: it affects tumor metabolism, the immune system, cell cycle regulation and apoptosis. (Combs GF Jr; Chemopreventive mechanism of selenium; Med Klin 199; 94 Suppl 3; 18-24)
Selenium has a protective effect on cancer incidence (RR 0.76), particularly pronounced in people with low selenium levels and in high-risk patients. (meta-analysis; Lee EH et al.; Effects of selenium supplements on cancer prevention: meta-analysis of randomized controlled trials; Nutr Cancer 2011; 63; 1185-1195)
People with the lowest selenium levels have a 5.8-fold increased risk of fatal cancer compared to those with the highest selenium levels. It was increased 11.4 times in people with low selenium and low vitamin E levels. A reduced intake of vitamin A or provitamin A increases the risk of lung cancer in smokers with low selenium levels. (Salonen JT et al.; isk of cancer in relation to serum concentrations of selenium and vitamins A and E: matched case-control analysis of prospective data; Br Med J 1985; 290; 4127-420)
High selenium levels (between 130-150 ng/ml) greatly reduce all-cause mortality (HR 0.83), cancer mortality (HR 0.69) and cardiovascular mortality (HR 0.94). high selenium levels (> 150 ng/ml), on the other hand, slightly increase mortality. (13887 participants; Bleys J et al.; Serum selenium levels and all-cause, cancer and cardiovascular mortality among US adults; Arch Intern Med 2008;168;4040-410)
ii) Cancer risk for individual tumor types
Prostate
selenium
Men who are well supplied with selenium in the long term (measurement of the selenium content in toenails) have a lower risk of prostate cancer. (Prospective cohort study; 58279 participants; Geybels MS et al.; Advanced prostate cancer risk in relation to toenail selenium levels; J Natl Cancer Inst 2013; 105; 1394-1401)
There is a 63% lower risk of prostate Ca from selenium 200 mcg. (Randomized, double-blind, placebo-controlled; Clark LC et al.; Decreased incidence of prostate cancer with selenium supplementation; Br J Urol 1998; 730-734 (cf. original study evaluation from 1996 in JAMA 1996; 276; 1957-1963))
Selenium 200 mcg has a significant effect on the total prostate Ca incidence (RR 0.51; 95% CI ) (Randomised, placebo-controlled, double-blind; NPC trial; 1312 participants; Duffield-Lillico AJ et al.; Selenium supplementation, baselone plasma selenium status and incidence of prostate cancer; an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial; BJU international 2003; 91; 608-612)
Low selenium levels are associated with a 4-5-fold increased risk of prostate cancer. (case-control study; Baltimore Longitudinal Study of Aging; 148 participants; Brooks JD et al.; plasma sleenium level before diagnosis and the risk of prostate cancer development; The Journal of Urology; 2001; 166; 2034-2038)
Higher selenium levels are associated with a lower risk of advanced prostate cancer (OR 0.49; 95% CI for highest versus lowest levels). After additional control for family history for prostate cancer, BMI, calcium and saturated fat intake, vasectomy, and geographic region, the OR was 0.35 (95% CI). (Prospective Health Professionals case-control study; 51529 participants; Yoshizawa K et al.;Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer;J Natl Cancer Inst 1998;90:1219-1224)
Inorganic selenium in high doses significantly reduces the growth of primary hormone-refractory prostate carcinomas and the development of retroperitoneal lymph node metastases in the experimental mouse model. (Corcoran NM et al.; Inorganic selenium retards progression of experimental hormone refractory prostate cancer;J Urol 2004;171:907-910)
Selenium reduces the risk of prostate cancer (RR 0.74). (Review, meta-analysis Etminan M et al.; Intake of selenium in the prevention of prostate cancer: a systemic review and meta-analysis ; Cancer Causes Control 2005; 16; 1125-1131)
The risk of prostate cancer decreases with increasing seleniumlevels up to 170 ng/ml. (Hurst R et al.; Selenium and prostate cancer: systematic review and meta-analysis ; Am J Clin Nutr July 2012 vol. 96 no. 1 111-122)
Higher selenium intake reduces the risk of prostate cancer. (Van den Brandt PA et al.; Selenium levels and the subsequent risk of pro cancer state: a prospective cohort study; Cancer Epidemiol Biomerkers Prevent 2003; 12; 866-871)
Vitamin E
Vitamin E (+alpha-tocopheryl-succinate) and selenium (methylselenic acid) alone lead to a moderate inhibition of survival time and growth of human prostate cancer cells. A combination results in a dramatic increase in the Growth inhibition of prostate cancer cells. Apoptosis is induced, Bax, Bak and Bi proteins increase and Bcl-2 protein decreases. (Reagan-Shaw S et al.; Combination of vitamin E and selenium causes an induction of apoptosis of human prostate cancer cells by enhancing Bax/Bcl-2 ratio; Prostate 2008; 68: 1624-1634)
The incidence of prostate Ca is reduced by 1/3 with vitamin E 50 mg. (randomized, double-blind, placebo-controlled; ATBC study; Heinonen OP et al.; Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial;J Natl Cancer Inst 1998;90:440-446)
Smokers and ex-smokers who consume at least 100 IU vitamin E have a reduced risk of metastatic or fatal prostate. (RR 0.44; 95% CI). (47780 participants; Chan JM et al.; Supplemental Vitamin E Intake and Prostate Cancer Risk in a Large Cohort of Men in the United States; Cancer Epidemiology Biomarkers & Prevention 1999;8;893-899)
Supplementation with vitamin E 400 IU hardly reduced the overall prostate carcinoma risk (HR 0.86; 95% CI). The risk of advanced prostate carcinoma (regionally invasive or metastatic) decreased significantly in relation to the dose of vitamin E (HR 0.43; 95% CI). There was no stronger association between the administration of selenium ( (Prospective cohort study; 35242 participants over 10 years; Peters et al .; Vitamin E and selenium supplementation and risk of prostate cancer in the Vitamins and lifestyle (VITAL) study cohort; Cancer Causes Control 2008; 19: 75-87)
Vitamin K2
There is a non-significant relationship between prostate cancer incidence and vitamin K2. The reduction in risk is 35% (RR 0.65), the risk of advanced prostate ca. is reduced by 63% (RR 0.37). The association with menaquinone from dairy products is more pronounced than with meat-based vitamin K2. Vitamin K1 (phylloquinone, mainly from leafy vegetables and vegetable oil) shows no correlation. (EPIC study, 11319 participants over 8.6 years; Nimptsch K et al.; Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg); Am J Clin Nutr 2008; 87; 985-992)
Tomatoes
The risk of prostate cancer is reduced with a high intake of raw tomatoes (RR 0.89; 95% CI) and higher with cooked tomato products (RR 0.81; 95% CI). (Meta-analysis from 11 case control studies and 10 cohort studies; Etminan M et al.; The Role of Tomato Products and Lycopene in the Prevention of Prostate Cancer: A MetaAnalysis of Observational Studies; Cancer Epidemiology Biomarkers & Prevention 2004; 13; 340-345 )
Soy
Soy isoflavones can reduce the risk of prostate cancer in 2 studies (RR 0.49; 95% CI). (Van Die MD et al.; Soy and soy isoflavones in prostate cancer : a systematic review and meta-analysis of randomized controlled trials.)
Japanese have 7-110 times higher isoflavonoid levels than Finns.The high levels of phyto-oestrogens may inhibit the growth of prostate cancer in Japanese and explain the low mortality from prostate cancer in Japan (Adlerkreutz H et al.; Plasma concentrations of phyto-oestrogens in Japanese men; Lancet 1993; 342; 1209-1210)
Fish (omega 3 fatty acids EPA and DHA)
Fish intake more than 3 times per week reduces the risk of prostate cancer and particularly the risk of metastatic carcinoma (RR 0.56; 95% CI). Each 0.5 g intake of fish oil is associated with a 24% risk reduction for metastatic prostate cancer (Health professionals follow-up study; 47882 participants over 12 years; Augustsson K et al.; A Prospective Study of Intake of Fish and Marine Fatty Acids and Prostate Cancer; Cancer Epidemiology Biomarkers & Prevention 2003;12;64-67)
Men who do not eat fish have a 2-3 times higher risk of prostate cancer than men who eat moderate or high amounts of fish. (Prospective cohort study; 6272 participants over 30 years old; Terry P et al.; Fatty fish consumption at risk of prostate cancer; The Lancet 2001; 357; 1764)
Gynecological tumors / breast carcinoma
Western lifestyle
Asian American women who were born in the West and practice Western lifestyleshave at least a 60% greater risk of breast cancer than Eastern-born controls, regardless of whether the ancestors were born in the West or East. Among eastern-born emigrants, those from urban areas have a 30% higher risk than emigrants from rural areas. (A up to 6-fold increased risk of breast cancer due to migration has been observed). (Case-control study; 1563 participants; Ziegler RG et al.; Migration patterns and breast cancer risk in Asian-American women; JNCI 1993 ;85;1819-1827)
Body weight / obesity
The risk of breast cancer increases by 45% in women who have gained at least 25 kg weight after the age of 18 - and by 18% in women who gained approx. 11 kg after menopause. 15% of all breast cancer cases can be traced back to a weight gain of at least 2 kg after the 18th year and 4.4% of the cases to a weight gain of at least 2 kg after the menopause. Women who lost at least 11 kg after menopause have a 57% reduced risk of breast cancer. (Prospective cohort study; Nurses Health Study; 87143 participants; Eliassen AH et al.; Adult Weight Change and Risk of Postmenopausal Breast cancer; JAMA 2006; 296; 193-201)
High-fat diet (with little bread and fruit juices) significantly doubles the risk of breast cancer compared to low-fat consumption (HR 2.0; 95% CI). (EPIC study; 15351 participants; Schulz M et al.; Identification of a dietary pattern characterized by high-fat food choices associated with increased risk of breast cancer: the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study; British Journal of Nutrition 2008; 100; 942 -946)
Carotenoids
Carotenoids: There was no general relationship between total postmenopausal breast cancer and micronutrient intake. Dietary beta-carotene reduces risk of lobular breast cancer (IRR 0.72). Dietary vitamin E reduces risk of estrogen receptor- and progesterone receptor-positive breast cancer (IRR 0.50). Dietary folic acid potentially increases risk of estrogen receptor and progesterone receptor positive breast cancer (IRR 1.27). (Prospective cohort study; 26224 participants; Roswall N et al.; Micronutrient intake and breast cancer characteristics among postmenopausal women; Eur J Cancer Prev 2010; 19: 360-365)
Carotenoids: Dietary alpha- (RR 0.83) and beta-carotene (RR 0.78) as well as lycopene (RR 0.85) are inversely correlated with the risk of estrogen- and progesterone-receptor-positive breast cancer vitamin E does not correlate with breast cancer risk. Vitamin C intake has a weak positive association with breast cancer in general. (84,805 participants; Cuii Y et al.; Selected antioxidants and risk of hormone receptor-defined invasive breast cancers among postmenopausal women in the Women's Health Initiative Observational Study;Am J Clin Nutr.2008;87:1009-1018)
Carotenoids: Dietary carotenoids do not correlate with the overall risk of breast cancer. Dietary alpha- and beta-carotene are inversely correlated with the risk of estrogen- and progesterone-receptor-negative breast cancer in smokers (RR 0.32 and RR 0.35, respectively) and in women who do not take supplements. (cohort study; 36664 participants over 9.4 years; Larsson SC et al.; Dietary carotenoids and risk of hormone receptor-defined breast cancer in a prospective cohort of Swedish women; Eur J Cancer 2010; 46: 1079-1085)
Carotenoids: The concentrations of total carotenoids, beta-carotene, lycopene and lutein were significantly lower in cancer than in healthy controls. Breast cancer risk was greatly reduced for beta-carotene (OR 0.41), lycopene (OR 0.55), and total carotenoids (OR 0.55) between peak and trough blood levels. (case control study; 590 participants; Sato R et al.; Prospective study of carotenoids, tocopherols, and retinoid concentrations and the risk of breast cancer; Cancer Epidemiol Biomarkers Prev 2002; 11: 451-457)
folic acid
Low folate levels are associated with increased risk of prostate cancer (HR 4.79) as well as increased risk of breast cancer (HR 6.46). (cohort study; 1988 participants over more than 20 years; Rossi E et al.; Folate levels and cancer morbidity and mortality: prospective cohort study from Busselton, Western Australia; Ann Epidemiol 2006; 16; 206-212)
Higher intake of folate, B12 or methionine is associated with a reduced risk of ER breast cancer (ER = estrogen receptor negative). (Yang D et al.; Dietary intake of folate, B-vitamins and methionine and breast cancer risk among Hispanic and non-Hispanic white women.PLoS One.2013;8(2):e54495.)
The excessive risk of breast cancer associated with increased alcohol consumption is reduced by adequate intake of folic acid (RR for 600 mcg folic acid per day versus 150-299 mcg per day was 0.55, 95% CI). (Prospective cohort study over 16 years; 88818 participants from the Nurses Health Study; Zhang S et al.; A Prospective Study of Folate Intake and the Risk of Breast Cancer; JAMA 1999; 281; 1632-1637)
Cysteine
High levels of cysteine (precursor to glutathione) or NAC are dose-dependently significantly associated with a reduced risk of breast cancer (RR 0.44; 95% CI for highest versus lowest levels) (Prospective Nurses Health Study; 32826 participants; Zhang SM et al.; A prospective study of plasma total cysteine and risk of breast cancer; Cancer Epidemiol Biomarkers Prev 2003; 12: 1188-1193)
Omega 3 fatty acids (EPA and DHA)
There is clear evidence of an inverse relationship between the intake of omega 3 fatty acids and the risk of breast cancer. Omega 3 fatty acids reduce the risk by 14%. The risk decreased by 5% for every 0.1 g increase in O3-FA intake. (meta-analysis from 26 publications with 883585 participants; Zheng JS et al.; Intake of fish and marine n-3-polyunsaturated fatty acids and risk of breast cancer: metaanlysis of datafvrom 21 independent prospective cohort studies; BMJ 2013; 346; f37062)
Fish oil reduces the risk of ductal (HR 0.68) but not lobular breast cancer (cohort study; 35016 participants over 3 years; Brasky TM et al.; Specialty supplements and breast cancer risk in the VITamins And Lifestyle (VITAL) Cohort; Cancer Epidemiol Biomarkers Prev 2010;19: 1696-1708)
Soy / isoflavones
Increased soy intake significantly reduces the risk of breast cancer in Asians: with intake of > 19 mg isoflavones OR = 0.71 (29% reduction) and with intake of approx. 10 mg OR = 0.88 versus an intake of (meta-analysis from 1 cohort and 7 case control studies; Wu AH et al.; Epidemiology of soy exposures and breast cancer risk; British Journal of Cancer 2008; 98, 9-14; doi:10.1038/sj .bjc.6604145)
Frequent intake of miso soup and isoflavones is associated with a lower risk of breast cancer in Japanese women (OR 0.46; 95% CI comparing the lowest versus the highest intake), particularly in postmenopausal women. (Prospective JPHC cohort study; 21852 participants; Yamamoto S et al.; Soy, Isoflavones, an Breast Cancer Risk in Japan; Journal of the National Cancer Institute 2003; 95; 906-913)
Adolescent soy intake levels are inversely associated with breast cancer risk in both pre- and postmenopausal Chinese women (OR 0.51; 95% CI for the highest versus the lowest intake). (case control study; 3015 participants; Shu XO et al.; Soyfood Intake during Adolescence and Subsequent Risk of Breast Cancer among Chinese Women; Cancer Epidemiology, Biomarkers & Prevention; 2001; 10; 483- 488)
Excretion of isoflavonoids and lignans is significantly lower in women with breast cancer compared to controls. The risk of breast cancer decreases with increasing excretion of isoflavonoids and lignans (OR 0.62, 0.40 and 0.28, respectively; 95% CI at the highest versus lowest intake for isoflavonoids, lignans, and isoflavonoids and lignans, respectively)(Case control study; Shanghai Breast Cancer Study; 250 participants; Dai Q et al.; Urinary Excretion of Phytoestrogens and Risk of Breast Cancer among Chinese Women in Shanghai; Cancer Epidemiology, Biomarkers & Prevention 2002; 11; 815-821)
There is a significant risk reduction in women due to a high intake of phytoestrogens (isoflavones, lignans). (Randomized case-control study; Ingram D. et al.; case-control study of phyto-oestrogens and breast cancer; Lancet. 1997;350;990-994)
Soy isoflavones reduce free estradiol and estrone levels in premenopausal women (in 53.9% of cases versus 37.5% in controls). SHBG increases (by 41.4% vs. 37.5% in controls). The menstrual cycle lengthens by 3.5 days compared to controls and the follicular phase by 1.46 days. Longer cycles or fewer cycles are associated with a lower risk of breast cancer. (Double-blind, placebo-controlled; 66 participants; Kumar NB et al.; The specific role of isoflavones on estrogen metabolism in premenopausal women; Cancer 2002; 94; 1166-1174)
Soy and its components can reduce the risk of breast cancer if consumed regularly (regarding soy protein OR 0.39 for premenopausal and OR 0.22 for postmenopausal women and regarding tofu OR 0.23 for premenopausal women; each 95% CI) (Kim MK et al.; Dietary intake of soy protein and tofu in association with breast cancer risk based on a casecontrol study; Nutr Cancer 2008; 60: 568-576)
In postmenopausal American women, breast cancer risk decreases with flavonoid intake, most notably flavonols (OR=0.54; 95% CI), flavones (OR=0.61), flavan-3-ols (OR=0 .74) and lignans (OR=0.69) (case control study; 2874 participants; Fink BN et al.; Dietary flavonoid intake and breast cancer risk among women on Long Island; Am J Epidemiol 2007; 165: 514-523)
In pre- and postmenopausal American breast cancer patients, general mortality decreases with high intake of flavonoids compared to low intake, most notably for flavones (OR=0.63; 95% CI), anthocynidins (OR= 0 .64) and isoflavones (OR=0.52). Similar results are found for cancer-specific mortality. (Cohort study; 1210 participants over more than 5 years; Fink BN et al.; Dietary Flavonoid Intake and Breast Cancer Survival among Women on Long Island; Cancer Epidemiology Biomarkers & Prevention 2007;16, 2285-2292)
Green tea
Women who regularly drink green tea have a significantly reduced risk of breast cancer, which is clearly inversely correlated with the amount of tea drunk. (case-control study; 2018 participants; Zhang M et al.; Green tea and the prevention of breast cancer: a case-control study in southeast china; Carcinogenesis 2007; 28; 1074-1078)
Carotenoids
The risk of breast cancer in the group with the highest intake of beta-carotene, lycopene and total carotenoids was about half that in the group with the lowest intake. (Prospective Case-control study; 590 participants; Sato R et al.; Prospective Study of Carotenoids, Tocopherols, and Retinoid Concentrations and the Risk of Breast Cancer; Cancer Epidemiology Biomarkers & Prevention 2002; 11; 451-457)
The combined high intake of carotenoids (OR 0.57; 95% CI for beta-carotene in women not taking HRT) and the omega 3 fatty acid DHA Docosahexaenoic acid (OR 0.52; 95% CI in postmenopausal women) reduces the risk of breast cancer. (case control study; 843 participants; Nkondjock A et al.; Intake of specific carotenoids and Essential fatty acids and breast cancer risk in Montreal, Canada; Am J Clin Nutr 2004; 79; 857-864)
High levels of alpha and beta carotene, lutein, zeaxanthin, lycopene and total carotenoids reduce the risk of breast cancer. For some carotenoids (e.g. beta-carotene) the associations are stricter for estrogen receptor-negative than for estrogen receptor-positive tumors. (Eliassen AH et al.; Circulating carotenoids and risk of breast cancer: pooled analysis of eight prospective studies.J Natl Cancer Institute 2012;104(24):1905-16.)
Calcium and vitamin D
In women who have not previously taken calcium or vitamin D, calcium and vitamin D together significantly reduce the risk of breast and colorectal cancer. (15,646 women in the GHI Study; Bolland MJ et al.; Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set.Am J Clin Nutr 2011; 94: 1144-9) There is a significant inverse relationship between vitamin D levels or calcium levels and breast cancer risk(meta-analysis ; Chen P et al.; Meta-analysis of vitamin D, calcium and the prevention of breast cancer; Breast Cancer Res Treat 2010; 121; 469-477)
The calcium intake correlates significantly inversely with the risk of estrogen and progesterone receptor-negative breast cancer (RR 0.66). (Prospective cohort study; 61433 participants over 17.4 years ; Larsson SC et al.; Long-term dietary calcium intake and breast cancer risk in a prospective cohort of women; Am J Clin Nutr 2009; 89: 277-282)
choline / betaine
In China, there is a significant inverse association between the intake of choline and betaine and the risk of breast cancer, especially in women with low folate levels. (Zhang CX et al.; Choline and betaine intake is inversely associated with breast cancer risk: a two-stage casecontrol study in China. Cancer Sci. 2013; 104(2):250-8.)
selenium
Lower selenium concentrations are found in women with breast cancer than in healthy individuals (81.1 mcg/l versus 98.5 mcg/l). (Lopez-Saez Jb et al .; Selenium in breast cancer; Oncology 2003; 64; 227-231)
Women with BRCA1 mutations have an increased risk of breast and ovarian cancer. This BRCA1 increases susceptibility to DNA breaks. Seleniumsupplementation reduces the number of DNA breaks in mutation carriers to the level of non-carrier controls. (Kowalska E et al.; Increased rates of chromosome breakage in BRCA1 carriers are normalized byoral selenium supplementation; Cancer Epidemiol Biomarkers Prev 2005;14;1302-1306)
Zinc
Zinc has a significant positive effect in premenopausal breast cancer when supplemented > 10 years. Multivitamins and vitamin C, E and beta-carotene have a significant positive effect when supplemented > 10 years in postmenopausal breast cancer. (retrospective case control study; 7824 participants; Pan SY et al Antioxidants and breast cancer risk – a population-based case-control study in Canada BMC Cancer 2011;11:372)
lungs
Carotenoids and vitamin A
Intake of green vegetables, beta-carotene-rich vegetables, watermelon, vitamin A, and carotenoids is inversely associated with the risk of lung cancer (HR 0.72 for the highest vs. the lowest intake). (Takata Y et al.; Intakes of fruits, vegetables, and related vitamins and lung cancer risk: results from the Shanghai Men's Health Study (2002-2009). Nutr Cancer. 2013; 65(1):51-61)
folic acid and vitamin C
Significant protective effects were found for folic acid and vitamin C. (cohort study over 6.3 years; 58279 participants; Voorrips LE et al.; A Prospective Cohort Study on Antioxidant and Folate Intake and Male Lung Cancer Risk; Cancer Epidemiology Biomarkers & Prevention 2000; 9, 357-365)
Vitamin B6
High vitamin B6 levels reduce the risk by half (odds ratio 0.51; 95% CI). (case control study; Hartman TJ et al.; Association of the B-Vitamins Pyridoxal 5'-Phosphate (B6), B12, and Folate with Lung Cancer Risk in Older Men; Am J Epidemiol 2001; 153; 688-694)
selenium
With the administration of 200 mcg selenium (selenium yeast) there is a significant reduction in lung cancer incidence by 45% (95% CI) (Randomised; multicentre, double-blind, placebo-controlled: 1312 Participants over 8 years Clark LC et al.; Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin A randomized controlled trial. Nutritional Prevention of Cancer Study Group; JAMA 1996; 276; 1957-1963)
A low seleniumstatus is associated with an increased risk of lung cancer. (Cohort study, 500 participants; Hartman TJ et al.; Selenium concentration and lung cancer in male smokers; Cancer causes Control 2002 ;123;923-928)
Low selenium levels are associated with an increased risk of lung cancer. (120 participants; Zhuo H et al.; Serum and lung tissue selenium measurements in subjects with lung cancer from Xuanwei, China ; Zhogguo Fei Al Za Zhi 2011;14;39-42)
Selenium has a preventive effect against lung cancer in people with low selenium levels. It reduces cisplatin-induced nephrotoxicity and side effects of radiation in lung cancer patients. (Review; Fritz H et al.; Selenium and lung cancer: a systemic review and meta analysis; PLoS One 2011; 6; #26259)
People with the lowest selenium levels have a 5.8-fold increased risk of fatal cancer compared to those with the highest selenium levels. It was increased 11.4-fold in people with low selenium and low vitamin E levels. A reduced intake of vitamin A or provitamin A increases the risk of lung cancer in smokers with low selenium levels. (Salonen JT et al.; isk of cancer in relation to serum concentrations of selenium and vitamins A and E: matched case-control analysis of prospective data; Br Med J 1985; 290; 4127-420)
Red wine
The risk of lung cancer decreased by 60% in smokers if they smoked moderate red wine once a day Consumption of beer, white wine or liqueur did not reduce the risk. (California Men' 's Health Study with 84,170 participants; Chao C et al.; Alcoholic Beverage Intake and Risk of Lung Cancer: The California Men's Health Study; Cancer Epidemiol Biomarkers Prev 2008; 17: 2692-2699)
phytoestrogens (e.g. ashwagandha)
The risk of lung cancer decreases with increasing intake of phytoestrogens (more significant for isoflavones than for phytosterols) in food by up to 46% (95% CI). (Case control study; 3409 participants over 8 years; Schabath MB et al; Dietary Phytoestrogens and Lung Cancer Risk; JAMA 2005; 294:1493-1504)
flavones and proanthocyanidins
For the occurrence of lung cancer in postmenopausal women, there was an inverse correlation between the intake of flavanones and proanthocyanidins. Smokers and former smokers with a very high intake of flavanones and proanthocyanidins had a significantly lower incidence of lung cancer than smokers and former smokers with a very low intake. Women who consumed higher amounts of isoflavones were less likely to develop cancer. (34,708 participants aged 18+; Cutler GJ; Dietary flavonoid intake and risk of cancer in postmenopausal women: the Iowa Women's Health Study; Int J Cancer .2008 Aug 1;123(3):664-671)
gastrointestinal tract (incl. liver and pancreas)
Apples
The odds ratio of the incidence of cancer of the oral cavity and pharynx is 0.79 for intake of > 1 apple/day versus (case-control study; 14138 participants over 11 years; Gallus S et al.; Does an apple a day keep the oncologist away? Annals of Oncology 2005; 16: 1841-1844)
Fresh apple 100g has the same antioxidant activity as 1500 mg vitamin C and extract from whole apples dose-dependently inhibits the growth of colon and liver cancer in vitro (Eberhardt MV et al. ; Antioxidant activity of fresh apples; Nature 2000;405:903-904)
flavonoids
flavonoids (apagenin 20 mg and epigallocatechin gallate 20 mg) reduce the recurrence rate after curative colorectal cancer surgery (0% versus 20% in the control group; evidence level 2B). (87 participants over 3 -4 years; Hoensch H et al.; Prospective cohort comparison of flavonoid treatment in patients with resected colorectal cancer to prevent recurrence; World J Gastroenterol 2008; 14; 2187-2193)
Tomatoes
Intake of larger amounts of tomatoproducts reduces the risk of gastric cancer. (Yang T et al.; The role of tomato products and lycopene in the prevention of gastric cancer: a meta -analysis of epidemiologic studies.Med Hypotheses.2013;80(4):383-8)
Carotenoids
The risk of gastric cancer is inversely correlated with blood levels of the antioxidants beta-carotene (R 0.31), vitamin E (R 0.89), alpha-carotene (R 0.67), lycopene (R 0.56) and vitamin C (R 0.61). (634 participants; Tsubonon Y et al.; Plasma antioxidant vitamins and carotenoids in five Japanese populations with varied mortality from gastric cancer; Nutr Cancer 1999;34;56-61)
Lycopene results in a 31% significant reduction in the risk of pancreatic carcinoma (OR 0.69; 95% CI). Beta-carotene (OR 0.57; 95% CI) and total carotenoids (OR 0.58; 95% CI) significantly reduce the risk only in non-smokers. (Case control study with 5183 participants over 3 years; Nkondjock A et al.; Dietary intake of lycopene is associated with reduced pancreatic cancer risk; Nutr 2005; 135: 592-597)
Vitamins A and C
Patients taking supplements containing vitamin A have a reduced risk of gastric cancer (RR = 0.4; 95% CI). There is an inverse relationship between vitamin C intake and gastric cancer (RR 0.7; 95% CI for highest versus lowest intake) (Netherlands Cohort Study; 120852 participants over 6.3 years; Botterweck AA et al.; Vitamins, carotenoids, dietary fiber, and the risk of gastric carcinoma: results from a prospective study after 6.3 years of follow-up; Cancer 2000; 88; 737-748)
Magnesium
Magnesium significantly reduces the risk of colon carcinoma. (Prospective study with 35196 participants over 17 years; Folsom AR et al.; Magnesium Intake and Reduced Risk of Colon Cancer in a Prospective Study of Women; Am J Epidemiol 2006; 163; 232-235)
selenium
With the administration of 200 mcg selenium (selenium yeast) there is a significant reduction in the incidence of colon carcinoma by 58% (95% CI). (Randomized; multicentric, double-blind, placebo-controlled: 1312 participants over 8 years; Clark LC et al.; Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group; JAMA 1996; 276; 1957-1963)
There is an inverse relationship between seleniumlevels and risk of esophageal and gastric cancer. (Prospective cohort study; 120,852 participants; Steevens J et al.; Selenium status and the risk of Esophageal and gastric cancer subtypes: the Netherlands cohort study; Gastrenterology 2010; 138; 1704-1713)
High selenium levels reduce the risk of exocrine pancreatic cancer (high levels of cadmium, arsenic and lead increase it). (517 participants; Amarai AF et al; Pancreatic cancer risk and levels of trace elements; Gut 2011)
500 mcg selenium over 3 years increases selenium levels and GPx activity and significantly reduces liver cancer incidence in high-risk patients. (placebo-controlled; 2065 participants; Li H et al.; The prevention of liver Cancer by selenium in high-risk populations;Zhonghua Yu Fang Yi Xue Za Zhi 2000;34;696-703)
Men with low seleniumstatus have an increased risk of colorectal cancer (OR for highest versus lowest levels = 0.68; 95% CI). (case control study; 1609 participants; Takata X et al.; Serum selenium, genetic variation in selenoenzymes, and risk of colorectal cancer: primary analysis from the woman's health initiative Observational study and meta-analysis; Cancer Epidemiol Biomarkers Prev 2011; 20; 1822-1830)
selenium and vitamin C
Low serum levels of selenium, zinc, manganese, vitamin C and vitamin E increase the risk of gallbladder cancer. (Shukla VK et al.; Micronutrients, anbtioxidants, and carcinoma of the gallbladder; J Surg Oncol 2003; 84; 31-35)
High vitamin C intake reduces the risk of pankeas carcinoma (OR 0.45; 95% CI), high cholesterol significantly increases it. (109 participants; Lin Y et al .; Nutritional factors and risk of pancreatic cancer: a population-based case-control study based on direct interview in Japan; J Gastroenterol 2005; 40: 297-301)
folic acid
The intake of folic acid 71-660 μg/day (via preparations or food) is not associated with an increased risk of colon cancer folic acid reduces the risk by 19%. (Cancer Prevention Study II Nutrition Cohort; 99521 participants; Stevens VL et al.; High Levels of Folate, from Supplement and Fortification, are not associated with increased risk of colorectal cancer; Gastroenterology 2011; published ahead of print; doi: 10.1053/j .gastro.2011.04.004)
Colorectal tumors: The risk in women is inversely proportional to the intake of iron, folic acid and vitamin C. Folic acid is the best protective factor. In men , high intakes of calcium and vitamin E were associated with a reduced risk, with vitamin working best (RR 0.35; 95% CI). (Case control study; Tseng M et al.; Micronutrients and the risk of colorectal adenomas; American Journal of Epidemiology, Vol 144, Issue 11 1005-1014)
Low levels of folatein cell cultures increase the risk of DNA damage to colon cells (and the increase in proteins such as Nit2 and COMT) and thus the risk of colon cancer.
High dietary folic acid intake significantly reduces the risk of pancreatic carcinoma (multivariable rate ratio 0.25; 95% CI). (81,922 participants over 6.8 years of age; Larsson SC et al.; Folate intake and pancreatic cancer incidence: a prospective study of Swedish women and men; J Natl Cancer Inst 2006; 98: 407-413) (Duthie SJ et al.; The Response of human coloncytes to folate deficiency in vitro: functional and proteomic analyses; J Proteome Res 2008; 7; 3254-3266)
Calcium and vitamin D
In women who have not previously taken calcium or vitamin D, calcium and vitamin D together significantly reduce the risk of breast and colorectal cancer. (15,646 women in the GHI Study Bolland MJ et al.; Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am J Clin Nutr 2011; 94: 1144-9)
Colorectal adenomas: There is evidence that calcium and vitamin D intake is inversely related to the frequency of colorectal adenomas. (Randomized multicenter study; polyp pervention trial; 1st .905 participants; Hartman TJ et al; The Association of Calcium and Vitamin D with Risk of Colorectal Adenomas; J Nutr 2005; 135: 252-259)
Vitamin D
25(OH)D (= vitamin D) levels are inversely related to the risk of colorectal cancer (an increase of 20ng/ml reduces the risk by 43%). ( Meta-analysis; Yin L et al.; Meta-analysis: longitudinal studies of serum vitamin D and colorectal cancer risk; Aliment Pharmacol Ther 2009; 30; 113-125)
A high intake of vitamin D (over 25 mcg/day) or a vitamin D serum level of 33 ng/ml reduces the risk of colon cancer by 50% (note: vitamin D increases calcium absorption in the intestine) . (Gorham ED et al.; Vitamin D and prevention of colorectal cancer; J Steroid Biochem Mol Biol 2005; 97; 179-194)
High intake and serum levels of vitamin D are associated with a significant reduction in the risk of colorectal cancer. (Research of epidemiological studies; Grant WB et al; A critical review of studies on vitamin D in relation to colorectal cancer.Nutrition and Cancer 2004;48:115-123)
The risk of colorectal cancer is reduced by half when 25-hydroxyvitamin D levels are above 33 ng/mL compared to levels below 2 ng/mL (RR 0.49; 95% CI). (Meta-analysis from 5 studies; Gorham ED et al. "Optimal Vitamin D Status for Colorectal Cancer Prevention: A Quantitative Meta Analysis." Am J Prev Med 2007; 32: 210-216 )
Vitamin D intake and levels are inversely associated with the risk of colorectal cancer. (Ma Y et al.; Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies J Clin Oncol 2011;29(28):3775-82)
Rectal carcinoma: The risk is strongly dependent on calcium intake (RR 0.59 with high calcium intake versus RR 1.00 with low intake) and vitamin D3 -Intake (RR 0.76 vs. RR 1.00 at low intake). For calcium and vitamin D3 together, the risk reduction was 45% (RR 0.55). (9-year cohort study; 34,702 postmenopausal women; Zheng W et al.; A prospective cohort study of intake of calcium, vitamin D, and other micronutrients in relation to incidence of rectal cancer among postmenopausal women;Cancer Epidemiol Biomarkers Prev.1998;7:221-225)
Vitamin D affects the pathogenesis of pancreatic carcinoma (RR 0.59 at the highest versus the lowest intake). (Health Professionals Follow-up Study with 46,771 men; Nurses'''' Health study with 75,427 women; Skinner HG et al.; Vitamin D intake and the risk for pancreatic cancer in two cohort studies; Cancer Epidemiol Biomarkers Prev 2006; 15: 1688-1695)
Vitamin K2
Vitamin K2 beneficial in the prevention of hepatocellular carcinoma in women with viral cirrhosis (OR 0.13; 95% CI). (Habu D et al.; Role of vitamin K2 in the Development of hepatocellular carcinoma in women with viral cirrhosis of the liver JAMA 2004 Jul 21;292(3):358-61.)
Methionine
Higher intake of methionine significantly reduces the risk of pancreatic carcinoma (multivariate rate ratio 0.44; 95% CI). (81,022 participants over 7.2 years; Larsson SC et al.; Methionine and vitamin B6 intake and risk of pancreatic cancer: a prospective study of Swedish women and men; Gastroenterology 2007; 132: 113-118)
Intake of folate or methionine is inversely associated with the risk of colorectal cancer. (Razzak AA et al.; Associations between intake of folate and related micronutrients with molecularly defined colorectal Cancer risks in the Iowa Women's Health Study. Nutr Cancer.2012;64(7):899-910)
glutathione
Glutathione from food reduces the risk of oral and pharyngeal carcinomas by 50% (Jones DP; Glutathione distribution in natural products: absorption and tissue distribution; Methods in Enzymology 1995; 25; 3 -13)
Fish (omega 3 fatty acids EPA and DHA)
The amount of fish consumption is inversely associated with colorectal cancer. (Wu S et al.; Fish consumption and colorectal cancer risk in humans: a systematic review and meta-analysis. Am J Med 2012;125(6):551-9.e5)
Urology
Carotenoids
Taking into account various influencing factors such as smoking and age of the participants, the odds ratio of bladder cancer with carotenoids as protective substances was determined: alpha-carotene 0.22, lutein 0.42, lycopene 0.94 and beta-cryptoxanthine 0.90. Regarding the combined effect of plasma carotenoids and smoking, the odds ratio for smokers with low lutein levels was 6.22 and low zeaxanthin levels was 5.18. The results of the study suggest that carotenoids protect against bladder cancer. Smokers in particular could benefit from a higher carotenoid intake. (case control study; 448 participants over 4 years; Hung RJ et al.; Protective effects of plasma carotenoids on the risk of bladder cancer; J Urol 2006; 176: 1192- 1197)
Fish (omega 3 fatty acids EPA and DHA)
Fatty sea fish (such as mackerel, herring, sardines, salmon) with lots of omega-3 fatty acids and vitamin D at least once a week reduces the risk of kidney cancer significantly (OR 0.56) compared to the control group. If the diet lasted more than 10 years, the risk decreases even further (OR 0.26). (Cohort study with 61433 participants over 15 years; Wolk A et al.; Long-term Fatty Fish Consumption and Renal Cell Carcinoma Incidence in Women;JAMA 2006;296:1371-1376)
There is an inverse connection between the consumption of fatty fish and a risk of renal cell carcinoma (risk 0.26 with regular consumption of oily fish compared to no fish intake), but no connection with the consumption of lean types of fish. (Swedish Mammography Cohort Study; 61,433 participants over 10 years; Wolk A et al.; Long-term fatty fish consumption and renal cell carcinoma incidence in women; JAMA 2006; 20; 296: 1371-1376)
selenium
There is an inverse relationship between selenium concentration and bladder cancer risk. (case-control study; 540 participants; Kellen E et al.; Selenium is inversely associated with bladder cancer risk ; a report form the Belgian case-control study on bladder cancer; Int J Urol 2006; 13; 1180-1184)
seleniumconcentration is inversely related to bladder cancer risk in women (case control study; 679 participants; Michaud DS et al.; Toenail selenium concentrations and bladder cancer risk in woman and men; Brit J Cancer 2005;93;443-458)
There is an inverse relationship between selenium levels and bladder cancer risk. (Prospective cohort study; 120,852 participants; Zeegers MP et al.; Prediagnostic toenail selenium and risk of bladder cancer; Cancer Epidemiol Biomarkers Prev 2002;11;1292-1297)
People with high levels of selenium have a lower risk of bladder cancer. Folic acid or a high intake of fruit reduce the risk in smokers. (Altwein JE; Primary prevention of bladder cancer; What's new? Urologe A 2007; 46; 616-621)
High selenium status significantly reduces bladder cancer risk by 39% (Or 0.61; 95% CI). (meta-analysis from 7 epidemiological studies; Amarai M et al; Selenium and bladder cancer risk: a meta-analysis; Cancer Epidemiol Biomarkers Prev 2010; 19; 2407-2415)
Selenium protects risk groups such as smokers, women and people with a mutation in the p53 gene from bladder cancer. (1,875 participants; Wallace K et al.; Selenium and risko of bladder cancer: a population- based case-control study; Cancer Prev Res 2009;2;70-73)
Hematology
Carotenoids and glutathione
Leukemia (hematological neoplasia): The intake amount of vegetables (OR 0.53; 95% CI), protein sources (OR 0.40; 95% CI) and fruits (OR 0.71; 95% CI) and especially carotenoids (OR 0.65; 95% CI) and antioxidant glutathione (OR 0.43; 95% CI) is inversely associated with acute lymphoblastic leukemia (ALL) in children (ALL may arise in utero). (Population-based Northern California Childhood Leukemia Study; 276 participants; Jensen CD et al.; Maternal dietary risk factors in childhood acute lymphoblastic leukemia; Cancer Causes and Control 2004; 15; 559 -570)
Iron and folic acid
Acute lymphoblastic leukemia (haematological neoplasia): In children aged 0-14 years, there is a connection between iron or folic acid supplementation during pregnancy and the development of ALL in the child (OR 0.37; 95% CI). For iron alone, the odds ratio is 0.75. (249 participants over 10 years; Thompson JR et al.; The Lancet 2001; 358; 9297)
Polyunsaturated fatty acids and vitamin D
There is an inverse relationship between the risk of non-Hodgkin's lymphoma (hematological neoplasia) and the intake of polyunsaturated fatty acids, linoleic acid and vitamin D (OR 0.6 each; 95% CI). The effect is stronger in women. (Case control study; 674 participants over 3 years; Polesel J et al.; Linoleic acid, vitamin D and other nutrient intakes in the risk of non-Hodgkin lymphoma: an Italian case-control study; Ann Oncol 2006;17:713-718)
selenium
The anti-leukemic effect of selenite is linked to the inhibition of DNA replication, transcription and translation. (Jiang XR et al.; The anti-leucaemic effects and the mechanism of sodium selenite; Leuk Res 1992; 16; 347-352)
Individual tumor types
A) Prostate
Fish / Omega 3 fatty acids
Arachidonic acid and its metabolite, prostaglandin E2, promote the migration of cancer cells, driving invasion into the bone marrow. Omega-3 fatty acids inhibit the migration of prostate cancer cells into the bone marrow when they are present in half the concentration of omega-6 fatty acids. The omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid can prevent prostate cancer cells from reaching the bone marrow. (Brown MD et al.; Promotion of prostatic metastatic migration towards human bone marrow stoma by Omega 6 and its inhibition by omega 3 PUFAs; Br J Cancer 2006;27;94:842-853)
There is no association between fishintake and prostate cancer, but (in studies with 49,641 participants) a significant reduction in prostate cancer-specific mortality (RR 0.37). (meta-analysis ( including 12 case control studies with 15,582 participants and 12 cohort studies with 445,820 participants); Szymanski KM et al.; Fish consumption and prostate cancer risk: a review and meta-analysis; Am J Clin Nutr 2010; 92: 1223-1233)
Prostate carcinoma: fat content of food and fat type have a significant influence on cancer cell growth: A fat-modified diet, in contrast to a western diet rich in fat, leads to a significant inhibition of prostate Cancer cell growth (randomized, prospective; Aronson WJ et al. "growth inhibitory effects of a low fat diet on prostate cancer cells in vitro: results of a prospective randomized dietary intervention trial in men with prostate cancer". AUA 2005 , Abstr. 1417)
Vitamin E
Prostate carcinoma: Mortality is significantly reduced by 41% with alpha-tocopherol (vitamin E) 50 mg. (Randomized, double-blind; 29,133 smokers; Heinonen OP et al .;ATCB study;J Natl Cancer Inst 1998;90;440-446)
Long-term vitamin E supplementation of 400 IU and more is associated with a reduced extent (locally invasive and/or metastatic) of existing prostate Ca by 57% (HR = 0.43; 95 % CI). (Prospective cohort study; 35,242 participants; Peters U et al.; Vitamin E and selenium supplementation and risk of prostate cancer in the Vitamins and lifestyle (VITAL) study cohort; Cancer Causes Control 2008; 19 : 75-87)
Prostate carcinoma: Vitamin E suppresses the release of PSA and androgen receptors. Combined use of vitamin E and antiandrogen flutamide inhibits LNCaP cell growth significantly more. Selenomethionine also shows an inhibitory effect on LNCaP cell growth. (Yu Zhang et al.; Vitamin E succinate inhibits the function of androgen receptor and the expression of prostate-specific antigen in prostate cancer cells; Proc Natl Acad Sci U S A 2002;99;7408-7413)
Soy
Soy isoflavone supplementation 60 mg in early stage prostate cancer affects surrogate markers for cancer proliferation such as PSA and free testosterone. (76 participants over 12 weeks; Kumar NB et al .; The Specific Role of Isoflavones in Reducing Prostate Cancer Risk; The Prostate 2004; 59; 141-147)
Broccoli (sulforaphane)
Broccoli (or the ingredient sulforaphane) makes aggressive and resistant pancreatic stem cells (pancreatic carcinomas contain about 10% of these cells) vulnerable and slows down metastasis of the pancreas (in Germany approx. 12650 cases of pancreatic ca.) (Kallifatidis G, Herr I et al.; Sulforaphane targets pancreatic tumor-initiating cells by NF-kB-induced antiapoptotic signaling. GUT 2008 , in press)
selenium
Selenite significantly increases p53 in prostate cancer cells. This is important for the activation of caspase-mediated apoptosis of cancer cells (involving the caspase-8 and caspase-9 pathway). (Jiang C et al.; Selenite-induced p53 Ser-15 phosphorylation and caspase -mediated apoptosis in LNCaP human prostate cancer cells; Mol Cancer Ther 2004; 3; 877-884)
B) Gynecological tumors
Antioxidants
Breast cancer and antioxidants: Levels of ROS, MDA and antioxidant enzyme activities are significantly higher in patients with breast cancer than in controls. The levels of vitamin C, GSH, GSSG (oxidized glutathione) and GSH/GSSG ratio are significantly lower. (Yeh CC et al.; Superoxide anion radical, lipid peroxides and antioxidant status in the blood of patients with breast cancer; Clinica Chimica Acta 2005; 361; 104-111)
Vitamin D
Women with early breast cancer have significantly higher vitamin D levels than women with advanced or metastatic breast cancer Vitamin D affects cell cycle regulation and may delay tumor growth. (558 Participants; Palmieri C et al.; Serum 25-hydroxyvitamin D levels in early and advanced breast cancer; J Clin Pathol 2006; 59; 1334-1336)
Vitamin E
Cervical cancer and vitamin E: The plasma levels of alpha-tocopherol and alpha-tocopheryl-quinone (oxidized alpha-tocopherol) are significantly reduced in the study group compared to controls. ( 72 participants; Palan PR et al.; [alpha]-tocopherol and [alpha]-tocopheryl quinone levels in cervical intraepithelial neoplasia and cervical cancer; American Journal of Obstetrics & Gynecology. 2004; 190; 1407-1410 )
Resveratrol
Resveratrol induces S-phase arrest in human ovarian carcinoma Ovcar-3 cells via Tyr15 phosphorylation of Cdc2. Overexpression of Cdc2AF, a mutant resistant to Thr14 and Tyr15 phosphorylation, reduced resveratrol-induced S-phase arrest. Resveratrol causes phosphorylation of cell division cycle 25C (CDC25C) tyrosine phosphatase via activation of checkpoint kinases Chk1 and Chk2, which in turn were activated via ATM (ataxia telangiectasia mutated) / ATR (ataxia telangiectasia Rad3-related ) kinase in response to DNA -Damage. Resveratrol also increases phospho-H2A.X (Ser139), which is phosphorylated by ATM/ATR in response to DNA damage. The involvement of these molecules in resveratrol-induced S-phase was also confirmed in studies showing that addition of the ATM/ATR inhibitor caffeine reduced resveratrol-induced activation of ATM/ATR Chk1/2 and phosphorylation of CDC25C, Cdc2 and H2A. X and reverses the S-phase arrest. Resveratrol also induces S-phase arrest and H2A.X (Ser139) phosphorylation in ovarian cancer cell lines PA-1 and SKOV-3 (albeit at different levels), while it does not in normal human foreskin fibroblasts detectable levels of Phospho-H2A.X (Ser139) showed only marginal S-phase arrest. Resveratrol establishes Cdc2-tyr15 phosphorylation via the ATM/ATR-Chk1/2-Cdc25C pathway as a central mechanism for DNA damage and S-phase arrest selectively in ovarian carcinoma cells and provides rationale for the potential efficacy of ATM/ATRA gonists in in cancer prevention and intervention. (Tyagi A et al.; Resveratrol causes Cdc2-tyr15 phosphorylation via ATM/ATR-Chk1/2-Cdc25C pathway as a central mechanism for S phase arrest in human ovarian carcinoma Ovcar -3 cells; Carcinogenesis 2005;26:1978-1987)
Resveratrol has antineoplastic activity. It inhibits the growth and induces the death of ovarian carcinoma cells (more via autophagy than via apoptosis), inter alia associated with caspase activation. It thus induces cell death in two different ways: non-apoptotic and apoptotic (via release of the anti-apoptotic proteins Bcl-xL and Bcl-2) (Opipari AW et al.; Resveratrol-induced autophagocytosis in ovarian cancer cells ; Cancer Research 2004; 64, 696-703)
selenium
Selenium is an important cofactor in the production of antioxidant enzymes. Selenium reduces cancer mortality in intervention studies. Selenium intake (in subjects with low selenium intake) prior to breast cancer diagnosis is inversely associated with breast cancer-specific mortality (HR 0.69) and all-cause mortality (Harris HR et al.; Selenium intake and breast cancer mortality in a cohort of Swedish women Breast Cancer Res Treat. 2012; 134(3):1269-77)
Increased selenium intake leads to a significant reduction in VEGF and the intratumoral density of microvessels in breast cancer. Selenium thus reduces angiogenesis. (Jiang C et al.; Selenium induced inhibition of angiogenesis in mammary cancer at chemopreventive levels of intake; Mol Carcinog 1999; 26; 213-225)
C) Gastrointestinal tract and pancreas
Antioxidants
5-FU has a responder rate of only 20% in colorectal cancer, but it remains the single most effective therapy. Antioxidants (such as Vit E) induce apoptosis in CRC cells via activation of p21 WAF1/CIP1, a potent cell cycle inhibitor (with incorporation of C/EBPbeta, a member of the CCAAT enhancer-binding protein family of transcription factors) - independent of p53 . Antioxidants significantly increase tumor growth inhibition by cytostatic therapy with 5 FU (and doxorubicin). The combination of chemotherapy and antioxidants provides a new therapy for CRC. (Chinery R et al.; Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21 via C/EBP-beta; Nat Med 1997;3;1233-1241)
Supplementation of vitamin C alone and in combination with beta-carotene leads to a reduced number of advanced ductular lesions in rat pancreatic carcinoma. Vitamin E and/or selenium have no effect. (Appel MJ et al.; Lack of inhibitory effects of beta-carotene, vitamin C, vitamin E and selenium on development of ductular adenocarcinomas in exocrine pancreas of hamsters; Cancer Lett 1996;103:157-162)
Vitamin E significantly inhibits cell growth in human pancreatic cancer cell lines. (Heisler T et al.; Peptide YY augments gross inhibition by vitamin E succinate of human pancreatic cancer cell growth; J Surg Res 2000; 88: 23-25)
Treatment with vitamin C, vitamin E and selenium significantly reduces deaths from gastric and esophageal cancer (Randomised, placebo-controlled; 3365 participants; Ma Jl et al.; Fifteen year effects of Helicbacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality; J Natl Cancer Inst 2012; 104; 488-492)
Vitamin D
Vitamin D decreased in patients with kolonka. significantly the mortality for all causes of death (HR 0.52 for highest versus lowest levels). For colonca mortality, the reduction is 39%. (304 participants (Nurses Health Study, Health Professionals Follow Up Study); Ng K et al.; Circulating 25-Hydroxyvitamin D Levels and Survival in Patients With Colorectal Cancer; Journal of Clinical Oncology 2008, 26, 2984-2991)
Calcium
Colorectal adenomas: With supplementation with calcium (calcium carbonate or calcium gluconolactate), the number of adenoma recurrences was significantly lower than in the randomized comparison group (RR: 0.80, CI: 0.68, 0.93) (Meta-analysis from 3 studies with 1485 participants; Shaukat A et al.; Role of supplemental calcium in the recurrence of colorectal adenomas: a metaanalysis of randomized controlled trials; Am J Gastroenterol. 2005; 100; 390-294)
Alpha lipoic acid
There is evidence that alpha-lipoic acid or the reduced form dihydrolipoic acid effectively induces apoptosis in human HAT-29 colon cancer cells through a pro-oxidative (mitochondrial) mechanism. (Wenzel U et al:; alpha-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2-*-generation; Apoptosis 2005 Mar; 10(2):359-368)
Lycopene
Lycopene inhibits cell proliferation in human colon carcinoma cells and activation of phosphoinositide-2-kinase/Akt signaling pathway (regulates cancer cell survival) (Tang FY et al.; Lycopene inhibits growth of human colon cancer cells via suppression of the Akt signaling pathway; Mol Nutr Food Res 2008; 52; 646-654)
Resveratrol
Resveratrol 25 microM reduces human colon cancer cell growth by 70%. The cells accumulated in the S/G2 phase transition of the cell cycle. Resveratrol significantly reduces the activity of ornithine decarboxylase (a key enzyme in polyamine biosynthesis involved in cancer growth). (Schneider Y et al.; Anti-proliferative effect of resveratrol, a natural component of grapes and wine , on human colonic cancer cells.Cancer Lett. 2000; 158, 85-91)
Resveratrol 200 mcg/kg significantly reduces carcinogenesis of colon cancer in rats. It significantly reduces cell number and alters bax and p21 expression. (Tessitore L et al.; Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21 (CIP) expression. Carcinogenesis 2000;21, 1619-1622)
Resveratrol 100 mcmol/l significantly inhibits cell growth in pancreatic carcinoma cell lines (PANC-1 and AsPC-1) in a concentration- and time-dependent manner and induces cell apoptosis. (Ding XZ et al.; Resveratrol inhibits proliferation and induces apoptosis in human pancreatic cancer cells; Pancreas 2002; 25: e71-76)
Alcohol consumption (wine vs other alcohols)
There is a dose-response relationship between alcohol and rectal carcinoma. More than 41 drinks per week conferred a relative risk of rectal cancer of 2.2 (95% CI) compared to non-drinkers. More than 14 drinks of beer and spirits - but not wine - per week resulted in an RR of 3.5 for rectal cancer compared to non-drinkers, while those who drank the same amount of alcohol but consumed more than 30% than We had an RR of 1.8 for rectal cancer. No association was found between alcohol and colon cancer when examining the effects of the total amount of alcohol in beer, wine and spirits and the proportion of wine in total alcohol consumption. Alcohol intake is associated with a significantly increased risk of rectal cancer, but the risk appears to be reduced when wine is included. (Randomised, population-based cohort study (Copenhagen, Danish Cancer Registry); 29,132 participants over 14.7 Years; Pederson A, Johansen C, Groenbaek M; Relations between amount and type of alcohol and colon and rectal cancer in a Danish population based cohort study; Gut 2003;52:861-867)
Overall, alcoholconsumption itself is not associated with gastric cancer, but the type of alcohol appears to influence risk. Compared to non-wine drinkers, participants who drank 1-6 glasses of wine per week had a relative risk of 0.76 (95% CI), while those who drank more than 13 glasses of wine per week had an RR of 0.16 (95% CI). There is a significant association with an RR of 0.60 (95% CI) for each glass of wine consumed per day. There was no association between beer or spirits and gastric cancer. (3 prospective population-based studies; 28463 participants; Barstad B, Groenbaek M et al.; Intake of wine, beer and spirits and risk of gastric cancer; European Journal of Cancer Prevention 2005; 14; 239-243)
Broccoli (sulforaphane)
Treatment-resistant tumor stem cells play an important role in the pathogenesis of pancreatic cancer Substances such as the broccolicomponent sulforaphane inhibit NFkB, apoptosis inhibitors and angiogenesis and induce apoptosis. Combination with TRAIL (tumor necrosis factor-dependent-apoptosis-inducing ligand) enhances apoptosis in tumor stem cells. (Kallifatidis G et al.; Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB-induced antiapoptotic signalling. Good 2009;58:949-63)
Resveratrol
Resveratrol has a strong growth-inhibiting effect against various human cancer cells. Here, the inhibitory effect of resveratrol on experimental liver cancer is examined using a two-stage model in rats. Resveratrol 50-300 mg/kg body weight reduces the incidence, number, volume and multiplicity of visible hepatocyte nodules in a dose-dependent manner. It leads to a decrease in cell proliferation and an increase in apoptotic cells in the liver. It also induces expression of the pro-apoptotic protein Bax, reduces expression of the anti-apoptotic Bcl-2, and at the same time increases the Bax/Bcl-2 ratio. Due to its favorable toxicity profile, resveratrol has the potential to be developed as a chemopreventive drug against human hepatocellular carcinoma. (Bishayee A, Dhir N; Resveratrol-mediated chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis: inhibition of cell proliferation and induction of apoptosis; Chem Biol Interact 2009;179:131-44)
Resveratrol has a cancer-preventive effect and induces Bax-mediated and Bax-independent mitochondrial apoptosis in human HCT116 colon carcinoma cells at physiological doses. Both pathways limit the cells' ability to form colonies. (Mahyar-Roemer M et al.; Role of Bax in resveratrol-induced apoptosis of colorectal carcinoma cells; BMC Cancer 2002; 2; 27-36)
Quercetin
Quercetin inhibits the growth of human gastric cancer cells. DNA synthesis and cell progression from G1 to S phase of mitosis are suppressed (Yoshida M et al.; The effect of quercetin on cell cycle progression and growth of human gastric cancer cells; FEBS Lett 1990;260;10-13)
Zinc
Zinc inhibits the growth of pancreatic carcinoma cells more effectively than gemcitabine (gold standard of chemotherapy). (Donadelli M etal.; Intracellular zinc increase inhibits p53(-/-) pancreatic adenocarcinoma cell growth by ROS/AIF-mediated apoptosis (Biochim Biophys Acta. 2008)
Omega 3 fatty acids
Polyunsaturated fatty acids (especially the omega 3 fatty acid EPA) have a significant inhibitory effect on the growth of human pancreatic carcinoma cell lines. (Falconer JS et al.; Effect of eicosapentaenoic acid and other fatty acids on the growth in vitro of human pancreatic cancer cell lines;Br J Cancer 1994;69:826-832)
D) Hematology
Vitamin K2
Myeloma cells and B-cell lymphomas (hematological neoplasms) are sensitive to vitamin K2. Growth inhibition occurs, among other things, via apoptosis and activation of caspase-3. K2 represents a good treatment for myeloma patients, particularly those who are unsuitable for intensive cell-reducing chemotherapy due to age or complications. (Tsujioka T et al; The mechanisms of vitamin K2-induced apoptosis of myeloma cells; Haematologica 2006; 91: 613-619)
Vitamin D
Vitamin D levels are seasonal The season of diagnosis is also a strong prognostic factor for Hodgkin's disease (hematological neoplasia), with approximately 20% fewer fatal cases in autumn versus winter (RR 0.783; 95% CI ). Survival time is increased by more than 60% in autumn patients under 30 years (RR 0.364; 95% CI). The increased vitamin D levels have a beneficial effect on conventional therapy. (Epidemiological study over 36 years; Porojnicu AC et al.; Season of diagnosis is a prognostic factor in Hodgkin's lymphoma: a possible role of suninduced vitamin D;Br J Cancer 2005;93:571-574)
Magnesium and Zinc
In children with acute lymphocytic leukemia ALL and malignant lymphoma (hematological neoplasia), there are lower levels of magnesium (significant only in T-cell ALL) and significantly lower levels of Zinc. The serum zinc levels are also reduced. (58 participants; Sahin G et al.; High prevelance of chronic magnesium deficiency in T cell lymphoblastic leukemia and chronic zinc deficiency in children with acute lymphoblastic leukemia and malignant lymphoma; Leuk Lymphoma 2000;39:555-562)
selenium
In patients with aggressive B-cell non-Hodgkin's lymphoma (hematological neoplasia) receiving anthracycline-based chemotherapy and/or radiation, serum selenium levels correlate positively with response rate (OR 0.62; 95% CI) and long-term remission after initial treatment and overall survival time (HR 0.76 for 0.2 mcmol/l increase; 95% CI). (Last KW et al.; Presentation serum selenium predicts for overall survival, dose delivery , and first treatment response in aggressive non-Hodgkin's lymphoma;J Clin Oncol 2003;15;2:2335-2341)
Grape seed extract (OPC)
Grape seed extract (OPC) induces apoptosis in human leukemia cells in a dose- and time-dependent manner (via activation of the c-Jun NH2-terminal kinase). (Gao N et al.; Induction of apoptosis in human leukemia cells by grape seed extract occurs via activation of c-Jun NH2-terminal kinase Clinical Cancer Research 15, 140, January 1, 2009. doi: 10.1158/1078-0432.CCR-08-1447)
Resveratrol
Resveratrol induces downregulation in survivin expression and apoptosis and inhibition of cell growth in T-cell leukemia cell lines. (Hayashibara T et al.; Resveratrol induces downregulation in survivin expression and apoptosis in HTLV- 1-infected cell lines: A prospective agent for adult T cell leukemia chemotherapy; Nutrition and cancer 2002, 44, 192-201)
Resveratrol inhibits the growth of leukemia cells in culture. It induces leukemia cell differentiation, apoptosis, cell cycle arrest in S phase, inhibition of DNA synthesis by blocking ribonucleotide reductase or DNA polymerase. (Tsan MF et al.; Anti-leukemia effect of resveratrol.Leuk.Lymphoma 2002;43, 983-987)
Resveratrol 50 microM induces apoptosis in more than 80% of CD95-sensitive and CD95-resistant acute lymphoblastic leukemia (ALL) cells by depolarizing mitochondrial membranes and by activating caspase-9, independent of CD-95 signaling . There is no significant cytotoxicity to normal peripheral blood cells. (Dorrie J et al.; Resveratrol induces extensive apoptosis by depolarizing mitochondrial membranes and activating caspase-9 in acute lymphoblastic leukemia cells. Cancer Res. 2001;61, 4731-4739)
Resveratrol develops antiproliferative activity.It inhibits proliferation and induces cytotoxicity or apoptosis of cells in Waldenstrom's macroglobulinemia (WM) lymphoma malignancy. Peripheral blood cells are not affected. Resveratrol shows synergistic cytotoxicity when combined with dexamethasone, fludarabine and bortzomib. (Roccaro AM et al.; Resveratrol Exerts Antiproliferative Activity and Induces Apoptosis in Waldenstrom's Macroglobulinemia; Clin. Cancer Res 2008; 14: 1849-1858)
The aim of this study was to investigate interactions of ellagic acid and quercetin with resveratrol (polyphenols) in the induction of apoptosis and reduction of cell growth in the human leukemia cells (MOLT-4). The combination of ellagic acid with resveratrol has a synergistic effect more than additive. Both substances alone and together induce significant changes in cell cycle kinetics. There are positive synergistic interactions between ellagic acid and resveratrol and between quercetin and resveratrol in inducing caspase-3 activity. The anticarcinogenic potential of foods with polyphenols can be enhanced through synergistic effects. (Mertens-Talcott SU, Percival SS; Ellagic acid and quercetin interact synergistically with resveratrol in the induction of apoptosis and cause translent cell cycle arrest in human lekemia cells; Cancer Lett 2005;218;141-151)
E) SKIN
Vitamin C
Vitamin C induces apoptosis of melanoma cells in vitro. (Kang JS et al.; Sodium ascorbate (vitamin C) induces apoptosis in melanoma cells via the down-regulation of transferrin receptor dependent iron uptake; J Cell Physiol 2005;204:192-197)
Vitamin E
Vitamin E promotes quiescence and inhibits angiogenesis in melanoma cells in vitro. It also significantly suppresses the expression of VEGF (endothelial growth factor), VEGF receptor 1 and VEGF receptor 2 in melanoma. (Malafa MP et al.; Inhibition of angiogenesis and promotion of melanoma dormancy by vitamin E succinate; Ann Surg Oncol 2002;9:1023-1032)
Vitamin D
Low vitamin D levels are significantly associated with greater tumor thickness (according to Berslow) in malignant melanoma and an advanced stage. 564 patients had 25-OH-D levels (764 participants; Gambichler T et al.; Serum-25-hydroxyvitamin D serum levels in a large German cohort of patinets with melanoma; Br J Dermatol 2013; 168; 625-628)
Vitamin D receptor gene polymorphisms are associated with susceptibility and prognosis for malignant melanoma (MM). The data suggest that the antiproliferative calcitriol (1,25(OH)2D3), the ligand of VDR, has a protective effect against MM. (case control study; 424 Participants; Hutchinson PE et al.; Vitamin D receptor polymorphisms are associated with altered prognosis in patients with malignant melanoma; Clin Cancer Res 2000; 6: 498-504)
selenium
In malignant melanomas and cutaneous T-cell lymphomas (CTCL) there are reduced serum selenium levels depending on the stage of the disease: they are significantly lower in tumor recurrences than in tumors without recurrence. (251 participants; Deffuant C et al.; Serum selenium in melanoma and epidermotropic cutaneous T-cell lymphoma; Acta Derm Venereol 1994; 74: 90-92)
Patients with malignant melanoma have significantly lower selenium levels (increasing with severity) than controls. (101 participants; Reinhold U et al.; Serum selenium levels in patients with malignant melanoma; Acta Derm Venereol 1989; 69: 132-136)
Resveratrol
Solar radiation covers a large electromagnetic spectrum including UV radiation, which is potentially harmful to normal cells, and ionizing radiation, which is therapeutically useful in destroying cancer cells responsible for keratosis. Chemoprevention of UV damage via non-toxic substances, especially plant antioxidants, is an approach to prevent photodamage including photocarcinogenesis. In this paper, the photoprotective effects of resveratrol against UVB exposure-mediated damage are discussed. In addition, we also discussed studies showing that resveratrol can enhance the therapeutic effects of ionizing radiation on cancer cells. Based on literature data, resveratrol may be useful in preventing UVB-mediated damage, including skin cancer, and in enhancing the efficacy of radiation therapy against hyperproliferative, precancerous, and neoplastic conditions. (Reagan-Shaw S et al.; Resveratrol imparts photoprotection of normal cells and enhances the efficacy of radiation therapy in cancer cells; Photochem Photobiol 2008; 84: 415-421)
Non-melanoma skin cancer is the most commonly diagnosed malignancy in the United States. The main cause is multiple exposure to the sun's ultraviolet (UV) radiation (particularly the UV-B component, 290-320 nm). Chemoprevention by naturally occurring agents is considered a newer dimension in the management of neoplasia (including skin cancer). We have shown that resveratrol mediates protection against acute UVB-mediated cutaneous damage in SKH-1 hairless mice. Understanding this mechanism is important. We have previously shown that resveratrol has chemopreventive effects against a range of UV exposure-mediated changes in the cki-cyclin-CDK network, and the mitogen-activated protein kinase (MAPK) signaling pathway. In this study, the skin of SKH-1 nude mice was irradiated with UV-B on alternate days. Topical pretreatment with resveratrol significantly inhibited a UV-B exposure-mediated increase in cell proliferation (Ki-67 immunostaining), epidermal cyclooxygenase-2 and ornithine decarboxylase, established markers of tumor promotion, protein and messenger RNA -Levels of survivin and phosphorylation of survivin in mouse skin. Resveratrol pretreatment also reversed the UV-B-mediated decrease in Smac/DIABLO and the increase in UV-B-mediated induction of apoptosis in mouse skin and increased UV-B-mediated induction of apoptosis in the mouse skin. Overall, our study shows that resveratrol has chemopreventive effects against UV-B exposure-mediated damage in the skin of SKH-1 hairless mice via inhibition of survivin and associated events. (Aziz MH et al.; Prevention of ultraviolet-B radiation damage by resveratrol in mouse skin is mediated via modulation in surviving; Photochem Photobiol 2005; 81: 25-31)
Source: Dr. Udo Böhm, Handbuch Krebs, 2014
.">
40 years
> 50 years
> 50 years
-
> 50 years
Anamnestic malignancies
X
X
-
X
-
Diabetes mellitus
-
-
-
-
X
Inflammatory diseases
Inflammation of the intestine
-
Prostatitis
-
-
Unbalanced diet, heavy on meat, low in fiber
X
-
X
-
-
Nutrition (more than 1 liter milk per day)
X
-
X
-
-
Genetics
Familial Polyposis
approx. 5% (mainly BRCA-1, BRCA-2)
approx. 5-10 %
X
approx. 5-10% (e.g.HNPCC syndrome)
Sex
-
X
X
-
X
Infections
-
-
-
-
Sexually transmitted HPV
immunosuppression
-
-
-
-
X
Childlessness
-
-
-
-
X
Medications
-
hormone replacement therapy, calcium antagonist
-
-
estrogens, tamoxifen, aromatase inhibitors
early menarche,late menopause
-
-
-
-
X
Nicotine abuse
X
X
-
XX
X
polyps, cysts
intestinal polyps
-
-
-
ovarian cysts
race
-
-
Black
-
-
pollution load
-
-
-
e.g. Asbestos
-
Shift work (especially with night work)
X
X
X
X
-
Sexual partner alternating
-
-
-
-
X
radiation exposure (e.g.through diagnostic or therapeutic medicine, profession)
-
X
-
X
X
Overweight
X
X
X
-
X
Factor
urinary bladder
Malignant melanoma (skin)
head neck tumors
pancreas
Non Hodgkin lymphoma
Leukemia
Frequency in % (Ø)
4w, 8m
1w, 3m
3
3
3
3
Alcohol abuse
-
-
X
-
-
-
Anamnestic malignancies
-
X
-
-
-
-
Diabetes mellitus
-
-
-
X
-
-
Inflammatory diseases
Inflammation of the bladder
-
-
Inflammation of the pancreas
-
-
Unbalanced diet, heavy on meat, low in fiber
X
-
-
-
-
-
Genetics
-
X
-
X
-
-
Skin nevi
-
X
-
-
-
-
immunosuppression
-
X
-
-
-
-
Infections
-
-
Eppstein Barr
-
Eppstein Barr
HTLV
Medications
cyclophosphamide, phenacetin
Arsenic
-
-
-
cytostatics, immunosuppressants
mouth hygiene lacking
-
-
X
-
-
-
Nicotine abuse
X
-
X
X
-
X
race
-
fairness
-
-
-
-
pollution load
e.g. aromatic amines
-
X
-
-
X
shift work (especially with night work)
X
-
-
X
X
X
radiation exposure (eg.through diagnostic or therapeutic medicine, profession)
-
UV light
X
-
-
X
Radiation exposure (living within 5 km to nuclear power plant)
X
Factor
Ovaries
Testicles
Liver
stomach
kidney
Frequency in % (Ø)
5w
2m
4
4
Alcohol abuse
-
-
X
X
X
age
X
-
-
-
-
Anamnestic malignancies
-
X
-
-
-
Cystic kidney disease
-
-
-
-
X
Iron storage disease
-
-
X
-
-
Inflammatory diseases
-
-
-
stomach lining
-
Unbalanced diet, heavy on meat, low in fiber
-
-
-
-
X
birth weight low
-
X
-
-
-
Genetics
X
X
-
X
X
Sex
-
X
-
-
-
undescended testicles
-
X
-
-
-
Infections
-
-
hepatitis, moulds
Helicobacter pylori
-
Childlessness
X
-
-
-
-
Cirrhosis of the liver
-
-
X
-
-
Medications
-
-
-
-
painkillers
Nicotine abuse
-
-
-
X
X
Estrogen levels ↑ (mother or man)
-
X
-
-
-
reflux esophagitis
-
-
-
X
-
pollution load
-
-
X
X
X
Overweight
-
-
-
-
X
Factor
pharynx larynx
thyroid
Esophagus
Penis
Frequency in % (Ø)
1-2
2w, 1m
1w, 2m
Alcohol abuse
X
-
X
-
Diabetes mellitus
-
-
-
-
Unbalanced diet, heavy on meat, low in fiber
X
-
-
-
Genetics
-
X
X
-
Infections
-
X
-
HPV
Oral hygiene lacking
X
-
-
-
Nicotine abuse
X
-
X
-
reflux esophagitis
-
-
X
-
pollution load
X
-
-
-
SD node cold
-
X
-
-
radiation exposure (e.gB by diagnostic or therapeutic medicine, profession)
-
X
-
-
Overweight
-
-
X
-
Cancer risk factors and types of cancer that trigger these factors preferentially
If, after knowing the basic data, we want to decide in the direction of "early cancer therapy" at a point in time when the tumor is still too small to be generally visible, tumor markers, ultrasound examinations or whole-body CT scans bring this at a very early stage Tumor stage often no reliable results. However, the laboratories in particular offer a large number of further diagnostic parameters, which are tables are listed.
measure
Parameters
Use
General laboratory screening
BKS, blood count, creatinine, BG, uric acid, protein electrophoresis, LDH, GOT, GPT, y-GT, AP, SP, TSH, K, Na, calcium, Fe, HDL, LDL, triglycerides, urinary status
General information and screening for organ disorders and tissue breakdown
Immune screening (initial, tumor phase I)
Differential blood count with granulocytes, monocytes, lymphocytes (cellular), immunoglobulins IgA, IgG, IgM, IgE (humoral), TH1/TH2 balance
Primarily measures the quality of the defense, says little about tumor-specific defense (since tumor cells are mostly camouflaged, at least initially)
Immune system advanced (tumour phase II)
lymphocyte differentiation, B cells, T cells, T helper cells, naive helper cells, memory cells, IL-2 expressing helper cells, T suppressor cells, NK cells, T-cytotoxic suppressor cells, activated killer cells, neopterin, CD 25, CD 69, TGFβ
Indication of tumor-associated changes in immune competence and help in therapy decisions, therapy monitoring
Inflammation screening
hsCRP, TNFα, histamine, IP-10 IL-1, IL-6, NFkB
Indications of acute or chronic inflammation
Detox Screening Detox advanced
GSH (intracellular) Paracetamol, caffeine metabolite test GSH/GSSG
Indications of the quality of the detoxification function
Screening of oxidative-nitrosative stress Oxidative-nitrosative stress advanced
MDA-LDL, nitrotyrosine, Antioxidant capacity (TAS), hydroperoxides, antioxidants, lactate pyruvate, methylmalonic acid, 8-OH-deoxyguanosine
Indications of exposure to radicals and antioxidant capacity
Acid-base screening Acid-base advanced
Daily urine pH profile with test strips Sander titration
Indications of acidosis
Intestinal function screening Intestinal function advanced
Intestinal flora determination, zonulin (serum marker for intestinal permeability) antitrypsin (inflammatory marker in stool)
Indications of the function of the intestine
Neuro-endocrine screening Neuro-endocrine function advanced
Daily cortisol profile (saliva), noradrenaline, serotonin tryptophan, tyrosine, dopamine, DHEA
Indications of the function of the neurotransmitter metabolism
Mitochondrial screening Mitochondria advanced
ATP L-carnitine, coenzyme Q10
Indications of the function of mitochondria
Nutrition of the tumor
TKTL1
Indication of energy production in the tumor
Micronutrient diagnostics
e.g.Zinc and iron (low levels indicate tumor activity), copper and ferritin (high levels indicate tumor activity), selenium, Vit B12, Vit B2, glutathione, homocysteine , folic acid
Indications of undersupply and imbalance as well as tumor activity
Bleeding diagnostics
hemoglobin-haptoglobin in stool erythrocytes in urine
Indications of microbleeds
What can make sense for graded oncologically oriented laboratory diagnostics in practice
measure
Use
TPA (tissue polypeptide antigen) Tumor associated proliferation antigen
Non-specific tumor marker, Independent of the primary tumor and generally applicable
mutation of the gene p53
capacity for apoptosis unspecific (prognostic factor for various tumors)
p53 autoantibody
Non-specific tumor marker positive in 10-30% of tumors (healthy cells are p53 autoantibody negative)
Apo10 antigen
Non-specific tumor marker (healthy cells are Apo10-negative), which indicates disturbances in apoptosis of tumor cells
Cyp1B1 enzyme (from the cytochrome p450 family)
Non-specific tumor marker (according to Dr. Dan Burke, healthy cells are Cyp1B1 negative)
Chemosensitivity test
Tumor tissue is treated with medication in order to find the most suitable substance for the tumor in question
CEA (carcinoembrional antigen) tumor associated antigen
Highly specific, especially for colon-Ca (80%) and less specific for pancreatic-Ca (60%), mamma-Ca (55%) and bile-duct and bronchial-Ca (50%) or similar tumors
PSA (prostate specific antigen) Tissue specific antigen
In suspected prostate Ca
TG (thyroglobulin), hCT (human calcitonin)
In suspected thyroid Ca
AFP (α1-fetoprotein)
In suspected liver Ca, teratoma
AFP and HCG (human chorionic gonadotropin)
In suspected germ cell tumors (testicles, ovary)
CA 72-4
In case of suspected stomach-Ca, breast-Ca
Monoclonal immunoglobulins and Bence Jones proteins
In suspected multiple fibroids
CA 19-9, CA 195, TPA
In suspected pancreas-.Ca
CA 15-3, CA 549, MCA (Mucin-like Carcinoma Associated Antigen)
In suspected mammary ca
CA 24, CA 50
In suspected intestinal Ca, pancreatic Ca
CA 125
In suspected gastric Ca
NSE (neuron-specific enolase)
In suspected bronchial Ca, neuroblastoma
CYFRA 21-1 (cytokeratin fragment)
In suspected bronchial Ca
Skeletal alkaline phosphatase (ostasis, bone AP)
In suspected bone metastasis11
SCC (squamous cell carcinoma antigen)
In V.a.Cervical Ca
Bence Jones proteins and beta-2 microglobulin
In suspected plasmacytoma
5-S-cysteinyldopa
In suspected malignant melanoma
neopterine, ß2-microglobulin
In suspected leukemia, lymphoma
BTA (bladder tumor antigen)
In suspected bladder Ca
M2-PK
In suspected renal cell carcinoma, colon and rectal carcinoma
5-HIES (5-hydroxyindoleacetic acid)
In suspected carcinoid (especially in the gastrointestinal tract)
protein S100
Prognostic factor in malignant melanoma
HER2-neu oncogene
Prognostic factor in mamma-Ca
BRCA 1+2 gene mutations
Indication of breast cancer risk
Approaches for meaningful backup diagnostics in practice (including common tumor markers)
Sample questionnaire for a "cancer check"
The below Of course, questionnaires do not replace medical diagnostics, but serve to raise awareness of one's own cancer risk by asking about some relevant cancer risk factors. Even if all questions are answered in the negative, this is of course not to be understood as meaning that there is no risk of cancer.
YES
Has one or more relatives in your family had any of the following cancers: breast cancer, colon cancer, ovarian cancer, uterine cancer, stomach cancer?
Have there been periods of prolonged alcohol abuse in your life?
Have you ever had cancer in the past?
Do you have diabetes mellitus?
Have you ever had an inflammatory disease (e.g. of the intestines, prostate, bladder, pancreas, gastric mucosa, reflux oesophagitis)?
Have or do you have colon polyps?
Have or do you have ovarian cysts (valid only for women)?
Are you childless (valid only for women)?
Did you or your mother have elevated estrogen levels (valid only for men)?
Have or do you have birthmarks?
Have or do you have cold thyroid nodules?
Have you had or do you have an iron storage disease?
Do you have cystic kidney disease?
Did you have a low birth weight?
Did you have or do you have undescended testicles?
Would you be able to say that your oral hygiene is inadequate?
Is your diet rather unbalanced, heavy on meat, low in fibre?
Do you drink more than 1 liter of milk per day?
Have or do you have conspicuous infectious diseases (e.g.STDs, HPV, Eppstein-Barr, HTLV, AIDS, hepatitis, mold, Helicobacter pylori)
Do you have a known weakness of the immune system or immunosuppression?
Is there childlessness (valid only for women)?
Did you take or do you take medication over a longer period of time, such as calcium antagonists, contraceptives, estrogens, tamoxifen, phenacetin, painkillers, cyclophosphamide, arsenic, cytostatics, immunosuppressants or so-called aromatase inhibitors?
Did your menarche occur rather early (valid only for women)?
If you have already had menopause, did it come on late (valid only for women)?
Do you smoke or have you smoked regularly for a long time?
Have you been or are you exposed to pollutants over a longer period of time (e.g. asbestos, mercury, aromatic amines)?
Shift work (particularly with night work)
Do you have frequently changing sexual partners?
Are you or were you exposed to increased radiation (e.g. from UV light, job, diagnostic or therapeutic medicine)?
Do you live - or have you lived - within a 5 km radius of a nuclear power plant?
Are you overweight?
If you answered "yes" to one or more of these questions, it is likely that you are at increased risk of cancer. In this case, be sure to discuss with your therapist what further steps should be taken.
Important micronutrient groups for general cancer prevention
micronutrient
Special features (general effects)
Antioxidants (e.g. Vit. C, Vit E, glutathione)
have an antioxidant effect (protect cells from damage caused by radicals), support detoxification, reduce the overall risk of cancer
polyphenols (e.g. isoflavonoids) carotenoids (e.g. β-carotene, lycopene)
have an antioxidant and anti-inflammatory effect, support detoxification, reduce the overall risk of cancer
zinc
Balances the immune system, activates lymphocytes, controls apoptosis,Zinc deficiency increases cancer incidence
selenium
activates DNA repair enzymes, induces tumor cell apoptosis, reduces overall cancer risk
magnesium, calcium
Deficiency increases cancer incidence
iron
Deficiency increases cancer incidence
folic acid, Vit B6
Deficiency increases cancer risk (especially in women > 65 years)
Vit B12
Caution: different statements regarding cancer protection or cancer promotion by B12, but: deficiency increases cancer incidence
fatty acids (e.g.γ-linolenic acid, omega-3 fatty acids)
Reduce overall cancer risk
vitamin D
Reduces overall cancer risk
vitamin K2
Reduces overall cancer risk
Key micronutrients for primary prevention of cancer and their characteristics
micronutrient
Special features
vitamin C standard substance
Antioxidant, cytotoxic, anti-inflammatory, antiangiogenic, detoxification phase I cofactor, promotes collagen formation
Cave: Distance to inorganic selenium and in late therapy distance to free-radical-forming cytostatics and to radiation
Vitamin E (most effective as natural Vit E with all tocopherols)
Antioxidant, anti-inflammatory, has anticancer activity in its own right and inhibits growth and mitosis of cancer cells, probably only in high pharmacological doses
glutathione
Antioxidant, detoxifying, strengthens repair and apoptosis mechanisms, reduces cancer cell and tumor growth, improves tolerability of the basic therapy without damaging healthy cells In late therapy, possibly tumor cell protection factor (protection from therapeutic radicals) and possibly Multi-drug resistance (when levels ↑)
α-lipoic acid
Antioxidant, detoxifying (chelating agent)
Secondary plant substances (polyphenols, carotenoids)
Antioxidant, anti-inflammatory, antiproliferative, Cave high-dose phytoestrogens in Re+ breast cancer (KI under hormone therapy)
selenium (inorganic) standard substance
reduces resistance and angiogenesis caveat: distance to Vit C
iron
Iron deficiency is common in cancer patients and must be optimally treated
zinc
Immune balancing, possibly inhibits tumor cell apoptosis (administration after basic therapy and in case of deficiency)
B vitamins
poss. B12 administration only after basic therapy and in case of deficiency as well as combined with Vit C (high doses of B12 may increase tumor cell growth), other B vitamins unproblematic
vitamin D
Anti-inflammatory, inhibits cell proliferation and angiogenesis, promotes apoptosis and cell differentiation, reduces tumor growth and metastasis
Vitamin A
Antioxidant, promotes cell differentiation, reduces tumor cell transformation
proteases
Anti-inflammatory, immunotherapy, anti-carcinogenic
Omega 3 fatty acids
Anti-inflammatory
probiotics
immunotherapy
Lead substances in early cancer therapy and late cancer therapy
micronutrient
Study results on the effect of individual micronutrients on certain types of cancer
antioxidants (e.g. Vit.C, glutathione)
Prostate, breast, uterus, ovaries, intestines, lungs, pancreas, glioblastoma, melanoma
polyphenols (e.g. resveratrol, isoflavonoids), carotenoids (e.g. lycopene)
breast, ovaries, prostate, gastrointestinal, leukemia, pancreas, liver
selenium
Melanoma, thyroid, non-Hodgkin's lymphoma, bladder, gastrointestinal, esophagus, leukemia, prostate, liver, lung, breast
zinc
Acute lymphocytic leukemia (ALL), malignant lymphoma, pancreas, bladder
calcium
intestines
magnesium
Acute lymphocytic leukemia (ALL), malignant lymphoma
Omega-3 fatty acids
prostate, pancreas
vitamin D
breast, bowel, Hodgkin's disease, melanoma, thyroid, bladder, pancreas, B-CLL, myeloma
Vitamin A
bubble
Lead substances in cancer therapy and a proven effect on certain types of cancer
Effect
substance
cytotoxic activity
Vit C (increases cytotoxicity in general, especially of doxorubicin, cisplatin, docetaxel, paclitaxel, dacarbazine, epirubicin, irinotecan, 5-FU, bleomycin, carboplastin and gemcitabine as well as that of arsenic trioxide in hematological diseases) selenium (increases cytotoxicity of taxol, doxorubicin, does not reduce cytotoxicity of radiation on cancer cells) quercetin (enhances cytotoxicity of cisplatin, busulfan) β-carotene (enhances cytotoxicity of 5-FU, adriamycin, etoposide, melphalan, cyclophosphamide) γ-linolenic acid and oleic acid (enhance cytotoxic effect of docetaxel, paclitaxel) Vit E (enhance cytotoxic effect of cisplatin)
apoptosis
selenium, α-tocopherol, resveratrol
inhibition of angiogenesis
selenium, α-tocopherol, resveratrol, coenzyme Q10 (with tamoxifen)
Inhibition of proliferation
Antioxidants, Genistein, Quercetin, Vit D
inflammation inhibition
Omega-3 fatty acids
Increase in response rate and prolongation of survival time
Vit C, Vit E and β-carotene (with paclitaxel, carboplatin), antioxidants (general), omega-3 fatty acids
Enhancement of tamoxifen effect
Genistein (in Re-neg breast cancer), Vit D, γ-linolenic acid, coenzyme Q10,Vit B2 and Vit B3
Increase in the number of therapy cycles
glutathione
Improvement of the operation success (e.g.Improvement of wound healing, reduction of infection risk and organ failure)
Antioxidants (such as Vit C, Vit E, glutathione) Selenium Zinc L-arginine, L-glutamine Omega-3 fatty acids Probiotics
improvement of radiation success
resveratrol, proteases, selenium
synergistic effects of micronutrients on the university basic therapy
The benefits of the above Micronutrients can be explained from their biochemical effects and from a large number of positive study results:
Antioxidant and detoxifying substances:
The various synergistically complementary antioxidants fulfill important functions in the primary prevention of cancer by detoxifying harmful radicals and other pollutants and make a significant contribution to preventing their fatal carcinogenic effects. The antioxidants that make sense here include vitamin C, vitamin E, vitamin A, glutathione, α-lipoic acid, coenzyme Q10 and phytochemicals (polyphenols, carotenoids) as well as cofactors of enzymatic antioxidants such as selenium, manganese, zinc or iron.
Anti-inflammatory and immune-modulating substances: Omega-3 fatty acids and vitamin D as well as zinc, selenium and secondary plant substances have proven their worth in this function. In addition to anti-inflammatory tasks, vitamin D, for example, has important functions for a balanced immune system (acts as a regulator in the immune system, activates macrophages and the formation of endogenous antibiotics) and for calcium metabolism.
In addition to these substances, other substances described in the above table are directly or indirectly involved in the optimization of metabolism, energy balance and repair mechanisms - such as Resveratrol:
Resveratrol
Using the example of the secondary plant substance resveratrol, some mechanisms of action of micronutrients for prevention (and possibly unavoidable later tumor therapy) will be described in more detail: Secondary plant substances such as resveratrol are active in all three phases of cancer formation and cancer development and can be used as a chemopreventive substances against cancer initiation, but also against cancer promotion and cancer progression for a wide use, which is why they can also be used in a complementary manner in the basic treatment of the disease.
Resveratrol initially has a primary preventive effect as a potent antioxidant and anti-inflammatory agent and has a positive effect on mitochondrial function and transcription factors. It blocks the activation of carcinogens and affects cancer initiation (phase I). It protects DNA from oxidative damage through its antioxidant effects and the promotion of the formation of antioxidant enzymes (e.g. catalase, superoxide dismutase and hemoxygenase-1). In connection with its anti-inflammatory effect, it alters gene expression and signal transduction pathways, e.g. by inhibiting transcription factors such as EGR-1, AP-1 and NFkB including a reduction in phosphorylation and degradation of the NFkB inhibitor IκBα. In addition, it probably prevents the activation of the aryl hydrocarbon receptor (AhR), which controls cell differentiation and cell growth.
Resveratrol influences numerous other transcription factors such as multi-drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and FlATPase as well as NFKB, STAT3, HIF-1α, β-catenin and PPAR-y.It blocks the transcription of the Cyp1A1 gene and reacts with the enzymes Cyp-1A1 and Cyp-1B1 (from the cytochrome p450 family) produced by mutant cells. These enzymes can have a pro-carcinogenic effect and create therapy resistance because they inactivate chemotherapeutic agents such as tamoxifen or docetaxel. The reaction of resveratrol with Cyp 1B1 also produces the resveratrol metabolite and tyrosine kinase inhibitor piceatannol, which activates apoptosis of tumor cells. The hypoxia-inducible transcription factor-1α (HIF-1α) is overexpressed in many human tumors and their metastases and is closely associated with an aggressive tumor phenotype. Resveratrol inhibits both basal levels and accumulation of the HIF-1α protein in cancer cells. It reduces the activities of the hypoxia-induced VEGF promoter and the release of VEGF as well as the activity of various protein kinases in cancer diseases, which also leads to a significant decrease in the accumulation of the HIF-1α protein and the activation of the VEGF transcription.
Resveratrol also significantly inhibits the invasiveness of cancer cells. In its role in detoxification processes, it inhibits phase I enzymes that can activate procarcinogens and promotes the formation of phase II enzymes that contribute to detoxification of carcinogens. It thereby improves DNA stability, influences cell differentiation and cell transformation and prevents the development of preneoplastic lesions and tumor formation in the mouse cancer model.
Resveratrol acts in secondary prevention or early therapy on various factors involved in tumor promotion and tumor progression and thereby inhibits tumor cell count, tumor growth and tumor spread. Here, too, it is initially involved in the downregulation of inflammatory processes in several ways. It inhibits synthesis and release of pro-inflammatory and carcinogenic substances such as TNF, COX-2, ornithine decarboxylase (key enzyme in polyamine biosynthesis), 5-LOX, VEGF, IL-1, IL-6, IL-8, AR, PSA, iNOS and CRP. It blocks activated immune cells, as well as nuclear factor B (NF-B) and AP-1, and it blocks AP-1-mediated gene expression.
Furthermore, resveratrol inhibits division and growth of tumor cells. It induces cell cycle arrest in S, G or M phase. It modulates cell cycle regulatory genes such as p53, Rb, PTEN, cyclin A, cyclin B1, cyclin E, Stat3-regulated cyclin D1 and CDK, while inducing p53-independent and p21 expression-mediated cell cycle inhibition.
Resveratrol suppresses angiogenesis, which is important for tumor growth by reducing the expression of VEGF and other angiogenic and pro-metastatic gene products (e.g. MMP's, cathepsin D and ICAM-1) . It inhibits DNA synthesis by blocking ribonucleotide reductase or DNA polymerase and altering biomarker expression.
Resveratrol promotes pro-apoptotic factors and induces programmed cell death (see figure), which is essential for protection against cancer and in which two main forms can be distinguished: "deadly" autophagy (programmed cell death type II ) and apoptosis (programmed cell death type I).
Factors affecting programmed cell death in cancer
Apoptosis is the better known form of programmed cell death and can be initiated either extrinsically or intrinsically.
The extrinsic pathway begins with the binding of a ligand (e.g. TNF or similar cytokines) to a receptor of the TNF receptor family (e.g. CD95), which triggers the caspase cascade and leads to apoptosis.
In the intrinsic pathway, DNA damage activates tumor suppressors such as p53.P53 stimulates substances of the pro-apoptotic Bcl-2 family (Bax, Bad), which release cytochrome C from mitochondria and thereby in turn trigger the caspase cascade and subsequent apoptosis
Apoptosis can be suppressed by anti-apoptotic substances of the Bcl-2 family (Bcl-2, Bcl-xL) and by protein kinase B and IAP (inhibitor of the apoptosis protein). The induction of programmed cell death by resveratrol occurs through expression of the pro-apoptotic proteins Bax, p53 and p21 as well as through depolarization of mitochondrial membranes and activation of CD95 independently Caspases (e.g. caspase-9, caspase-3).
Resveratrol also inhibits anti-apoptotic influences and inhibits various protein kinases in cancer cells such as IκBα kinase, src, JN kinase, MAP kinase, protein kinase B, protein kinase D as well as the COX-2 mRNA and TPA-induced protein kinase C and casein kinase 2. It represses the expression of anti-apoptotic genes and gene products such as Clap-2, Bcl-2, Bcl-xL and XIAP. It blocks the release of survivin by inhibiting survivin mRNA and activating sirtuin deacetylase. Survivin is produced by cancer cells and is one of the inhibitors of the apoptosis proteins that are secreted in most human cancers. It can inhibit mitochondria-dependent apoptosis and facilitate aberrant mitotic progression by inactivating the cell death protease caspase-9.
Resveratrol can also be used to support late cancer therapy . It sensitizes tumor cells to other therapies and shows its own cytotoxic activity. It can synergistically improve the effects of chemotherapy and radiation and can reduce both side effects and resistance to chemotherapy drugs.
In addition to resveratrol, a similar effect has been described for many other secondary plant substances, such as the epigallocatechin-3-gallate (EGCG) in green tea , which blocks an important enzyme in the proliferation of cancer cells. The less well-known phytochemicals include the protease inhibitors, which are mainly found in soybeans, legumes and various grains. They are also said to have a good anti-cancer effect, which is also reflected in the fact that synthetic protease inhibitors such as bortezomib are now being used in university oncology. Particularly interesting is the approach that resveratrol has a positive synergistic effect with other phytochemicals (e.g. quercetin) and that none of the processes influenced by resveratrol have any significant cytotoxicity towards healthy cells.
Selected studies on resveratrol in oncology
Resveratrol acts as a cancer chemopreventive agent. Here we discovered a new function of resveratrol: resveratrol is a potent sensitizer of tumor cells to tumor necrosis factor-dependent apoptosis-inducing ligand (TRAIL)-induced apoptosis through a p53-independent induction of p21 and linked to p21-mediated cell cycle inhibition with a depletion of survivin. Simultaneous analysis of cell cycle, survivin expression and apoptosis showed that resveratro-induced G(1) inhibition was associated with down-regulation of survivin expression and sensitization to TRAIL-induced apoptosis. Accordingly, G(1) inhibition by the cell cycle inhibitor mimosine or by overexpression of p21 t reduced survivin expression and sensitized cells to TRAIL treatment.Resveratrol-mediated cell cycle inhibition with subsequent survivin depletion and sensitization to TRAIL was impaired in p21-deficient cells. Down-regulation of survivin with survivin antisense oligonucleotides also sensitized cells to TRAIL-induced apoptosis. Importantly, resveratrol sensitizes various tumor cell lines, but not normal human fibroblasts, to dead receptor ligation or anticancer drug-induced apoptosis. This combined sensitizer (resveratrol) and inducer (e.g. TRAIL) strategy may be a new approach to improve the efficacy of TRAIL-based therapies in a variety of cancers. (Fulda S, Debatin KM ; Sensitization for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by the chemopreventive agent resveratrol; Cancer Res 2004; 64; 337-346)
Resveratrol is a chemopreventive agent against cancer. It has been shown to be anti-oxidant and anti-mutagenic, and thus an anti-initiation agent. Resveratrol selectively represses the activation of cytochrome P-450 1A1 transcription and inhibits the formation of carcinogen-induced preneoplastic lesions in the mouse model. It also inhibits the formation of 12-OTetradecanoylphorbol-13-Acetate (TPA) promoted skin tumors in the two-phase model. The enzymatic activity of COX-1 and -2 is inhibited in cell-free models and the COX-2 mRNA- and TPA-induced activation of protein kinase C and the AP-1-mediated gene expression are suppressed by resveratrol in mammary epithelial cells. In addition, resveratrol strongly inhibits the generation of nitric oxide and the expression of the iNOS protein. NFκB is closely associated with inflammatory and immune responses, and with oncogenesis in some models of carcinogenesis. Resveratrol suppresses the induction of this transcription factor. The mechanism also involves a decrease in phosphorylation and degradation of IκBα. At the cellular level, resveratrol induces apoptosis, cell cycle delay, or blockage of the G1→S transition phase in a variety of cell lines. (Bhat K, Pezzuto JM; Cancer Chemopreventive Activity of Resveratrol, Annals of the New York Academy of Sciences 2006; 957; 210-229)
Resveratrol works against inflammation and disease by modulating many different pathways. It binds to numerous cell signaling molecules such as multi-drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and Fl-ATPase. It activates various transcription factors (e.g. NFKB, STAT3, HIF-1α, β-catenin and PPAR-y), suppresses the expression of anti-apoptotic gene products (e.g. Bcl-2, Bcl-XL, XIAP and survivin) and of protein kinases ( e.g. src, PI3K, JNK and AKT), induces antioxidant enzymes (e.g. catalase, superoxide dismutase and hemoxygenase-1), suppresses the expression of inflammatory biomarkers (e.g. TNF, COX-2, iNOS and CRP), inhibits the expression of angiogenic and metastatic gene products (e.g. MMPs, VEGF, cathepsin D and ICAM-1) and modulates cell cycle regulatory genes (e.g. p53, Rb, PTEN, cyclins and CDK). Numerous animal studies have shown that resveratrol is effective against numerous age-related diseases including cancer, diabetes, Alzheimer's, cardiovascular and lung diseases. Efforts are also underway to improve its effects in vivo through structural modification and reformulation. (Harikumar KB et al.; Resveratrol: a multitargeted agent for age-associated chronic diseases; Cell Cycle 2008; 7; 1020 -1035)
Compelling evidence shows the positive effects of resveratrol on the nervous system, liver, cardiovascular system and cancer chemoprevention.In doing so, it blocks the different phases of carcinogenesis (tumor initiation, promotion and progression). One of the possible mechanisms for its biological activities includes downregulation of inflammatory responses by inhibiting the synthesis and release of pro-inflammatory mediators, altering eicosanoid synthesis, inhibition of activated immune cells of inducible nitric oxide synthase (iNOS) and of cyclooxygenase-2 (COX-2) via its inhibitory effect on nuclear factor B (NF-B) or activator protein-1 (AP-1). Recent data offer interesting insights into the effects of resveratrol on the lifespan of yeast and flies, demonstrating the potential of resveratrol as an anti-aging agent in the treatment of age-related diseases in humans. It must be mentioned that resveratrol has low bioavailability and rapid clearance from plasma. This article considers its potent anti-inflammatory activity and the plausibility of these mechanisms, and provides an update on resveratrol's bioavailability, pharmacokinetics and effects on lifespan. (De la Lastra CA, Villegas I; Resveratrol as an anti -inflammatory and anti-aging agent: mechanism and clinical implications; Molecular Nutrition and Food Research 2005; 49; 405-430)
Resveratrol inhibits growth, S-phase cell cycle arrest and changes in biomarker expression in human cancer cell lines. It differentially reduces the expression of cyclin B1, cyclin A, cyclin D1 and beta-catenin. It induces apoptosis. (Joe AK et al.; Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines. Cancer Res .2002;8, 893-903)
Resveratrol inhibits the growth of leukemia cells in culture. It induces leukemia cell differentiation, apoptosis, cell cycle arrest in S phase, inhibition of DNA synthesis by blocking ribonucleotide reductase or DNA polymerase. (Tsan MF et al.; Anti-leukemia effect of resveratrol.Leuk.Lymphoma 2002;43, 983-987)
Resveratrol reduces human colon cancer cell growth by 70%. The cells accumulated in the S/G2 phase transition of the cell cycle. Resveratrol significantly reduces the activity of ornithine decarboxylase (a key enzyme in polyamine biosynthesis involved in cancer growth). (Schneider Y et al.; Anti-proliferative effect of resveratrol, a natural component of grapes and wine , on human colonic cancer cells.Cancer Lett. 2000; 158, 85-91)
Resveratrol significantly reduces tumor growth in rapidly growing rat tumors and leads to an increase in the number of cells in the G2/M cell cycle phase. It induces apoptosis and leads to a decrease in cell numbers. (Carbo N et al; Resveratrol, a natural product present in wine, decreases tumor growth in a rat tumor model. Biophys. Res Commun 1999;254, 739-743)
Resveratrol induces apoptosis in more than 80% of CD95-sensitive and CD95-resistant acute lymphoblastic leukemia (ALL) cells by depolarizing mitochondrial membranes and by activating caspase-9, independent of CD-95 signaling. There is no significant cytotoxicity to normal peripheral blood cells. (Dorrie J et al.; Resveratrol induces extensive apoptosis by depolarizing mitochondrial membranes and activating caspase-9 in acute lymphoblastic leukemia cells. Cancer Res. 2001; 61, 4731-4739 )
Resveratrol (200 mcg/kg) significantly reduces carcinogenesis of colon cancer in rats. It significantly reduces cell number and alters bax and p21 expression. (Tessitore L et al.; Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21 (CIP) expression Carcinogenesis 2000; 21, 1619-1622)
Resveratrol develops antiproliferative activity. It inhibits proliferation and induces cytotoxicity and apoptosis in cells of Waldenstrom's macroglobulinemia (WM). Peripheral blood cells are not affected. Resveratrol shows synergistic cytotoxicity when combined with dexamethasone, fludarabine and bortzomib. (Roccaro AM et al.; Resveratrol Exerts Antiproliferative Activity and Induces Apoptosis in Waldenstrom's Macroglobulinemia; Clin. Cancer Res 2008; 14: 1849-1858)
Resveratrol acts on all three stages of carcinogenesis (initiation, promotion and progression) by altering signal transduction pathways that control cell division, cell growth, apoptosis, inflammation, angiogenesis and metastasis. Resveratrol's anti-cancer properties are supported by its ability to inhibit the proliferation of a variety of human tumor cells in vitro and in animal studies. In this review, data from preclinical in vivo studies and interventional studies on cancer and associated mechanisms of action are presented. In addition, bioavailability, pharmacokinetics and potential toxicity of resveratrol as well as its usefulness in cancer are discussed. (Bishayee A; Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials; Cancer Prev Res (Phila Pa) 2009; 2: 409-418)
Resveratrol significantly inhibits cell growth in pancreatic carcinoma cell lines (PANC-1 and AsPC-1) in a concentration- and time-dependent manner and induces cell apoptosis. (Ding XZ et al.; Resveratrol inhibits proliferation and induces apoptosis in human pancreatic cancer cells; Pancreas 2002; 25: e71-76)
Resveratrol has anti-cancer properties and suppresses the proliferation of a variety of tumor cells. The growth inhibitory effect is mediated by cell cycle inhibition with upregulation of p21(CIP1/WAF1), p53 and Bax and downregulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs and activation of caspases. Resveratrol suppresses the activation of transcription factors such as NFkB, AP-1 and EGR-1 and inhibits protein kinases including IkBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II. It downregulates COX2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities are responsible for the suppression of angiogenesis. Resveratrol also enhances the apoptotic effects of cytokines, chemotherapy drugs and radiation. It blocks carcinogen activation by inhibiting CYP1A1 expression and activity and suppresses tumor initiation, promotion and promotion. In addition to chemopreventive effects, resveratrol appears to have therapeutic effects against cancer. (Aggarwal BB et al.; Role of Resveratrol in prevention and therapy of cancer: preclinical and clinical studies; Anti-cancer Res 2004; 24; 2783-2840 )
Resveratrol influences (in addition to its protective function on the cardiovascular system) all three stages of cancer development (tumor initiation, promotion and progression). It also suppresses angiogenesis and metastasis. The anti-cancer effects of resveratrol appear to be closely related to its ability to interact with several molecular parameters involved in carcinogenesis while minimizing toxicity in healthy tissues. Therefore, resveratrol should be used in human cancer chemoprevention in combination with chemotherapeutic agents or cytotoxic factors for highly efficient treatment of drug-refractory tumor cells.The anti-carcinogenic potential of resveratrol for cancer chemoprevention and anti-cancer therapy represents, so to speak, a new explanation of the French paradox (Liu BL et al.; New enlightenment of French Paradox: resveratrol's potential for cancer chemoprevention and anti-cancer therapy; Cancer Biol Ther 2007;6:1833-1836)
Several studies have demonstrated the modulating effect of resveratrol on a variety of cell signaling and gene expression pathways. This article summarizes the effects of resveratrol in chemoprevention. (Goswami SK, Das DK; Resveratrol and chemoprevention; Cancer Lett 2009; 284: 1-6)
Resveratrol has a strong growth-inhibiting effect against various human cancer cells. Here, the inhibitory effect of resveratrol on experimental liver cancer is examined using a two-stage model in rats. Resveratrol 50-300 mg/kg body weight reduces the incidence, number, volume and multiplicity of visible hepatocyte nodules in a dose-dependent manner. It leads to a decrease in cell proliferation and an increase in apoptotic cells in the liver. It also induces expression of the pro-apoptotic protein Bax, reduces expression of the anti-apoptotic Bcl-2, and at the same time increases the Bax/Bcl-2 ratio. Due to its favorable toxicity profile, resveratrol has the potential to be developed as a chemopreventive drug against human hepatocellular carcinoma. (Bishayee A, Dhir N; Resveratrol-mediated chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis: inhibition of cell proliferation and induction of apoptosis; Chem Biol Interact 2009;179:131-44)
The aim of this study was to demonstrate interactions of ellagic acid and quercetin with resveratrol (polyphenols) in inducing apoptosis and reducing cell growth in human leukemia cells (MOLT-4). The combination of ellagic acid with resveratrol has a synergistic effect more than additive. Both substances alone and together induce significant changes in cell cycle kinetics. There are positive synergistic interactions between ellagic acid and resveratrol and between quercetin and resveratrol in inducing caspase-3 activity. The anticarcinogenic potential of foods with polyphenols can be enhanced through synergistic effects. (Mertens-Talcott SU, Percival SS; Ellagic acid and quercetin interact synergistically with resveratrol in the induction of apoptosis and cause translent cell cycle arrest in human lekemia cells; Cancer Lett 2005;218;141-151)
Resveratrol has a cancer-preventive effect and, in physiological doses, induces Bax-mediated and Bax-independent mitochondrial apoptosis in human HCT116 colon carcinoma cells. Both pathways limit the cells' ability to form colonies. (Mahyar-Roemer M et al.; Role of Bax in resveratrol-induced apoptosis of colorectal carcinoma cells; BMC Cancer 2002; 2; 27-36)
Interfering with multistep carcinogenesis by modulating intracellular signaling pathways may provide a molecular basis for phytochemical chemoprevention. Resveratrol has been extensively studied for its chemopreventive activity related to its ability to intervene in multistage carcinogenesis. Numerous intracellular signaling cascades converge with the activation of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), which act independently or coordinately to regulate expression of target genes. These ubiquitous eukaryotic transcription factors mediate pleiotropic effects on cellular transformation and tumor promotion.The aim of this review is to update the molecular mechanisms of resveratrol chemoprevention with particular attention to its effect on cellular signaling cascades mediated by NF-kappaB and AP-1.Resveratroldownregulates Survivin significantly in a dose- and time-dependent manner and the cell cycle, induces apoptosis and enhances the effects of chemotherapeutic agents in multidrug-resistant non-small cell lung cancer cells. (Zhao W et al.; Resveratrol down-regulates surviving and induces apoptosis in human multidrug-resistant SPC -A-1/CDDP cells; Oncology Reports 2010;23;279-286)
Resveratrol has antineoplastic activity. It inhibits the growth and induces the death of ovarian carcinoma cells (more via autophagy than via apoptosis), inter alia associated with caspase activation. It thus induces cell death via 2 different pathways: non-apoptotic and apoptotic (via release of the anti-apoptotic proteins Bcl-xL and Bcl-2) (Opipari AW et al.; Resveratrol-induced autophagy in the ovary Cancer Cells; Cancer Research 2004; 64, 696-703)
Resveratrol inhibits Src tyrosine kinase activity, thereby blocking activation of the constitutive signaling and transcription activator-3 (Stat3) protein in malignant cells. Analyzes of resveratrol-treated malignant cells harboring constitutively active Stat3 show irreversible cell cycle arrest of v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), human mammary (MDAMB-231), pancreatic (Panc-1 ) and prostate carcinoma (DU145) cell lines in G0-G1 or S phase human breast cancer (MDA-MB-468) and pancreatic cancer (Colo-357) cells, and loss of viability due to apoptosis. In contrast, cells treated with resveratrol but lacking aberrant Stat3 activity show reversible growth arrest and minimal loss of viability. Furthermore, in malignant cells that harbor constitutively active Stat3, including human prostate cancer DU145 cells and v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), resveratrol represses Stat3-regulated cyclin D1 as well as Bcl-xL and Mcl-1 genes, suggesting that resveratrol's anti-tumor cell activity is due in part to blockade of Stat3-mediated dysregulation of growth and survival pathways. Our study is among the first to identify Src-Stat3 signaling as a target of resveratrol, define the mechanism of resveratrol's antitumor cell activity, and demonstrate its potential for application to tumors with an activated Stat3 profile. (Kotha A et al.; Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein; Mol. Cancer Ther 2006; 5: 621 – 629)
Hypoxia-inducible factor-1α (HIF-1α) is overexpressed in many human tumors and their metastases and is closely associated with an aggressive tumor phenotype. In this study we investigated the effect of resveratrol on the accumulation of the hypoxia-induced HIF-1α protein and the expression of vascular endothelial growth factor (VEGF) in squamous cell carcinoma of the tongue and in hepatoma cells. Resveratrol markedly inhibits both basal levels and accumulation of hypoxia-induced HIF-1α protein in cancer cells, but not HIF-1α mRNA levels. Pretreatment of the cells with resveratrol markedly reduced the activities of the hypoxia-induced VEGF promoter and the release of VEGF at both the mRNA and protein level.The mechanism of resveratrol's inhibition of hypoxia-induced HIF-1α accumulation appears to involve a shortened HIF-1α protein half-life caused by increased degradation of proteins by the 26S proteasome system. In addition, resveratrol inhibits hypoxia-mediated HIF-1α accumulation Activation of extracellular signal-regulated kinase 1/2 and Akt, resulting in a marked decrease in accumulation of the hypoxia-induced HIF-1α protein and activation of VEGF transcription. Resveratrol also markedly inhibits the hypoxia-stimulated invasiveness of cancer cells. These data indicate that HIF-1α/VEGF could represent a promising target for resveratrol in the development of effective chemoprevention and therapy for human cancers. (Zhang Q et al.; Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1{alpha} and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells; Mol
Many recent studies have shown promising health benefits of red wine. This article provides an overview of some of the most important studies and the mechanisms for these beneficial effects. It has been shown that these positive effects are due to polyphenols in red wine, especially resveratrol in grape skins. These effects include a reduction of approximately 30% to 50%, 57%, and 50% in cardiovascular morbidity and mortality, lung cancer, and prostate cancer. Polyphenols possess antioxidant, superoxide scavenging, ischemia preconditioning, and angiogenesis properties. Some of these properties of polyphenols may explain their protective effects on the cardiovascular system and other organs of the body. Therefore, the United States Department of Health and Human Services recommended moderate alcohol consumption in their national health promotion and prevention initiative, Healthy People 2010. (Review; Vidavalur R et al.; Significance of wine and resveratrol in cardiovascular disease: French paradox revisited;Exp Clin Cardiol.2006;11:217-225)
Vitamin C
Vitamin C in particular plays an outstanding role in cancer therapy (see figure). Several different mechanisms of action of the substance come into play:
The antioxidant effect, for which there is sufficient evidence for use in supportive oncological therapy. In this way, vitamin C protects healthy cells and leads to a reduction in side effects as well as an improvement in the effect of usual therapy and an improvement in the quality of life
The cytotoxic effect on cancer cells especially with high-dose parenteral administration. As with radiation and some chemotherapeutic agents, it is mediated by the formation of H2O2 via anti-proliferative, but especially via pro-oxidative effects . With oral vitamin C administration, a cytotoxic effect was only found in early therapy, where it can also reduce the level of tumor markers, for example, but not in late therapy (e.g. Creagan, Moertel et al.; 1979) . This can be explained by the fact that with oral intake, the absorbed amounts of vitamin C are too low to achieve sufficiently high plasma levels over a longer period of time for a cytotoxic effect in the sense of apoptosis and autophagy in tumors that are already visible. On the other hand, there is sufficient evidence that parenteral vitamin C in pharmacological doses in late therapy achieves sufficient effective levels from approx. 25-30 mmol/l and, above all, in combination with other active substances, taking into account any possibleInteractions with chemotherapeutic agents and radiation in a wide variety of tumor forms in first-line chemotherapy is useful - without fear of systemic toxicity or damage to healthy cells
Vitamin C also has an anti-inflammatory effect, activates collagen formation, increases the cytotoxic potency of chemotherapeutic agents, reduces side effects such as pain, fatigue, vomiting or loss of appetite and contributes to improving the quality of life of tumor patients.
Antioxidant and prooxidative effects of vitamin C in oncology
selenium
Similar to vitamin C, selenium also plays a key role in the early and late treatment of malignant tumors.
It has antineoplastic and tumor-selective cytotoxic effects, inhibits tumor growth, invasion and angiogenesis and improves the detectability of tumor tissue
It promotes apoptosis of non-repairable cells (e.g. via activation of p53, p21, BAX and cytochrome C)
It increases the expression of selenium-dependent enzymatic antioxidants
It activates NK cells and potentiates the antitumor cytotoxicity of NK cell-based immunotherapies
It protects healthy cells and reduces side effects of basic therapy without loss of effectiveness
It has a prophylactic effect against lymphedema and erysipelas
It reduces the risk of resistance and sensitizes resistant tumor cells to therapy again
It reduces the risk of metastasis and recurrence as well as mortality
A selenium undersupply reduces the chances of success of basic university therapy, a good selenium supply and additional selenium doses increase it
Selected studies on selenium in oncology
CD94/NKG2A controls the activity of NK cells. Selenite reduces the expression of HLA-E on tumor cells and can potentiate the antitumor cytotoxicity of NK cell-based immunotherapies. (Enquist M et al.; Selenite induces posttranscriptional blockade of HLA-E expression and sensitizes tumor cells to CD94/NKG2A-positive N cells; J Immunol 2011; 187; 3546-3554)
Selenite oxidizes polythiols to corresponding disulfides and does not react with monothiols. It makes cancer cells more vulnerable to immune system surveillance and destruction. It activates NK cells and inhibits angiogenesis. (Lipinski B; Rationale for the treatment of cancer with sodium selenite; Med Hypotheses 2005; 64; 806-810)
Redox-active selenium inhibits the growth of cancer cells and has tumor-selective cytotoxic effects without resistance development. (Wallenberg M et al.; Selenium cytotoxicity in cancer; Basic & Clinical Pharmacology & Taxocology 2014; 1-10)
Low doses of selenium promote cell growth, high concentrations inhibit it. Selenium induces apoptosis of malignant cells and does not affect normal cells. (Björnstedt M, Fernandes AP; Selenium in the prevention of human cancers. EPMA J 2010;1: 389-95)
Low seleniumconcentrations are essential for cell growth, high concentrations selectively induce cell death in tumor cells. (Selenius M et al.; Selenium and the selenoprotein thioredoxin reductase in the prevention, treatment and diagnostics of cancer. Antioxid Redox Signal 2010;12:867-80) Selenium can reduce cancer risk as well as progression and metastasis in all cancer types (and specifically in prostate, liver, gastrointestinal and lung cancer), especially in people with a low selenium status (there is a reduction in DNA damage and oxidative stress, among other things). (Rayman MP; Selenium in cancer prevention: a review of the evidence and mechanism of action; Proc Nutr Soc 2005; 64; 527-542)
Seleniumsupplementation increases antioxidant protection through increased expression of selenium-dependent GSHPeroxidase and thioredoxin reductase Selenium protects against cancer: it affects tumor metabolism, the immune system, cell cycle regulation and apoptosis. (Combs GF Jr; Chemopreventive mechanism of selenium; Med Klin 199; 94 Suppl 3; 18-24)
Enzymes
There are basically three main groups of enzymes to be distinguished in therapeutic use in cancer:
the antioxidant enzymes (see under antioxidants)
the detoxifying enzymes (see under detoxification)
the proteolytic enzymes (proteases)
Many of these enzymes require cofactors, coenzymes or co-substrates for their activities, such as B vitamins, iron, zinc, selenium, manganese, magnesium or polyphenols, which belong to the closest group of micronutrients.
The proteases belong to the hydrolases. In complementary oncology, the substances bromelain and papain as well as trypsin and chymotrypsin are mostly used in combination in enteric-coated preparations.
The proteases have an anti-inflammatory effect, for example, improve phagocytosis, stimulate the body's own defences, reduce immune and cytokine complexes as well as adhesion molecules and TGFβ, absorb edema and hematomas and contribute to the unmasking of tumor cells. They are mainly used in late cancer therapy, where they have a synergistic effect with basic university therapy and improve the quality of life. However, they can also be used in early therapy and to prevent metastases, as palliative treatment and in the case of malignant effusions.
Examples of studies and articles on the use of micronutrients in tumor diseases
PREVENTION
i) Risk of cancer in general
Chronic inflammation
Different effects of inflammatory processes on cancer have been described. Acute inflammation usually reduces the development of cancer, while chronic inflammation promotes it. For example, while IL-6 inhibits apoptosis and can promote cancer development, interferons can promote DNA repair and stabilize p53. They have an anti-oncogenic effect. (Philip M et al.; Inflammation as a tumor promoter in cancer induction; Semin Cancer Biol 2004; 14; 433-439)
Chronic inflammation is responsible for up to 20% of all cancers, e.g. inflammatory bowel diseases (Crohn's disease, ulcerative colitis), viral infections, bacterial infections (e.g. caused by Helicobacter pylori), parasitosis, exposure to asbestos , alcohol and nicotine abuse or overweight. They lead to radical overproduction and lipid peroxidation. These are responsible for DNA damage, tumor cell growth, tumor spread and activation of cancer genes. (Deutsches Ärzteblatt; how chronic inflammation leads to cancer; international expert meeting at the German Cancer Research Institute in Heidelberg; March 10, 2006)
Inflammation contributes to the development of about 15% of all cancers. Inflammation and inflammation-induced NFkB protein contribute to uncontrolled cancer cell growth, and macrophages produce substances that stimulate tumor growth, including TNFalpha, which boosts NFkB activity. Tumor cells produce substances such as CSF-1 (colony stimulating factor 1) and COX-2, which in turn promote inflammation. NSAIDs reduce the risk of cancer by reducing inflammation. Components of red wine and green tea act as NFkB inhibitors. (Marx J; Cancer research.Inflammation and cancer: the link goes stronger; Science 2004; 306; 966-968)
Antioxidants
Apples have a high antioxidant capacity, suppress cancer cell proliferation, reduce lipid oxidation and cholesterol. They contain various phytochemicals including quercetin, catechin or phloridzin. The content of phytochemicals varies greatly between different apples and there are also differences in phytochemical content during the ripening process. (Review; Boyer J et al.; Apple phytochemicals and their health benefits; Nutr J 2004; 3; 5)
After 7.5 years, antioxidants (beta-carotene 6 mg, zinc 20 mg, selenium 100 mcg, vitamin C 100 mg, vitamin E 30 mg) significantly reduce the risk of cancer (relative risk 0.69, 95% CI ) and all-cause mortality (risk ratio, 0.63, 95% CI) in males. Note: In women, the results were not available: men had lower blood levels of antioxidants. (Randomized, double-blind, placebo-controlled; 13017 participants; SU.VI.MAX; 2004; Serge Hercberg et al.; Arch Intern Med .2004;164;2335-2342)
All-cause mortality is associated with low levels of carotene and vitamin C (and retinol). Low vitamin E levels are associated with an increased risk of lung cancer and in smokers with an increased risk of prostate cancer. (2974 participants over 17 years; Eichholzer M et al.; Prediction of male cancer Mortality by plasma levels of interacting vitamins; 17-year follow-up of the prospective Basel Study; Int J of Can 1996; 66; 145-150; Stahelin HB et al.; Plasma antioxidant vitamins and subsequent cancer mortality in twelve-year follow-up of the prospective Basel Study. Amer J of Epidem 1991; 133; 766-775)
Vitamin and mineral supplementation (particularly with the combination of beta-carotene, vitamin E, and selenium) reduces the risk of cancer in the Linxian population (RR 0.91; 95% CI). (Randomized, 29584 participants; Blot W et al.; Nutrition intervention trials in Linxian, China: Supplementation with specific vitamin/mineral combinations, cancer incidences and disease-specific mortality in the general population. J of the Nat Can Inst; 1993; 85; 1483-1492)
Low alpha-tocopherol levels increase cancer risk 1.5-fold for various types of cancer, the correlation being strongest for gastrointestinal tumors and for cancers independent of nicotine abuse and for non-smokers with low selenium levels . (36265 participants over 8 years; Knekt P et al.; Vitamin E and cancer prevention; The Amer J of Clin Nutr 1991; 53; 283S-286S)
The risk of malignant melanoma is reduced at the highest versus lowest plasma levels of β-carotene (OR 0.9; 95% CI) and for total vitamin E ( OR 0.7; 95% CI). (452 participants; Stryker WS et al.; Diet, plasma levels of beta-carotene and alpha-tocopherol, and risk of malignant melanoma; Am J Epidemiol 1990; 131: 597-611)
Resveratrol
The inhibition of tumor initiation by resveratrol probably occurs by preventing the activation of the Ah receptor. Resveratrol also affects several factors involved in tumor promotion and progression. Because tumor-promoting agents alter the expression of genes whose products are implicated in inflammation, chemoprevention of cardiovascular disease, and cancer, common mechanisms may exist. This includes, above all, the modulation of the expression of growth factors and cytokines. Recently, chemopreventive properties of resveratrol have been linked to inhibition of NF-kappaB.This transcription factor is closely linked to inflammatory and immune responses and to the regulation of cell proliferation and apoptosis. It is therefore important for tumorigenesis and many other diseases such as atherosclerosis. Although the mechanisms by which resveratrol interferes with NF-κB activation are not clear, it appears that inhibition of its degradation, which is necessary for its cellular activation, is the most important target. Based on the amount and variety of data available on the biological activity of resveratrol, it must be considered as a very promising chemoprotectant and chemotherapeutic agent. (Ignatowicz E et al.; Resveratrol, a natural chemopreventive agent against degenerative diseases; Pol J; Pharmacol 2001; 53; 557-569)
Resveratrol has cancer chemopreventive activity at three key stages of carcinogenesis. It has antioxidant, antimutagenic and induces phase II drug-metabolizing enzymes (anti-initiation activity). It mediates anti-inflammatory effects and inhibits cyclooxygenase and hydroperoxidase functions (anti-promotional activity) and induces differentiation of human promyelocytic leukemia cells (anti-progressive activity). In addition, it prevents the development of preneoplastic lesions in carcinogen-treated mice and inhibits tumorigenesis in the mouse skin cancer model. These data suggest that resveratrol is a potential chemopreventive agent for human use. (Jang MS et al.; Cancer chemopreventive activity of reseveratrol, a natural product derived from grapes; Science; 1997; 275 ; 218-220)
Resveratrol is a chemoprotective substance against skin cancer and activates sirtuin deacetylase. It extends the lifespan of lower organisms and has protective effects against stress and disease. (Baur JA, Sinclair DA; Therapeutic potential of resveratrol: the in vivo evidence; Nature Reviews Drug Discovery 2006; 5, 493 -506)
selenium
In patients with a history of skin cancer, selenium 200 mcg versus placebo did not significantly affect the incidence of basal cell carcinoma and squamous cell carcinoma (RR 1.10 and RR 1.14, respectively; 95% CI). The patients receiving selenium had a non-significant reduction in all-cause mortality (RR 0.83; 95% CI) and a significant reduction in all-cause mortality (RR 0.50; 95% CI) and all-cause incidence (RR 0.63; 95% CI). (Double-blind, rendomized, placebo-controlled; 1312 participants over 8 years (1983-1991); Clark LC et al.; Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group; JAMA 1996; 276; 1957-1963)
Vitamin D
Low vitamin D levels are associated with an increased risk of cancer incidence and mortality in men, particularly in the gastrointestinal system. A 25 nmol/L increase in vitamin D levels is associated with a 17% reduction in overall cancer risk and a 45% reduction in gastrointestinal cancer mortality. (Prospective Cohort Study; Health Professionals Follow-Up Study with 47,800 participants over the age of 14. Giovannucci E et al.; Prospective Study of Predictors of Vitamin D Status and Cancer Incidence and Mortality in Men; JNCI Journal of the National Cancer Institute 2006 98(7):451 -459)
There is a clear association between vitamin D status and the risk of colon, breast, prostate and ovarian cancer. (30 colon, 13 breast, 26 prostate and 7 ovarian carcinomas from 63 clinical studies Garland CF et al.; The role of vitamin D in cancer prevention; Am J Public Health 2006; 96; 252-261)
Calcium
Calcium generally protects women from cancer With doses of more than 1300 mg, there is no increasing risk reduction. Dairy products (eg, 3 cups of low-fat or non-fat dairy products) and calcium dose-dependently protect men (RR 0.84) and women (RR 0.77) from gastrointestinal and especially colorectal cancer. Calcium intake does not correlate with the risk of breast, endometrial, ovarian, and prostate cancer. (Prospective National Institutes of Health-AARP Diet and Health Study (cohort study) over 7 years Park Y et al .; Dairy Food, Calcium, and Risk of Cancer in the NIH-AARP Diet and Health Study; Arch Intern Med 2009; 169; 391-401)
Calcium intake is associated with the overall cancer risk in women and decreases up to a calcium intake of 1300 mg/d. Higher doses do not lower the risk any further. Calcium intake is inversely associated with the risk of gastrointestinal cancer in males and females (RR 0.84; 95 CI in males and RR 0.77; 95% CI in females) and especially colorectal cancer. ( National Institutes of Health-AARP-Diet and Health Study Approximately 500,000 participants over the age of 7 Park Park et al Dairy Food, Calcium, and Risk of Cancer in the NIH-AARP Diet and Health Study Arch Intern Med 2009 169(4):391-401)
selenium
Selenium can activate the p53 tumor suppressor protein (through redox mechanisms) and the DNA repair arm of p53 in cancer prevention (Seo YR et al.; selenomethionine regulation of p53 by a ref1-dependent redox mechanism; Proc Natl Acad Sci USA 2002;99;14548-14553)
Selenium can reduce the risk of cancer as well as the progression and metastasis of all types of cancer (and especially prostate, liver, gastrointestinal and lung cancer), especially in people with low selenium status (there is a reduction DNA damage and oxidative stress). (Rayman MP; Selenium in cancer prevention: a review of the evidence and mechanism of action; Proc Nutr Soc 2005; 64; 527-542)
Low seleniumlevels increase cancer incidence compared to high levels (OR 1.95) cohort study with 4857 participants (Ujiie S et al.; Serum Selenium contents and the risk of cancer; Gan To Kagaku Ryoho 1998;25;1891-1897)
Selenium supplementation increases antioxidant protection through increased expression of selenium-dependent GSHPeroxidase and thioredoxin reductase. Selenium protects against cancer: it affects tumor metabolism, the immune system, cell cycle regulation and apoptosis. (Combs GF Jr; Chemopreventive mechanism of selenium; Med Klin 199; 94 Suppl 3; 18-24)
Selenium has a protective effect on cancer incidence (RR 0.76), particularly pronounced in people with low selenium levels and in high-risk patients. (meta-analysis; Lee EH et al.; Effects of selenium supplements on cancer prevention: meta-analysis of randomized controlled trials; Nutr Cancer 2011; 63; 1185-1195)
People with the lowest selenium levels have a 5.8-fold increased risk of fatal cancer compared to those with the highest selenium levels. It was increased 11.4 times in people with low selenium and low vitamin E levels. A reduced intake of vitamin A or provitamin A increases the risk of lung cancer in smokers with low selenium levels. (Salonen JT et al.; isk of cancer in relation to serum concentrations of selenium and vitamins A and E: matched case-control analysis of prospective data; Br Med J 1985; 290; 4127-420)
High selenium levels (between 130-150 ng/ml) greatly reduce all-cause mortality (HR 0.83), cancer mortality (HR 0.69) and cardiovascular mortality (HR 0.94). high selenium levels (> 150 ng/ml), on the other hand, slightly increase mortality. (13887 participants; Bleys J et al.; Serum selenium levels and all-cause, cancer and cardiovascular mortality among US adults; Arch Intern Med 2008;168;4040-410)
ii) Cancer risk for individual tumor types
Prostate
selenium
Men who are well supplied with selenium in the long term (measurement of the selenium content in toenails) have a lower risk of prostate cancer. (Prospective cohort study; 58279 participants; Geybels MS et al.; Advanced prostate cancer risk in relation to toenail selenium levels; J Natl Cancer Inst 2013; 105; 1394-1401)
There is a 63% lower risk of prostate Ca from selenium 200 mcg. (Randomized, double-blind, placebo-controlled; Clark LC et al.; Decreased incidence of prostate cancer with selenium supplementation; Br J Urol 1998; 730-734 (cf. original study evaluation from 1996 in JAMA 1996; 276; 1957-1963))
Selenium 200 mcg has a significant effect on the total prostate Ca incidence (RR 0.51; 95% CI ) (Randomised, placebo-controlled, double-blind; NPC trial; 1312 participants; Duffield-Lillico AJ et al.; Selenium supplementation, baselone plasma selenium status and incidence of prostate cancer; an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial; BJU international 2003; 91; 608-612)
Low selenium levels are associated with a 4-5-fold increased risk of prostate cancer. (case-control study; Baltimore Longitudinal Study of Aging; 148 participants; Brooks JD et al.; plasma sleenium level before diagnosis and the risk of prostate cancer development; The Journal of Urology; 2001; 166; 2034-2038)
Higher selenium levels are associated with a lower risk of advanced prostate cancer (OR 0.49; 95% CI for highest versus lowest levels). After additional control for family history for prostate cancer, BMI, calcium and saturated fat intake, vasectomy, and geographic region, the OR was 0.35 (95% CI). (Prospective Health Professionals case-control study; 51529 participants; Yoshizawa K et al.;Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer;J Natl Cancer Inst 1998;90:1219-1224)
Inorganic selenium in high doses significantly reduces the growth of primary hormone-refractory prostate carcinomas and the development of retroperitoneal lymph node metastases in the experimental mouse model. (Corcoran NM et al.; Inorganic selenium retards progression of experimental hormone refractory prostate cancer;J Urol 2004;171:907-910)
Selenium reduces the risk of prostate cancer (RR 0.74). (Review, meta-analysis Etminan M et al.; Intake of selenium in the prevention of prostate cancer: a systemic review and meta-analysis ; Cancer Causes Control 2005; 16; 1125-1131)
The risk of prostate cancer decreases with increasing seleniumlevels up to 170 ng/ml. (Hurst R et al.; Selenium and prostate cancer: systematic review and meta-analysis ; Am J Clin Nutr July 2012 vol. 96 no. 1 111-122)
Higher selenium intake reduces the risk of prostate cancer. (Van den Brandt PA et al.; Selenium levels and the subsequent risk of pro cancer state: a prospective cohort study; Cancer Epidemiol Biomerkers Prevent 2003; 12; 866-871)
Vitamin E
Vitamin E (+alpha-tocopheryl-succinate) and selenium (methylselenic acid) alone lead to a moderate inhibition of survival time and growth of human prostate cancer cells. A combination results in a dramatic increase in the Growth inhibition of prostate cancer cells. Apoptosis is induced, Bax, Bak and Bi proteins increase and Bcl-2 protein decreases. (Reagan-Shaw S et al.; Combination of vitamin E and selenium causes an induction of apoptosis of human prostate cancer cells by enhancing Bax/Bcl-2 ratio; Prostate 2008; 68: 1624-1634)
The incidence of prostate Ca is reduced by 1/3 with vitamin E 50 mg. (randomized, double-blind, placebo-controlled; ATBC study; Heinonen OP et al.; Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial;J Natl Cancer Inst 1998;90:440-446)
Smokers and ex-smokers who consume at least 100 IU vitamin E have a reduced risk of metastatic or fatal prostate. (RR 0.44; 95% CI). (47780 participants; Chan JM et al.; Supplemental Vitamin E Intake and Prostate Cancer Risk in a Large Cohort of Men in the United States; Cancer Epidemiology Biomarkers & Prevention 1999;8;893-899)
Supplementation with vitamin E 400 IU hardly reduced the overall prostate carcinoma risk (HR 0.86; 95% CI). The risk of advanced prostate carcinoma (regionally invasive or metastatic) decreased significantly in relation to the dose of vitamin E (HR 0.43; 95% CI). There was no stronger association between the administration of selenium ( (Prospective cohort study; 35242 participants over 10 years; Peters et al .; Vitamin E and selenium supplementation and risk of prostate cancer in the Vitamins and lifestyle (VITAL) study cohort; Cancer Causes Control 2008; 19: 75-87)
Vitamin K2
There is a non-significant relationship between prostate cancer incidence and vitamin K2. The reduction in risk is 35% (RR 0.65), the risk of advanced prostate ca. is reduced by 63% (RR 0.37). The association with menaquinone from dairy products is more pronounced than with meat-based vitamin K2. Vitamin K1 (phylloquinone, mainly from leafy vegetables and vegetable oil) shows no correlation. (EPIC study, 11319 participants over 8.6 years; Nimptsch K et al.; Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg); Am J Clin Nutr 2008; 87; 985-992)
Tomatoes
The risk of prostate cancer is reduced with a high intake of raw tomatoes (RR 0.89; 95% CI) and higher with cooked tomato products (RR 0.81; 95% CI). (Meta-analysis from 11 case control studies and 10 cohort studies; Etminan M et al.; The Role of Tomato Products and Lycopene in the Prevention of Prostate Cancer: A MetaAnalysis of Observational Studies; Cancer Epidemiology Biomarkers & Prevention 2004; 13; 340-345 )
Soy
Soy isoflavones can reduce the risk of prostate cancer in 2 studies (RR 0.49; 95% CI). (Van Die MD et al.; Soy and soy isoflavones in prostate cancer : a systematic review and meta-analysis of randomized controlled trials.)
Japanese have 7-110 times higher isoflavonoid levels than Finns.The high levels of phyto-oestrogens may inhibit the growth of prostate cancer in Japanese and explain the low mortality from prostate cancer in Japan (Adlerkreutz H et al.; Plasma concentrations of phyto-oestrogens in Japanese men; Lancet 1993; 342; 1209-1210)
Fish (omega 3 fatty acids EPA and DHA)
Fish intake more than 3 times per week reduces the risk of prostate cancer and particularly the risk of metastatic carcinoma (RR 0.56; 95% CI). Each 0.5 g intake of fish oil is associated with a 24% risk reduction for metastatic prostate cancer (Health professionals follow-up study; 47882 participants over 12 years; Augustsson K et al.; A Prospective Study of Intake of Fish and Marine Fatty Acids and Prostate Cancer; Cancer Epidemiology Biomarkers & Prevention 2003;12;64-67)
Men who do not eat fish have a 2-3 times higher risk of prostate cancer than men who eat moderate or high amounts of fish. (Prospective cohort study; 6272 participants over 30 years old; Terry P et al.; Fatty fish consumption at risk of prostate cancer; The Lancet 2001; 357; 1764)
Gynecological tumors / breast carcinoma
Western lifestyle
Asian American women who were born in the West and practice Western lifestyleshave at least a 60% greater risk of breast cancer than Eastern-born controls, regardless of whether the ancestors were born in the West or East. Among eastern-born emigrants, those from urban areas have a 30% higher risk than emigrants from rural areas. (A up to 6-fold increased risk of breast cancer due to migration has been observed). (Case-control study; 1563 participants; Ziegler RG et al.; Migration patterns and breast cancer risk in Asian-American women; JNCI 1993 ;85;1819-1827)
Body weight / obesity
The risk of breast cancer increases by 45% in women who have gained at least 25 kg weight after the age of 18 - and by 18% in women who gained approx. 11 kg after menopause. 15% of all breast cancer cases can be traced back to a weight gain of at least 2 kg after the 18th year and 4.4% of the cases to a weight gain of at least 2 kg after the menopause. Women who lost at least 11 kg after menopause have a 57% reduced risk of breast cancer. (Prospective cohort study; Nurses Health Study; 87143 participants; Eliassen AH et al.; Adult Weight Change and Risk of Postmenopausal Breast cancer; JAMA 2006; 296; 193-201)
High-fat diet (with little bread and fruit juices) significantly doubles the risk of breast cancer compared to low-fat consumption (HR 2.0; 95% CI). (EPIC study; 15351 participants; Schulz M et al.; Identification of a dietary pattern characterized by high-fat food choices associated with increased risk of breast cancer: the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study; British Journal of Nutrition 2008; 100; 942 -946)
Carotenoids
Carotenoids: There was no general relationship between total postmenopausal breast cancer and micronutrient intake. Dietary beta-carotene reduces risk of lobular breast cancer (IRR 0.72). Dietary vitamin E reduces risk of estrogen receptor- and progesterone receptor-positive breast cancer (IRR 0.50). Dietary folic acid potentially increases risk of estrogen receptor and progesterone receptor positive breast cancer (IRR 1.27). (Prospective cohort study; 26224 participants; Roswall N et al.; Micronutrient intake and breast cancer characteristics among postmenopausal women; Eur J Cancer Prev 2010; 19: 360-365)
Carotenoids: Dietary alpha- (RR 0.83) and beta-carotene (RR 0.78) as well as lycopene (RR 0.85) are inversely correlated with the risk of estrogen- and progesterone-receptor-positive breast cancer vitamin E does not correlate with breast cancer risk. Vitamin C intake has a weak positive association with breast cancer in general. (84,805 participants; Cuii Y et al.; Selected antioxidants and risk of hormone receptor-defined invasive breast cancers among postmenopausal women in the Women's Health Initiative Observational Study;Am J Clin Nutr.2008;87:1009-1018)
Carotenoids: Dietary carotenoids do not correlate with the overall risk of breast cancer. Dietary alpha- and beta-carotene are inversely correlated with the risk of estrogen- and progesterone-receptor-negative breast cancer in smokers (RR 0.32 and RR 0.35, respectively) and in women who do not take supplements. (cohort study; 36664 participants over 9.4 years; Larsson SC et al.; Dietary carotenoids and risk of hormone receptor-defined breast cancer in a prospective cohort of Swedish women; Eur J Cancer 2010; 46: 1079-1085)
Carotenoids: The concentrations of total carotenoids, beta-carotene, lycopene and lutein were significantly lower in cancer than in healthy controls. Breast cancer risk was greatly reduced for beta-carotene (OR 0.41), lycopene (OR 0.55), and total carotenoids (OR 0.55) between peak and trough blood levels. (case control study; 590 participants; Sato R et al.; Prospective study of carotenoids, tocopherols, and retinoid concentrations and the risk of breast cancer; Cancer Epidemiol Biomarkers Prev 2002; 11: 451-457)
folic acid
Low folate levels are associated with increased risk of prostate cancer (HR 4.79) as well as increased risk of breast cancer (HR 6.46). (cohort study; 1988 participants over more than 20 years; Rossi E et al.; Folate levels and cancer morbidity and mortality: prospective cohort study from Busselton, Western Australia; Ann Epidemiol 2006; 16; 206-212)
Higher intake of folate, B12 or methionine is associated with a reduced risk of ER breast cancer (ER = estrogen receptor negative). (Yang D et al.; Dietary intake of folate, B-vitamins and methionine and breast cancer risk among Hispanic and non-Hispanic white women.PLoS One.2013;8(2):e54495.)
The excessive risk of breast cancer associated with increased alcohol consumption is reduced by adequate intake of folic acid (RR for 600 mcg folic acid per day versus 150-299 mcg per day was 0.55, 95% CI). (Prospective cohort study over 16 years; 88818 participants from the Nurses Health Study; Zhang S et al.; A Prospective Study of Folate Intake and the Risk of Breast Cancer; JAMA 1999; 281; 1632-1637)
Cysteine
High levels of cysteine (precursor to glutathione) or NAC are dose-dependently significantly associated with a reduced risk of breast cancer (RR 0.44; 95% CI for highest versus lowest levels) (Prospective Nurses Health Study; 32826 participants; Zhang SM et al.; A prospective study of plasma total cysteine and risk of breast cancer; Cancer Epidemiol Biomarkers Prev 2003; 12: 1188-1193)
Omega 3 fatty acids (EPA and DHA)
There is clear evidence of an inverse relationship between the intake of omega 3 fatty acids and the risk of breast cancer. Omega 3 fatty acids reduce the risk by 14%. The risk decreased by 5% for every 0.1 g increase in O3-FA intake. (meta-analysis from 26 publications with 883585 participants; Zheng JS et al.; Intake of fish and marine n-3-polyunsaturated fatty acids and risk of breast cancer: metaanlysis of datafvrom 21 independent prospective cohort studies; BMJ 2013; 346; f37062)
Fish oil reduces the risk of ductal (HR 0.68) but not lobular breast cancer (cohort study; 35016 participants over 3 years; Brasky TM et al.; Specialty supplements and breast cancer risk in the VITamins And Lifestyle (VITAL) Cohort; Cancer Epidemiol Biomarkers Prev 2010;19: 1696-1708)
Soy / isoflavones
Increased soy intake significantly reduces the risk of breast cancer in Asians: with intake of > 19 mg isoflavones OR = 0.71 (29% reduction) and with intake of approx. 10 mg OR = 0.88 versus an intake of (meta-analysis from 1 cohort and 7 case control studies; Wu AH et al.; Epidemiology of soy exposures and breast cancer risk; British Journal of Cancer 2008; 98, 9-14; doi:10.1038/sj .bjc.6604145)
Frequent intake of miso soup and isoflavones is associated with a lower risk of breast cancer in Japanese women (OR 0.46; 95% CI comparing the lowest versus the highest intake), particularly in postmenopausal women. (Prospective JPHC cohort study; 21852 participants; Yamamoto S et al.; Soy, Isoflavones, an Breast Cancer Risk in Japan; Journal of the National Cancer Institute 2003; 95; 906-913)
Adolescent soy intake levels are inversely associated with breast cancer risk in both pre- and postmenopausal Chinese women (OR 0.51; 95% CI for the highest versus the lowest intake). (case control study; 3015 participants; Shu XO et al.; Soyfood Intake during Adolescence and Subsequent Risk of Breast Cancer among Chinese Women; Cancer Epidemiology, Biomarkers & Prevention; 2001; 10; 483- 488)
Excretion of isoflavonoids and lignans is significantly lower in women with breast cancer compared to controls. The risk of breast cancer decreases with increasing excretion of isoflavonoids and lignans (OR 0.62, 0.40 and 0.28, respectively; 95% CI at the highest versus lowest intake for isoflavonoids, lignans, and isoflavonoids and lignans, respectively)(Case control study; Shanghai Breast Cancer Study; 250 participants; Dai Q et al.; Urinary Excretion of Phytoestrogens and Risk of Breast Cancer among Chinese Women in Shanghai; Cancer Epidemiology, Biomarkers & Prevention 2002; 11; 815-821)
There is a significant risk reduction in women due to a high intake of phytoestrogens (isoflavones, lignans). (Randomized case-control study; Ingram D. et al.; case-control study of phyto-oestrogens and breast cancer; Lancet. 1997;350;990-994)
Soy isoflavones reduce free estradiol and estrone levels in premenopausal women (in 53.9% of cases versus 37.5% in controls). SHBG increases (by 41.4% vs. 37.5% in controls). The menstrual cycle lengthens by 3.5 days compared to controls and the follicular phase by 1.46 days. Longer cycles or fewer cycles are associated with a lower risk of breast cancer. (Double-blind, placebo-controlled; 66 participants; Kumar NB et al.; The specific role of isoflavones on estrogen metabolism in premenopausal women; Cancer 2002; 94; 1166-1174)
Soy and its components can reduce the risk of breast cancer if consumed regularly (regarding soy protein OR 0.39 for premenopausal and OR 0.22 for postmenopausal women and regarding tofu OR 0.23 for premenopausal women; each 95% CI) (Kim MK et al.; Dietary intake of soy protein and tofu in association with breast cancer risk based on a casecontrol study; Nutr Cancer 2008; 60: 568-576)
In postmenopausal American women, breast cancer risk decreases with flavonoid intake, most notably flavonols (OR=0.54; 95% CI), flavones (OR=0.61), flavan-3-ols (OR=0 .74) and lignans (OR=0.69) (case control study; 2874 participants; Fink BN et al.; Dietary flavonoid intake and breast cancer risk among women on Long Island; Am J Epidemiol 2007; 165: 514-523)
In pre- and postmenopausal American breast cancer patients, general mortality decreases with high intake of flavonoids compared to low intake, most notably for flavones (OR=0.63; 95% CI), anthocynidins (OR= 0 .64) and isoflavones (OR=0.52). Similar results are found for cancer-specific mortality. (Cohort study; 1210 participants over more than 5 years; Fink BN et al.; Dietary Flavonoid Intake and Breast Cancer Survival among Women on Long Island; Cancer Epidemiology Biomarkers & Prevention 2007;16, 2285-2292)
Green tea
Women who regularly drink green tea have a significantly reduced risk of breast cancer, which is clearly inversely correlated with the amount of tea drunk. (case-control study; 2018 participants; Zhang M et al.; Green tea and the prevention of breast cancer: a case-control study in southeast china; Carcinogenesis 2007; 28; 1074-1078)
Carotenoids
The risk of breast cancer in the group with the highest intake of beta-carotene, lycopene and total carotenoids was about half that in the group with the lowest intake. (Prospective Case-control study; 590 participants; Sato R et al.; Prospective Study of Carotenoids, Tocopherols, and Retinoid Concentrations and the Risk of Breast Cancer; Cancer Epidemiology Biomarkers & Prevention 2002; 11; 451-457)
The combined high intake of carotenoids (OR 0.57; 95% CI for beta-carotene in women not taking HRT) and the omega 3 fatty acid DHA Docosahexaenoic acid (OR 0.52; 95% CI in postmenopausal women) reduces the risk of breast cancer. (case control study; 843 participants; Nkondjock A et al.; Intake of specific carotenoids and Essential fatty acids and breast cancer risk in Montreal, Canada; Am J Clin Nutr 2004; 79; 857-864)
High levels of alpha and beta carotene, lutein, zeaxanthin, lycopene and total carotenoids reduce the risk of breast cancer. For some carotenoids (e.g. beta-carotene) the associations are stricter for estrogen receptor-negative than for estrogen receptor-positive tumors. (Eliassen AH et al.; Circulating carotenoids and risk of breast cancer: pooled analysis of eight prospective studies.J Natl Cancer Institute 2012;104(24):1905-16.)
Calcium and vitamin D
In women who have not previously taken calcium or vitamin D, calcium and vitamin D together significantly reduce the risk of breast and colorectal cancer. (15,646 women in the GHI Study; Bolland MJ et al.; Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set.Am J Clin Nutr 2011; 94: 1144-9) There is a significant inverse relationship between vitamin D levels or calcium levels and breast cancer risk(meta-analysis ; Chen P et al.; Meta-analysis of vitamin D, calcium and the prevention of breast cancer; Breast Cancer Res Treat 2010; 121; 469-477)
The calcium intake correlates significantly inversely with the risk of estrogen and progesterone receptor-negative breast cancer (RR 0.66). (Prospective cohort study; 61433 participants over 17.4 years ; Larsson SC et al.; Long-term dietary calcium intake and breast cancer risk in a prospective cohort of women; Am J Clin Nutr 2009; 89: 277-282)
choline / betaine
In China, there is a significant inverse association between the intake of choline and betaine and the risk of breast cancer, especially in women with low folate levels. (Zhang CX et al.; Choline and betaine intake is inversely associated with breast cancer risk: a two-stage casecontrol study in China. Cancer Sci. 2013; 104(2):250-8.)
selenium
Lower selenium concentrations are found in women with breast cancer than in healthy individuals (81.1 mcg/l versus 98.5 mcg/l). (Lopez-Saez Jb et al .; Selenium in breast cancer; Oncology 2003; 64; 227-231)
Women with BRCA1 mutations have an increased risk of breast and ovarian cancer. This BRCA1 increases susceptibility to DNA breaks. Seleniumsupplementation reduces the number of DNA breaks in mutation carriers to the level of non-carrier controls. (Kowalska E et al.; Increased rates of chromosome breakage in BRCA1 carriers are normalized byoral selenium supplementation; Cancer Epidemiol Biomarkers Prev 2005;14;1302-1306)
Zinc
Zinc has a significant positive effect in premenopausal breast cancer when supplemented > 10 years. Multivitamins and vitamin C, E and beta-carotene have a significant positive effect when supplemented > 10 years in postmenopausal breast cancer. (retrospective case control study; 7824 participants; Pan SY et al Antioxidants and breast cancer risk – a population-based case-control study in Canada BMC Cancer 2011;11:372)
lungs
Carotenoids and vitamin A
Intake of green vegetables, beta-carotene-rich vegetables, watermelon, vitamin A, and carotenoids is inversely associated with the risk of lung cancer (HR 0.72 for the highest vs. the lowest intake). (Takata Y et al.; Intakes of fruits, vegetables, and related vitamins and lung cancer risk: results from the Shanghai Men's Health Study (2002-2009). Nutr Cancer. 2013; 65(1):51-61)
folic acid and vitamin C
Significant protective effects were found for folic acid and vitamin C. (cohort study over 6.3 years; 58279 participants; Voorrips LE et al.; A Prospective Cohort Study on Antioxidant and Folate Intake and Male Lung Cancer Risk; Cancer Epidemiology Biomarkers & Prevention 2000; 9, 357-365)
Vitamin B6
High vitamin B6 levels reduce the risk by half (odds ratio 0.51; 95% CI). (case control study; Hartman TJ et al.; Association of the B-Vitamins Pyridoxal 5'-Phosphate (B6), B12, and Folate with Lung Cancer Risk in Older Men; Am J Epidemiol 2001; 153; 688-694)
selenium
With the administration of 200 mcg selenium (selenium yeast) there is a significant reduction in lung cancer incidence by 45% (95% CI) (Randomised; multicentre, double-blind, placebo-controlled: 1312 Participants over 8 years Clark LC et al.; Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin A randomized controlled trial. Nutritional Prevention of Cancer Study Group; JAMA 1996; 276; 1957-1963)
A low seleniumstatus is associated with an increased risk of lung cancer. (Cohort study, 500 participants; Hartman TJ et al.; Selenium concentration and lung cancer in male smokers; Cancer causes Control 2002 ;123;923-928)
Low selenium levels are associated with an increased risk of lung cancer. (120 participants; Zhuo H et al.; Serum and lung tissue selenium measurements in subjects with lung cancer from Xuanwei, China ; Zhogguo Fei Al Za Zhi 2011;14;39-42)
Selenium has a preventive effect against lung cancer in people with low selenium levels. It reduces cisplatin-induced nephrotoxicity and side effects of radiation in lung cancer patients. (Review; Fritz H et al.; Selenium and lung cancer: a systemic review and meta analysis; PLoS One 2011; 6; #26259)
People with the lowest selenium levels have a 5.8-fold increased risk of fatal cancer compared to those with the highest selenium levels. It was increased 11.4-fold in people with low selenium and low vitamin E levels. A reduced intake of vitamin A or provitamin A increases the risk of lung cancer in smokers with low selenium levels. (Salonen JT et al.; isk of cancer in relation to serum concentrations of selenium and vitamins A and E: matched case-control analysis of prospective data; Br Med J 1985; 290; 4127-420)
Red wine
The risk of lung cancer decreased by 60% in smokers if they smoked moderate red wine once a day Consumption of beer, white wine or liqueur did not reduce the risk. (California Men' 's Health Study with 84,170 participants; Chao C et al.; Alcoholic Beverage Intake and Risk of Lung Cancer: The California Men's Health Study; Cancer Epidemiol Biomarkers Prev 2008; 17: 2692-2699)
phytoestrogens (e.g. ashwagandha)
The risk of lung cancer decreases with increasing intake of phytoestrogens (more significant for isoflavones than for phytosterols) in food by up to 46% (95% CI). (Case control study; 3409 participants over 8 years; Schabath MB et al; Dietary Phytoestrogens and Lung Cancer Risk; JAMA 2005; 294:1493-1504)
flavones and proanthocyanidins
For the occurrence of lung cancer in postmenopausal women, there was an inverse correlation between the intake of flavanones and proanthocyanidins. Smokers and former smokers with a very high intake of flavanones and proanthocyanidins had a significantly lower incidence of lung cancer than smokers and former smokers with a very low intake. Women who consumed higher amounts of isoflavones were less likely to develop cancer. (34,708 participants aged 18+; Cutler GJ; Dietary flavonoid intake and risk of cancer in postmenopausal women: the Iowa Women's Health Study; Int J Cancer .2008 Aug 1;123(3):664-671)
gastrointestinal tract (incl. liver and pancreas)
Apples
The odds ratio of the incidence of cancer of the oral cavity and pharynx is 0.79 for intake of > 1 apple/day versus (case-control study; 14138 participants over 11 years; Gallus S et al.; Does an apple a day keep the oncologist away? Annals of Oncology 2005; 16: 1841-1844)
Fresh apple 100g has the same antioxidant activity as 1500 mg vitamin C and extract from whole apples dose-dependently inhibits the growth of colon and liver cancer in vitro (Eberhardt MV et al. ; Antioxidant activity of fresh apples; Nature 2000;405:903-904)
flavonoids
flavonoids (apagenin 20 mg and epigallocatechin gallate 20 mg) reduce the recurrence rate after curative colorectal cancer surgery (0% versus 20% in the control group; evidence level 2B). (87 participants over 3 -4 years; Hoensch H et al.; Prospective cohort comparison of flavonoid treatment in patients with resected colorectal cancer to prevent recurrence; World J Gastroenterol 2008; 14; 2187-2193)
Tomatoes
Intake of larger amounts of tomatoproducts reduces the risk of gastric cancer. (Yang T et al.; The role of tomato products and lycopene in the prevention of gastric cancer: a meta -analysis of epidemiologic studies.Med Hypotheses.2013;80(4):383-8)
Carotenoids
The risk of gastric cancer is inversely correlated with blood levels of the antioxidants beta-carotene (R 0.31), vitamin E (R 0.89), alpha-carotene (R 0.67), lycopene (R 0.56) and vitamin C (R 0.61). (634 participants; Tsubonon Y et al.; Plasma antioxidant vitamins and carotenoids in five Japanese populations with varied mortality from gastric cancer; Nutr Cancer 1999;34;56-61)
Lycopene results in a 31% significant reduction in the risk of pancreatic carcinoma (OR 0.69; 95% CI). Beta-carotene (OR 0.57; 95% CI) and total carotenoids (OR 0.58; 95% CI) significantly reduce the risk only in non-smokers. (Case control study with 5183 participants over 3 years; Nkondjock A et al.; Dietary intake of lycopene is associated with reduced pancreatic cancer risk; Nutr 2005; 135: 592-597)
Vitamins A and C
Patients taking supplements containing vitamin A have a reduced risk of gastric cancer (RR = 0.4; 95% CI). There is an inverse relationship between vitamin C intake and gastric cancer (RR 0.7; 95% CI for highest versus lowest intake) (Netherlands Cohort Study; 120852 participants over 6.3 years; Botterweck AA et al.; Vitamins, carotenoids, dietary fiber, and the risk of gastric carcinoma: results from a prospective study after 6.3 years of follow-up; Cancer 2000; 88; 737-748)
Magnesium
Magnesium significantly reduces the risk of colon carcinoma. (Prospective study with 35196 participants over 17 years; Folsom AR et al.; Magnesium Intake and Reduced Risk of Colon Cancer in a Prospective Study of Women; Am J Epidemiol 2006; 163; 232-235)
selenium
With the administration of 200 mcg selenium (selenium yeast) there is a significant reduction in the incidence of colon carcinoma by 58% (95% CI). (Randomized; multicentric, double-blind, placebo-controlled: 1312 participants over 8 years; Clark LC et al.; Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group; JAMA 1996; 276; 1957-1963)
There is an inverse relationship between seleniumlevels and risk of esophageal and gastric cancer. (Prospective cohort study; 120,852 participants; Steevens J et al.; Selenium status and the risk of Esophageal and gastric cancer subtypes: the Netherlands cohort study; Gastrenterology 2010; 138; 1704-1713)
High selenium levels reduce the risk of exocrine pancreatic cancer (high levels of cadmium, arsenic and lead increase it). (517 participants; Amarai AF et al; Pancreatic cancer risk and levels of trace elements; Gut 2011)
500 mcg selenium over 3 years increases selenium levels and GPx activity and significantly reduces liver cancer incidence in high-risk patients. (placebo-controlled; 2065 participants; Li H et al.; The prevention of liver Cancer by selenium in high-risk populations;Zhonghua Yu Fang Yi Xue Za Zhi 2000;34;696-703)
Men with low seleniumstatus have an increased risk of colorectal cancer (OR for highest versus lowest levels = 0.68; 95% CI). (case control study; 1609 participants; Takata X et al.; Serum selenium, genetic variation in selenoenzymes, and risk of colorectal cancer: primary analysis from the woman's health initiative Observational study and meta-analysis; Cancer Epidemiol Biomarkers Prev 2011; 20; 1822-1830)
selenium and vitamin C
Low serum levels of selenium, zinc, manganese, vitamin C and vitamin E increase the risk of gallbladder cancer. (Shukla VK et al.; Micronutrients, anbtioxidants, and carcinoma of the gallbladder; J Surg Oncol 2003; 84; 31-35)
High vitamin C intake reduces the risk of pankeas carcinoma (OR 0.45; 95% CI), high cholesterol significantly increases it. (109 participants; Lin Y et al .; Nutritional factors and risk of pancreatic cancer: a population-based case-control study based on direct interview in Japan; J Gastroenterol 2005; 40: 297-301)
folic acid
The intake of folic acid 71-660 μg/day (via preparations or food) is not associated with an increased risk of colon cancer folic acid reduces the risk by 19%. (Cancer Prevention Study II Nutrition Cohort; 99521 participants; Stevens VL et al.; High Levels of Folate, from Supplement and Fortification, are not associated with increased risk of colorectal cancer; Gastroenterology 2011; published ahead of print; doi: 10.1053/j .gastro.2011.04.004)
Colorectal tumors: The risk in women is inversely proportional to the intake of iron, folic acid and vitamin C. Folic acid is the best protective factor. In men , high intakes of calcium and vitamin E were associated with a reduced risk, with vitamin working best (RR 0.35; 95% CI). (Case control study; Tseng M et al.; Micronutrients and the risk of colorectal adenomas; American Journal of Epidemiology, Vol 144, Issue 11 1005-1014)
Low levels of folatein cell cultures increase the risk of DNA damage to colon cells (and the increase in proteins such as Nit2 and COMT) and thus the risk of colon cancer.
High dietary folic acid intake significantly reduces the risk of pancreatic carcinoma (multivariable rate ratio 0.25; 95% CI). (81,922 participants over 6.8 years of age; Larsson SC et al.; Folate intake and pancreatic cancer incidence: a prospective study of Swedish women and men; J Natl Cancer Inst 2006; 98: 407-413) (Duthie SJ et al.; The Response of human coloncytes to folate deficiency in vitro: functional and proteomic analyses; J Proteome Res 2008; 7; 3254-3266)
Calcium and vitamin D
In women who have not previously taken calcium or vitamin D, calcium and vitamin D together significantly reduce the risk of breast and colorectal cancer. (15,646 women in the GHI Study Bolland MJ et al.; Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am J Clin Nutr 2011; 94: 1144-9)
Colorectal adenomas: There is evidence that calcium and vitamin D intake is inversely related to the frequency of colorectal adenomas. (Randomized multicenter study; polyp pervention trial; 1st .905 participants; Hartman TJ et al; The Association of Calcium and Vitamin D with Risk of Colorectal Adenomas; J Nutr 2005; 135: 252-259)
Vitamin D
25(OH)D (= vitamin D) levels are inversely related to the risk of colorectal cancer (an increase of 20ng/ml reduces the risk by 43%). ( Meta-analysis; Yin L et al.; Meta-analysis: longitudinal studies of serum vitamin D and colorectal cancer risk; Aliment Pharmacol Ther 2009; 30; 113-125)
A high intake of vitamin D (over 25 mcg/day) or a vitamin D serum level of 33 ng/ml reduces the risk of colon cancer by 50% (note: vitamin D increases calcium absorption in the intestine) . (Gorham ED et al.; Vitamin D and prevention of colorectal cancer; J Steroid Biochem Mol Biol 2005; 97; 179-194)
High intake and serum levels of vitamin D are associated with a significant reduction in the risk of colorectal cancer. (Research of epidemiological studies; Grant WB et al; A critical review of studies on vitamin D in relation to colorectal cancer.Nutrition and Cancer 2004;48:115-123)
The risk of colorectal cancer is reduced by half when 25-hydroxyvitamin D levels are above 33 ng/mL compared to levels below 2 ng/mL (RR 0.49; 95% CI). (Meta-analysis from 5 studies; Gorham ED et al. "Optimal Vitamin D Status for Colorectal Cancer Prevention: A Quantitative Meta Analysis." Am J Prev Med 2007; 32: 210-216 )
Vitamin D intake and levels are inversely associated with the risk of colorectal cancer. (Ma Y et al.; Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies J Clin Oncol 2011;29(28):3775-82)
Rectal carcinoma: The risk is strongly dependent on calcium intake (RR 0.59 with high calcium intake versus RR 1.00 with low intake) and vitamin D3 -Intake (RR 0.76 vs. RR 1.00 at low intake). For calcium and vitamin D3 together, the risk reduction was 45% (RR 0.55). (9-year cohort study; 34,702 postmenopausal women; Zheng W et al.; A prospective cohort study of intake of calcium, vitamin D, and other micronutrients in relation to incidence of rectal cancer among postmenopausal women;Cancer Epidemiol Biomarkers Prev.1998;7:221-225)
Vitamin D affects the pathogenesis of pancreatic carcinoma (RR 0.59 at the highest versus the lowest intake). (Health Professionals Follow-up Study with 46,771 men; Nurses'''' Health study with 75,427 women; Skinner HG et al.; Vitamin D intake and the risk for pancreatic cancer in two cohort studies; Cancer Epidemiol Biomarkers Prev 2006; 15: 1688-1695)
Vitamin K2
Vitamin K2 beneficial in the prevention of hepatocellular carcinoma in women with viral cirrhosis (OR 0.13; 95% CI). (Habu D et al.; Role of vitamin K2 in the Development of hepatocellular carcinoma in women with viral cirrhosis of the liver JAMA 2004 Jul 21;292(3):358-61.)
Methionine
Higher intake of methionine significantly reduces the risk of pancreatic carcinoma (multivariate rate ratio 0.44; 95% CI). (81,022 participants over 7.2 years; Larsson SC et al.; Methionine and vitamin B6 intake and risk of pancreatic cancer: a prospective study of Swedish women and men; Gastroenterology 2007; 132: 113-118)
Intake of folate or methionine is inversely associated with the risk of colorectal cancer. (Razzak AA et al.; Associations between intake of folate and related micronutrients with molecularly defined colorectal Cancer risks in the Iowa Women's Health Study. Nutr Cancer.2012;64(7):899-910)
glutathione
Glutathione from food reduces the risk of oral and pharyngeal carcinomas by 50% (Jones DP; Glutathione distribution in natural products: absorption and tissue distribution; Methods in Enzymology 1995; 25; 3 -13)
Fish (omega 3 fatty acids EPA and DHA)
The amount of fish consumption is inversely associated with colorectal cancer. (Wu S et al.; Fish consumption and colorectal cancer risk in humans: a systematic review and meta-analysis. Am J Med 2012;125(6):551-9.e5)
Urology
Carotenoids
Taking into account various influencing factors such as smoking and age of the participants, the odds ratio of bladder cancer with carotenoids as protective substances was determined: alpha-carotene 0.22, lutein 0.42, lycopene 0.94 and beta-cryptoxanthine 0.90. Regarding the combined effect of plasma carotenoids and smoking, the odds ratio for smokers with low lutein levels was 6.22 and low zeaxanthin levels was 5.18. The results of the study suggest that carotenoids protect against bladder cancer. Smokers in particular could benefit from a higher carotenoid intake. (case control study; 448 participants over 4 years; Hung RJ et al.; Protective effects of plasma carotenoids on the risk of bladder cancer; J Urol 2006; 176: 1192- 1197)
Fish (omega 3 fatty acids EPA and DHA)
Fatty sea fish (such as mackerel, herring, sardines, salmon) with lots of omega-3 fatty acids and vitamin D at least once a week reduces the risk of kidney cancer significantly (OR 0.56) compared to the control group. If the diet lasted more than 10 years, the risk decreases even further (OR 0.26). (Cohort study with 61433 participants over 15 years; Wolk A et al.; Long-term Fatty Fish Consumption and Renal Cell Carcinoma Incidence in Women;JAMA 2006;296:1371-1376)
There is an inverse connection between the consumption of fatty fish and a risk of renal cell carcinoma (risk 0.26 with regular consumption of oily fish compared to no fish intake), but no connection with the consumption of lean types of fish. (Swedish Mammography Cohort Study; 61,433 participants over 10 years; Wolk A et al.; Long-term fatty fish consumption and renal cell carcinoma incidence in women; JAMA 2006; 20; 296: 1371-1376)
selenium
There is an inverse relationship between selenium concentration and bladder cancer risk. (case-control study; 540 participants; Kellen E et al.; Selenium is inversely associated with bladder cancer risk ; a report form the Belgian case-control study on bladder cancer; Int J Urol 2006; 13; 1180-1184)
seleniumconcentration is inversely related to bladder cancer risk in women (case control study; 679 participants; Michaud DS et al.; Toenail selenium concentrations and bladder cancer risk in woman and men; Brit J Cancer 2005;93;443-458)
There is an inverse relationship between selenium levels and bladder cancer risk. (Prospective cohort study; 120,852 participants; Zeegers MP et al.; Prediagnostic toenail selenium and risk of bladder cancer; Cancer Epidemiol Biomarkers Prev 2002;11;1292-1297)
People with high levels of selenium have a lower risk of bladder cancer. Folic acid or a high intake of fruit reduce the risk in smokers. (Altwein JE; Primary prevention of bladder cancer; What's new? Urologe A 2007; 46; 616-621)
High selenium status significantly reduces bladder cancer risk by 39% (Or 0.61; 95% CI). (meta-analysis from 7 epidemiological studies; Amarai M et al; Selenium and bladder cancer risk: a meta-analysis; Cancer Epidemiol Biomarkers Prev 2010; 19; 2407-2415)
Selenium protects risk groups such as smokers, women and people with a mutation in the p53 gene from bladder cancer. (1,875 participants; Wallace K et al.; Selenium and risko of bladder cancer: a population- based case-control study; Cancer Prev Res 2009;2;70-73)
Hematology
Carotenoids and glutathione
Leukemia (hematological neoplasia): The intake amount of vegetables (OR 0.53; 95% CI), protein sources (OR 0.40; 95% CI) and fruits (OR 0.71; 95% CI) and especially carotenoids (OR 0.65; 95% CI) and antioxidant glutathione (OR 0.43; 95% CI) is inversely associated with acute lymphoblastic leukemia (ALL) in children (ALL may arise in utero). (Population-based Northern California Childhood Leukemia Study; 276 participants; Jensen CD et al.; Maternal dietary risk factors in childhood acute lymphoblastic leukemia; Cancer Causes and Control 2004; 15; 559 -570)
Iron and folic acid
Acute lymphoblastic leukemia (haematological neoplasia): In children aged 0-14 years, there is a connection between iron or folic acid supplementation during pregnancy and the development of ALL in the child (OR 0.37; 95% CI). For iron alone, the odds ratio is 0.75. (249 participants over 10 years; Thompson JR et al.; The Lancet 2001; 358; 9297)
Polyunsaturated fatty acids and vitamin D
There is an inverse relationship between the risk of non-Hodgkin's lymphoma (hematological neoplasia) and the intake of polyunsaturated fatty acids, linoleic acid and vitamin D (OR 0.6 each; 95% CI). The effect is stronger in women. (Case control study; 674 participants over 3 years; Polesel J et al.; Linoleic acid, vitamin D and other nutrient intakes in the risk of non-Hodgkin lymphoma: an Italian case-control study; Ann Oncol 2006;17:713-718)
selenium
The anti-leukemic effect of selenite is linked to the inhibition of DNA replication, transcription and translation. (Jiang XR et al.; The anti-leucaemic effects and the mechanism of sodium selenite; Leuk Res 1992; 16; 347-352)
Individual tumor types
A) Prostate
Fish / Omega 3 fatty acids
Arachidonic acid and its metabolite, prostaglandin E2, promote the migration of cancer cells, driving invasion into the bone marrow. Omega-3 fatty acids inhibit the migration of prostate cancer cells into the bone marrow when they are present in half the concentration of omega-6 fatty acids. The omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid can prevent prostate cancer cells from reaching the bone marrow. (Brown MD et al.; Promotion of prostatic metastatic migration towards human bone marrow stoma by Omega 6 and its inhibition by omega 3 PUFAs; Br J Cancer 2006;27;94:842-853)
There is no association between fishintake and prostate cancer, but (in studies with 49,641 participants) a significant reduction in prostate cancer-specific mortality (RR 0.37). (meta-analysis ( including 12 case control studies with 15,582 participants and 12 cohort studies with 445,820 participants); Szymanski KM et al.; Fish consumption and prostate cancer risk: a review and meta-analysis; Am J Clin Nutr 2010; 92: 1223-1233)
Prostate carcinoma: fat content of food and fat type have a significant influence on cancer cell growth: A fat-modified diet, in contrast to a western diet rich in fat, leads to a significant inhibition of prostate Cancer cell growth (randomized, prospective; Aronson WJ et al. "growth inhibitory effects of a low fat diet on prostate cancer cells in vitro: results of a prospective randomized dietary intervention trial in men with prostate cancer". AUA 2005 , Abstr. 1417)
Vitamin E
Prostate carcinoma: Mortality is significantly reduced by 41% with alpha-tocopherol (vitamin E) 50 mg. (Randomized, double-blind; 29,133 smokers; Heinonen OP et al .;ATCB study;J Natl Cancer Inst 1998;90;440-446)
Long-term vitamin E supplementation of 400 IU and more is associated with a reduced extent (locally invasive and/or metastatic) of existing prostate Ca by 57% (HR = 0.43; 95 % CI). (Prospective cohort study; 35,242 participants; Peters U et al.; Vitamin E and selenium supplementation and risk of prostate cancer in the Vitamins and lifestyle (VITAL) study cohort; Cancer Causes Control 2008; 19 : 75-87)
Prostate carcinoma: Vitamin E suppresses the release of PSA and androgen receptors. Combined use of vitamin E and antiandrogen flutamide inhibits LNCaP cell growth significantly more. Selenomethionine also shows an inhibitory effect on LNCaP cell growth. (Yu Zhang et al.; Vitamin E succinate inhibits the function of androgen receptor and the expression of prostate-specific antigen in prostate cancer cells; Proc Natl Acad Sci U S A 2002;99;7408-7413)
Soy
Soy isoflavone supplementation 60 mg in early stage prostate cancer affects surrogate markers for cancer proliferation such as PSA and free testosterone. (76 participants over 12 weeks; Kumar NB et al .; The Specific Role of Isoflavones in Reducing Prostate Cancer Risk; The Prostate 2004; 59; 141-147)
Broccoli (sulforaphane)
Broccoli (or the ingredient sulforaphane) makes aggressive and resistant pancreatic stem cells (pancreatic carcinomas contain about 10% of these cells) vulnerable and slows down metastasis of the pancreas (in Germany approx. 12650 cases of pancreatic ca.) (Kallifatidis G, Herr I et al.; Sulforaphane targets pancreatic tumor-initiating cells by NF-kB-induced antiapoptotic signaling. GUT 2008 , in press)
selenium
Selenite significantly increases p53 in prostate cancer cells. This is important for the activation of caspase-mediated apoptosis of cancer cells (involving the caspase-8 and caspase-9 pathway). (Jiang C et al.; Selenite-induced p53 Ser-15 phosphorylation and caspase -mediated apoptosis in LNCaP human prostate cancer cells; Mol Cancer Ther 2004; 3; 877-884)
B) Gynecological tumors
Antioxidants
Breast cancer and antioxidants: Levels of ROS, MDA and antioxidant enzyme activities are significantly higher in patients with breast cancer than in controls. The levels of vitamin C, GSH, GSSG (oxidized glutathione) and GSH/GSSG ratio are significantly lower. (Yeh CC et al.; Superoxide anion radical, lipid peroxides and antioxidant status in the blood of patients with breast cancer; Clinica Chimica Acta 2005; 361; 104-111)
Vitamin D
Women with early breast cancer have significantly higher vitamin D levels than women with advanced or metastatic breast cancer Vitamin D affects cell cycle regulation and may delay tumor growth. (558 Participants; Palmieri C et al.; Serum 25-hydroxyvitamin D levels in early and advanced breast cancer; J Clin Pathol 2006; 59; 1334-1336)
Vitamin E
Cervical cancer and vitamin E: The plasma levels of alpha-tocopherol and alpha-tocopheryl-quinone (oxidized alpha-tocopherol) are significantly reduced in the study group compared to controls. ( 72 participants; Palan PR et al.; [alpha]-tocopherol and [alpha]-tocopheryl quinone levels in cervical intraepithelial neoplasia and cervical cancer; American Journal of Obstetrics & Gynecology. 2004; 190; 1407-1410 )
Resveratrol
Resveratrol induces S-phase arrest in human ovarian carcinoma Ovcar-3 cells via Tyr15 phosphorylation of Cdc2. Overexpression of Cdc2AF, a mutant resistant to Thr14 and Tyr15 phosphorylation, reduced resveratrol-induced S-phase arrest. Resveratrol causes phosphorylation of cell division cycle 25C (CDC25C) tyrosine phosphatase via activation of checkpoint kinases Chk1 and Chk2, which in turn were activated via ATM (ataxia telangiectasia mutated) / ATR (ataxia telangiectasia Rad3-related ) kinase in response to DNA -Damage. Resveratrol also increases phospho-H2A.X (Ser139), which is phosphorylated by ATM/ATR in response to DNA damage. The involvement of these molecules in resveratrol-induced S-phase was also confirmed in studies showing that addition of the ATM/ATR inhibitor caffeine reduced resveratrol-induced activation of ATM/ATR Chk1/2 and phosphorylation of CDC25C, Cdc2 and H2A. X and reverses the S-phase arrest. Resveratrol also induces S-phase arrest and H2A.X (Ser139) phosphorylation in ovarian cancer cell lines PA-1 and SKOV-3 (albeit at different levels), while it does not in normal human foreskin fibroblasts detectable levels of Phospho-H2A.X (Ser139) showed only marginal S-phase arrest. Resveratrol establishes Cdc2-tyr15 phosphorylation via the ATM/ATR-Chk1/2-Cdc25C pathway as a central mechanism for DNA damage and S-phase arrest selectively in ovarian carcinoma cells and provides rationale for the potential efficacy of ATM/ATRA gonists in in cancer prevention and intervention. (Tyagi A et al.; Resveratrol causes Cdc2-tyr15 phosphorylation via ATM/ATR-Chk1/2-Cdc25C pathway as a central mechanism for S phase arrest in human ovarian carcinoma Ovcar -3 cells; Carcinogenesis 2005;26:1978-1987)
Resveratrol has antineoplastic activity. It inhibits the growth and induces the death of ovarian carcinoma cells (more via autophagy than via apoptosis), inter alia associated with caspase activation. It thus induces cell death in two different ways: non-apoptotic and apoptotic (via release of the anti-apoptotic proteins Bcl-xL and Bcl-2) (Opipari AW et al.; Resveratrol-induced autophagocytosis in ovarian cancer cells ; Cancer Research 2004; 64, 696-703)
selenium
Selenium is an important cofactor in the production of antioxidant enzymes. Selenium reduces cancer mortality in intervention studies. Selenium intake (in subjects with low selenium intake) prior to breast cancer diagnosis is inversely associated with breast cancer-specific mortality (HR 0.69) and all-cause mortality (Harris HR et al.; Selenium intake and breast cancer mortality in a cohort of Swedish women Breast Cancer Res Treat. 2012; 134(3):1269-77)
Increased selenium intake leads to a significant reduction in VEGF and the intratumoral density of microvessels in breast cancer. Selenium thus reduces angiogenesis. (Jiang C et al.; Selenium induced inhibition of angiogenesis in mammary cancer at chemopreventive levels of intake; Mol Carcinog 1999; 26; 213-225)
C) Gastrointestinal tract and pancreas
Antioxidants
5-FU has a responder rate of only 20% in colorectal cancer, but it remains the single most effective therapy. Antioxidants (such as Vit E) induce apoptosis in CRC cells via activation of p21 WAF1/CIP1, a potent cell cycle inhibitor (with incorporation of C/EBPbeta, a member of the CCAAT enhancer-binding protein family of transcription factors) - independent of p53 . Antioxidants significantly increase tumor growth inhibition by cytostatic therapy with 5 FU (and doxorubicin). The combination of chemotherapy and antioxidants provides a new therapy for CRC. (Chinery R et al.; Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21 via C/EBP-beta; Nat Med 1997;3;1233-1241)
Supplementation of vitamin C alone and in combination with beta-carotene leads to a reduced number of advanced ductular lesions in rat pancreatic carcinoma. Vitamin E and/or selenium have no effect. (Appel MJ et al.; Lack of inhibitory effects of beta-carotene, vitamin C, vitamin E and selenium on development of ductular adenocarcinomas in exocrine pancreas of hamsters; Cancer Lett 1996;103:157-162)
Vitamin E significantly inhibits cell growth in human pancreatic cancer cell lines. (Heisler T et al.; Peptide YY augments gross inhibition by vitamin E succinate of human pancreatic cancer cell growth; J Surg Res 2000; 88: 23-25)
Treatment with vitamin C, vitamin E and selenium significantly reduces deaths from gastric and esophageal cancer (Randomised, placebo-controlled; 3365 participants; Ma Jl et al.; Fifteen year effects of Helicbacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality; J Natl Cancer Inst 2012; 104; 488-492)
Vitamin D
Vitamin D decreased in patients with kolonka. significantly the mortality for all causes of death (HR 0.52 for highest versus lowest levels). For colonca mortality, the reduction is 39%. (304 participants (Nurses Health Study, Health Professionals Follow Up Study); Ng K et al.; Circulating 25-Hydroxyvitamin D Levels and Survival in Patients With Colorectal Cancer; Journal of Clinical Oncology 2008, 26, 2984-2991)
Calcium
Colorectal adenomas: With supplementation with calcium (calcium carbonate or calcium gluconolactate), the number of adenoma recurrences was significantly lower than in the randomized comparison group (RR: 0.80, CI: 0.68, 0.93) (Meta-analysis from 3 studies with 1485 participants; Shaukat A et al.; Role of supplemental calcium in the recurrence of colorectal adenomas: a metaanalysis of randomized controlled trials; Am J Gastroenterol. 2005; 100; 390-294)
Alpha lipoic acid
There is evidence that alpha-lipoic acid or the reduced form dihydrolipoic acid effectively induces apoptosis in human HAT-29 colon cancer cells through a pro-oxidative (mitochondrial) mechanism. (Wenzel U et al:; alpha-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2-*-generation; Apoptosis 2005 Mar; 10(2):359-368)
Lycopene
Lycopene inhibits cell proliferation in human colon carcinoma cells and activation of phosphoinositide-2-kinase/Akt signaling pathway (regulates cancer cell survival) (Tang FY et al.; Lycopene inhibits growth of human colon cancer cells via suppression of the Akt signaling pathway; Mol Nutr Food Res 2008; 52; 646-654)
Resveratrol
Resveratrol 25 microM reduces human colon cancer cell growth by 70%. The cells accumulated in the S/G2 phase transition of the cell cycle. Resveratrol significantly reduces the activity of ornithine decarboxylase (a key enzyme in polyamine biosynthesis involved in cancer growth). (Schneider Y et al.; Anti-proliferative effect of resveratrol, a natural component of grapes and wine , on human colonic cancer cells.Cancer Lett. 2000; 158, 85-91)
Resveratrol 200 mcg/kg significantly reduces carcinogenesis of colon cancer in rats. It significantly reduces cell number and alters bax and p21 expression. (Tessitore L et al.; Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21 (CIP) expression. Carcinogenesis 2000;21, 1619-1622)
Resveratrol 100 mcmol/l significantly inhibits cell growth in pancreatic carcinoma cell lines (PANC-1 and AsPC-1) in a concentration- and time-dependent manner and induces cell apoptosis. (Ding XZ et al.; Resveratrol inhibits proliferation and induces apoptosis in human pancreatic cancer cells; Pancreas 2002; 25: e71-76)
Alcohol consumption (wine vs other alcohols)
There is a dose-response relationship between alcohol and rectal carcinoma. More than 41 drinks per week conferred a relative risk of rectal cancer of 2.2 (95% CI) compared to non-drinkers. More than 14 drinks of beer and spirits - but not wine - per week resulted in an RR of 3.5 for rectal cancer compared to non-drinkers, while those who drank the same amount of alcohol but consumed more than 30% than We had an RR of 1.8 for rectal cancer. No association was found between alcohol and colon cancer when examining the effects of the total amount of alcohol in beer, wine and spirits and the proportion of wine in total alcohol consumption. Alcohol intake is associated with a significantly increased risk of rectal cancer, but the risk appears to be reduced when wine is included. (Randomised, population-based cohort study (Copenhagen, Danish Cancer Registry); 29,132 participants over 14.7 Years; Pederson A, Johansen C, Groenbaek M; Relations between amount and type of alcohol and colon and rectal cancer in a Danish population based cohort study; Gut 2003;52:861-867)
Overall, alcoholconsumption itself is not associated with gastric cancer, but the type of alcohol appears to influence risk. Compared to non-wine drinkers, participants who drank 1-6 glasses of wine per week had a relative risk of 0.76 (95% CI), while those who drank more than 13 glasses of wine per week had an RR of 0.16 (95% CI). There is a significant association with an RR of 0.60 (95% CI) for each glass of wine consumed per day. There was no association between beer or spirits and gastric cancer. (3 prospective population-based studies; 28463 participants; Barstad B, Groenbaek M et al.; Intake of wine, beer and spirits and risk of gastric cancer; European Journal of Cancer Prevention 2005; 14; 239-243)
Broccoli (sulforaphane)
Treatment-resistant tumor stem cells play an important role in the pathogenesis of pancreatic cancer Substances such as the broccolicomponent sulforaphane inhibit NFkB, apoptosis inhibitors and angiogenesis and induce apoptosis. Combination with TRAIL (tumor necrosis factor-dependent-apoptosis-inducing ligand) enhances apoptosis in tumor stem cells. (Kallifatidis G et al.; Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB-induced antiapoptotic signalling. Good 2009;58:949-63)
Resveratrol
Resveratrol has a strong growth-inhibiting effect against various human cancer cells. Here, the inhibitory effect of resveratrol on experimental liver cancer is examined using a two-stage model in rats. Resveratrol 50-300 mg/kg body weight reduces the incidence, number, volume and multiplicity of visible hepatocyte nodules in a dose-dependent manner. It leads to a decrease in cell proliferation and an increase in apoptotic cells in the liver. It also induces expression of the pro-apoptotic protein Bax, reduces expression of the anti-apoptotic Bcl-2, and at the same time increases the Bax/Bcl-2 ratio. Due to its favorable toxicity profile, resveratrol has the potential to be developed as a chemopreventive drug against human hepatocellular carcinoma. (Bishayee A, Dhir N; Resveratrol-mediated chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis: inhibition of cell proliferation and induction of apoptosis; Chem Biol Interact 2009;179:131-44)
Resveratrol has a cancer-preventive effect and induces Bax-mediated and Bax-independent mitochondrial apoptosis in human HCT116 colon carcinoma cells at physiological doses. Both pathways limit the cells' ability to form colonies. (Mahyar-Roemer M et al.; Role of Bax in resveratrol-induced apoptosis of colorectal carcinoma cells; BMC Cancer 2002; 2; 27-36)
Quercetin
Quercetin inhibits the growth of human gastric cancer cells. DNA synthesis and cell progression from G1 to S phase of mitosis are suppressed (Yoshida M et al.; The effect of quercetin on cell cycle progression and growth of human gastric cancer cells; FEBS Lett 1990;260;10-13)
Zinc
Zinc inhibits the growth of pancreatic carcinoma cells more effectively than gemcitabine (gold standard of chemotherapy). (Donadelli M etal.; Intracellular zinc increase inhibits p53(-/-) pancreatic adenocarcinoma cell growth by ROS/AIF-mediated apoptosis (Biochim Biophys Acta. 2008)
Omega 3 fatty acids
Polyunsaturated fatty acids (especially the omega 3 fatty acid EPA) have a significant inhibitory effect on the growth of human pancreatic carcinoma cell lines. (Falconer JS et al.; Effect of eicosapentaenoic acid and other fatty acids on the growth in vitro of human pancreatic cancer cell lines;Br J Cancer 1994;69:826-832)
D) Hematology
Vitamin K2
Myeloma cells and B-cell lymphomas (hematological neoplasms) are sensitive to vitamin K2. Growth inhibition occurs, among other things, via apoptosis and activation of caspase-3. K2 represents a good treatment for myeloma patients, particularly those who are unsuitable for intensive cell-reducing chemotherapy due to age or complications. (Tsujioka T et al; The mechanisms of vitamin K2-induced apoptosis of myeloma cells; Haematologica 2006; 91: 613-619)
Vitamin D
Vitamin D levels are seasonal The season of diagnosis is also a strong prognostic factor for Hodgkin's disease (hematological neoplasia), with approximately 20% fewer fatal cases in autumn versus winter (RR 0.783; 95% CI ). Survival time is increased by more than 60% in autumn patients under 30 years (RR 0.364; 95% CI). The increased vitamin D levels have a beneficial effect on conventional therapy. (Epidemiological study over 36 years; Porojnicu AC et al.; Season of diagnosis is a prognostic factor in Hodgkin's lymphoma: a possible role of suninduced vitamin D;Br J Cancer 2005;93:571-574)
Magnesium and Zinc
In children with acute lymphocytic leukemia ALL and malignant lymphoma (hematological neoplasia), there are lower levels of magnesium (significant only in T-cell ALL) and significantly lower levels of Zinc. The serum zinc levels are also reduced. (58 participants; Sahin G et al.; High prevelance of chronic magnesium deficiency in T cell lymphoblastic leukemia and chronic zinc deficiency in children with acute lymphoblastic leukemia and malignant lymphoma; Leuk Lymphoma 2000;39:555-562)
selenium
In patients with aggressive B-cell non-Hodgkin's lymphoma (hematological neoplasia) receiving anthracycline-based chemotherapy and/or radiation, serum selenium levels correlate positively with response rate (OR 0.62; 95% CI) and long-term remission after initial treatment and overall survival time (HR 0.76 for 0.2 mcmol/l increase; 95% CI). (Last KW et al.; Presentation serum selenium predicts for overall survival, dose delivery , and first treatment response in aggressive non-Hodgkin's lymphoma;J Clin Oncol 2003;15;2:2335-2341)
Grape seed extract (OPC)
Grape seed extract (OPC) induces apoptosis in human leukemia cells in a dose- and time-dependent manner (via activation of the c-Jun NH2-terminal kinase). (Gao N et al.; Induction of apoptosis in human leukemia cells by grape seed extract occurs via activation of c-Jun NH2-terminal kinase Clinical Cancer Research 15, 140, January 1, 2009. doi: 10.1158/1078-0432.CCR-08-1447)
Resveratrol
Resveratrol induces downregulation in survivin expression and apoptosis and inhibition of cell growth in T-cell leukemia cell lines. (Hayashibara T et al.; Resveratrol induces downregulation in survivin expression and apoptosis in HTLV- 1-infected cell lines: A prospective agent for adult T cell leukemia chemotherapy; Nutrition and cancer 2002, 44, 192-201)
Resveratrol inhibits the growth of leukemia cells in culture. It induces leukemia cell differentiation, apoptosis, cell cycle arrest in S phase, inhibition of DNA synthesis by blocking ribonucleotide reductase or DNA polymerase. (Tsan MF et al.; Anti-leukemia effect of resveratrol.Leuk.Lymphoma 2002;43, 983-987)
Resveratrol 50 microM induces apoptosis in more than 80% of CD95-sensitive and CD95-resistant acute lymphoblastic leukemia (ALL) cells by depolarizing mitochondrial membranes and by activating caspase-9, independent of CD-95 signaling . There is no significant cytotoxicity to normal peripheral blood cells. (Dorrie J et al.; Resveratrol induces extensive apoptosis by depolarizing mitochondrial membranes and activating caspase-9 in acute lymphoblastic leukemia cells. Cancer Res. 2001;61, 4731-4739)
Resveratrol develops antiproliferative activity.It inhibits proliferation and induces cytotoxicity or apoptosis of cells in Waldenstrom's macroglobulinemia (WM) lymphoma malignancy. Peripheral blood cells are not affected. Resveratrol shows synergistic cytotoxicity when combined with dexamethasone, fludarabine and bortzomib. (Roccaro AM et al.; Resveratrol Exerts Antiproliferative Activity and Induces Apoptosis in Waldenstrom's Macroglobulinemia; Clin. Cancer Res 2008; 14: 1849-1858)
The aim of this study was to investigate interactions of ellagic acid and quercetin with resveratrol (polyphenols) in the induction of apoptosis and reduction of cell growth in the human leukemia cells (MOLT-4). The combination of ellagic acid with resveratrol has a synergistic effect more than additive. Both substances alone and together induce significant changes in cell cycle kinetics. There are positive synergistic interactions between ellagic acid and resveratrol and between quercetin and resveratrol in inducing caspase-3 activity. The anticarcinogenic potential of foods with polyphenols can be enhanced through synergistic effects. (Mertens-Talcott SU, Percival SS; Ellagic acid and quercetin interact synergistically with resveratrol in the induction of apoptosis and cause translent cell cycle arrest in human lekemia cells; Cancer Lett 2005;218;141-151)
E) SKIN
Vitamin C
Vitamin C induces apoptosis of melanoma cells in vitro. (Kang JS et al.; Sodium ascorbate (vitamin C) induces apoptosis in melanoma cells via the down-regulation of transferrin receptor dependent iron uptake; J Cell Physiol 2005;204:192-197)
Vitamin E
Vitamin E promotes quiescence and inhibits angiogenesis in melanoma cells in vitro. It also significantly suppresses the expression of VEGF (endothelial growth factor), VEGF receptor 1 and VEGF receptor 2 in melanoma. (Malafa MP et al.; Inhibition of angiogenesis and promotion of melanoma dormancy by vitamin E succinate; Ann Surg Oncol 2002;9:1023-1032)
Vitamin D
Low vitamin D levels are significantly associated with greater tumor thickness (according to Berslow) in malignant melanoma and an advanced stage. 564 patients had 25-OH-D levels (764 participants; Gambichler T et al.; Serum-25-hydroxyvitamin D serum levels in a large German cohort of patinets with melanoma; Br J Dermatol 2013; 168; 625-628)
Vitamin D receptor gene polymorphisms are associated with susceptibility and prognosis for malignant melanoma (MM). The data suggest that the antiproliferative calcitriol (1,25(OH)2D3), the ligand of VDR, has a protective effect against MM. (case control study; 424 Participants; Hutchinson PE et al.; Vitamin D receptor polymorphisms are associated with altered prognosis in patients with malignant melanoma; Clin Cancer Res 2000; 6: 498-504)
selenium
In malignant melanomas and cutaneous T-cell lymphomas (CTCL) there are reduced serum selenium levels depending on the stage of the disease: they are significantly lower in tumor recurrences than in tumors without recurrence. (251 participants; Deffuant C et al.; Serum selenium in melanoma and epidermotropic cutaneous T-cell lymphoma; Acta Derm Venereol 1994; 74: 90-92)
Patients with malignant melanoma have significantly lower selenium levels (increasing with severity) than controls. (101 participants; Reinhold U et al.; Serum selenium levels in patients with malignant melanoma; Acta Derm Venereol 1989; 69: 132-136)
Resveratrol
Solar radiation covers a large electromagnetic spectrum including UV radiation, which is potentially harmful to normal cells, and ionizing radiation, which is therapeutically useful in destroying cancer cells responsible for keratosis. Chemoprevention of UV damage via non-toxic substances, especially plant antioxidants, is an approach to prevent photodamage including photocarcinogenesis. In this paper, the photoprotective effects of resveratrol against UVB exposure-mediated damage are discussed. In addition, we also discussed studies showing that resveratrol can enhance the therapeutic effects of ionizing radiation on cancer cells. Based on literature data, resveratrol may be useful in preventing UVB-mediated damage, including skin cancer, and in enhancing the efficacy of radiation therapy against hyperproliferative, precancerous, and neoplastic conditions. (Reagan-Shaw S et al.; Resveratrol imparts photoprotection of normal cells and enhances the efficacy of radiation therapy in cancer cells; Photochem Photobiol 2008; 84: 415-421)
Non-melanoma skin cancer is the most commonly diagnosed malignancy in the United States. The main cause is multiple exposure to the sun's ultraviolet (UV) radiation (particularly the UV-B component, 290-320 nm). Chemoprevention by naturally occurring agents is considered a newer dimension in the management of neoplasia (including skin cancer). We have shown that resveratrol mediates protection against acute UVB-mediated cutaneous damage in SKH-1 hairless mice. Understanding this mechanism is important. We have previously shown that resveratrol has chemopreventive effects against a range of UV exposure-mediated changes in the cki-cyclin-CDK network, and the mitogen-activated protein kinase (MAPK) signaling pathway. In this study, the skin of SKH-1 nude mice was irradiated with UV-B on alternate days. Topical pretreatment with resveratrol significantly inhibited a UV-B exposure-mediated increase in cell proliferation (Ki-67 immunostaining), epidermal cyclooxygenase-2 and ornithine decarboxylase, established markers of tumor promotion, protein and messenger RNA -Levels of survivin and phosphorylation of survivin in mouse skin. Resveratrol pretreatment also reversed the UV-B-mediated decrease in Smac/DIABLO and the increase in UV-B-mediated induction of apoptosis in mouse skin and increased UV-B-mediated induction of apoptosis in the mouse skin. Overall, our study shows that resveratrol has chemopreventive effects against UV-B exposure-mediated damage in the skin of SKH-1 hairless mice via inhibition of survivin and associated events. (Aziz MH et al.; Prevention of ultraviolet-B radiation damage by resveratrol in mouse skin is mediated via modulation in surviving; Photochem Photobiol 2005; 81: 25-31)
Source: Dr. Udo Böhm, Handbuch Krebs, 2014
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This blog post is intended to provide information about micronutrients and encourage people to take responsibility for dealing with health issues. It is expressly not intended as a substitute for medical advice, diagnosis or treatment. Like any science, nutritional science is subject to constant change. However, the author and Qidosha GmbH cannot accept any liability for information on dosages, forms of application or any inaccuracies in content. Each application is the responsibility of the user.
Cancer as a multifactorial disease of the whole body
Cancer is not just a disease of one organ, it can be considered a disease of the whole body . The entire metabolism is involved in its prevention, establishment and progression. Its development is a complex multi-stage process that can take place over many years and is dependent on many factors (see figure below). In the development of malignant tumors, endogenous and exogenous causes interact in varying frequency with malfunctions or excessive demands on the metabolism. The sum of the factors initially leads to qualitative and quantitative changes in the structure and function of individual cells and then to greater damage from which malignancies can develop. So-called proto-oncogenes, which promote malignant transformations, and suppressor genes (e.g. control genes, repair genes), which inhibit transformation, are also associated with the development of cancer.
According to the current state of knowledge, genetic factors are on average onlyfor approx. 5.5% of Cancer diseases are responsible, but can occur more frequently with individual tumors, e.g. with carcinomas of the prostate (15.3%), intestine (10.1%) and breast (8.3%).
Inflammation and infections also play an important role in the development of cancer. The majority of malignant tumors can be traced back to exogenously mediated environmental and lifestyle factors, such as exposure to biological, physical and chemical noxae, physical and psychological stress, iatrogenic measures (e.g. ionizing radiation ), obesity and improper diet or abuse of everyday drugs (such as nicotine and alcohol). Risk factors for the development of prostate carcinoma are, for example - in addition to genetics - obesity, a diet with a high proportion of "unfavorable" fats, alcohol, lack of exercise and low sexual activity.
In addition, the damaged cells themselves must have special properties that allow them to survive in a "hostile environment" if they want to multiply and later develop into cancer. This includes the
ability
remaining invisible to the immune system (including repair mechanisms and apoptosis) for as long as possible
build up your own blood supply or form new vessels (angiogenesis)
survive in hypoxic environment
emigrate from a cell group and form metastases
In order to really "defeat" cancer or even just push it back, we have to deal intensively with the causes of cancer development mentioned above and with the factors that promote or inhibit cancer growth.
In order to prevent the development of cancer, the body has various effective tools at its disposal that cascade and complement each other in the event of danger. These include
the detoxification of risk factors (e.g.pollutants, radicals) and
the prevention of mutations and
the repair or elimination or killing of damaged cells
Therefore, cancer usually only breaks out when - in addition to the increased burden of endogenous and exogenous risks - the body's own resources are overtaxed or if they fail.
are important for the success of the repair measures:
, among others
a well-functioning metabolism (including energy production in the mitochondria)
a good detoxification performance
a fine tuning of the cellular (especially T-lymphocytes) and humoral (especially antibodies) components of the immune system
influencing inflammation and latent acidosis, and
reducing the occurrence of free radicals
The 3 phases of cancer
Today, cancer development is divided into three phases
Cancer initiation
Cancer Promotion
Cancer progression
In each of these phases, the above-mentioned factors such as oxidative stress, changes in the energy balance, infections or chronic inflammation are also involved, which is why considerations of influencing these functional cycles must be incorporated into future concepts.
In cancer initiation, one or more healthy cells change, which - if they are not repaired or destroyed - serve as "cancer stem cells", transforming over time into active cancer cells under favorable conditions and themselves can multiply uncontrollably. Damage to the mitochondrial or nuclear DNA is caused by unfavorable genetics or - more frequently - by one or more other factors (e.g. carcinogens, infections, oxidative stress). For example, chemical carcinogens such as polycyclic aromatic hydrocarbons are metabolized to reactive species, and tumor-promoting agents promote the expression of genes whose products are pro-inflammatory. This includes, above all, the modulation of the expression of growth factors and cytokines. In particular, the activator protein-1 (controls various cell processes such as differentiation, proliferation and apoptosis), NFkB (is a transcription factor that is stimulated by TNF-α and interleukin-1 as part of the immune response and above all in the regulation of the immune response, cell proliferation and the apoptosis of a cell is of great importance) and other transcription factors are closely associated with inflammatory and immune responses and with the regulation of cell proliferation and programmed cell death. These processes also block the body's own protective and repair mechanisms, which are of great importance for preventing the initiation of cancer. The genetic damage in the cell is passed on to daughter cells.
When "procancerous" factors are present (e.g., inflammation, growth factors, hormones) and the repair mechanisms and initiation of programmed cell death to dispose of cancer cells are not working, the cancer cells multiply and the tumor grows. One then speaks of the phase of cancer promotion. Here, too, activator protein 1, NFkB and other transcription factors involved in the regulation of cell proliferation and programmed cell death play a role. For example, inflammation induces NFkB, which in turn activates survival genes in the cell and contributes to uncontrolled cancer cell growth and metastasis. Macrophages also produce substances that stimulate tumor growth, including TNFα, which in turn boosts NFkB activity
After a mostly longer period of time (usually between 2 and 30 years), the thirdPhase of cancer development, the phase of cancer progression, in which the tumor grows New blood vessels (angiogenesis) and ultimately metastasis can occur – which is undesirable in this case. The increased angiogenesis secures the tumor's energy supply and facilitates its spread. Other essential promoters of tumor promotion and tumor progression are accelerated cell growth and renewed failure of programmed cell death, which is significantly influenced by various pro- and anti-apoptotic factors. These include, for example, the tumor-suppressing caspases and the transcription factor p53, the p53-induced cell cycle inhibitor p21 and various tumor-promoting substances such as protein kinases and cyclins.
Development of cancer
Metabolic cycles and cancer
The cancer itself, the effects associated with the disease and the therapeutic efforts change us in general and our body and in particular our metabolism in particular. Metabolic dysfunctions, in turn, intensify the diverse negative effects of cancer and its therapy on the body.
a) detoxification function and cancer
Our body has to deal with many endogenous and exogenous or diverse chemical, biological and physical pollutants every day. Above all, the exposure to exogenous pollutants is increasing sharply, with the fact that we do not recognize many of these pollutants at all and that even small individual amounts can accumulate to great overall damage is particularly problematic. Most pollutants are carcinogenic and must therefore be detoxified as quickly as possible before they can cause any damage. This takes place via a multi-stage detoxification program, mainly in the liver, where the pollutants are first processed or functionalized and conjugated for excretion. We must therefore ensure that the body's detoxification and elimination processes function optimally.
b) Oxidative stress and cancer
Radicals are formed in different types and amounts by a variety of exogenous and endogenous processes, depending on the individual lifestyle, genetics and metabolic situation. They usually have a negative effect on the metabolism and are recognized, among other things, as the cause of damage to mitochondrial DNA and cell DNA or to other structures (e.g. p53), which then often leads to cancer. In addition, radicals can promote the release of pro-inflammatory cytokines and put a strain on both immune function and energy balance. In addition to avoiding the formation of harmful radicals from endogenous and exogenous sources, it is therefore important to eliminate unavoidable radicals as soon as possible.
An exception to this rule is e.g. during oncological chemotherapy and radiation therapy, because here the formation of free radicals is intended to kill tumor cells. Unfortunately, the cells that are still healthy are also damaged as an unpleasant side effect. University and complementary oncology should therefore work together to find ways that, on the one hand, do not impede the desired radical effects on cancer and, on the other hand, prevent damaging effects on healthy cells. This is feasible, but requires a very well-structured approach when implementing it on the individual patient.
c) inflammation and cancer
Inflammation is now recognized as an important player in the development of cancer and many other diseases, whereby according to current scientific standards acute inflammation tends to have a protective effect and chronic inflammation promotes cancer development One walks assume that approx. 15-20% of all cancers are caused by inflammation (see study examples). A middle ground must therefore be found between promoting sensible inflammation and minimizing damaging inflammatory processes, and in particular undesirable chronic inflammation must be avoided or ended with measures that are as gentle as possible.
d) immune system and cancer
In the medical specialist literature one repeatedly finds information that up to 20% of all cancers are caused by infections or a weak immune system (see study examples). The immune system should act as the body's strong guard against cancer threats. It initially has the task of chronic inflammation (e.g. chronic hepatitis) or biological pollutants (e.g. oncogenic viruses such as EBV, HHV-8 , HTLV or HPV) in advance of any changes in body cells triggered by this and to prevent mutations. To do this, the immune system must function optimally and perceive these dangers without exception. This is hardly possible, for example, with a (also therapeutically) suppressed immune system. Next, the immune system has to destroy degenerated and no longer repairable body cells. This is more difficult because damaged cells are also endogenous cells and initially their antigens are not recognized by the immune system. However, since damaged cells can trigger inflammation and certain tumor-specific antigens can arise as a result of genetic reprogramming or oncogenic viruses, they are often presented to the immune system for destruction after all.
The defense against tumor cells roughly corresponds to the fight against intracellular pathogens. Tumor cells are destroyed by cytotoxic T cells, which can trigger apoptosis with the support of T helper cells, B cells and their antibodies, as well as NK cells and the complement system. And finally, the immune system must be able to protect the body, which has been weakened as part of cancer therapy, e.g. from uncontrolled proliferation of remaining cancer cells or from new infections, which is why any disease- and therapy-related immunosuppression quickly and must be eliminated with few side effects. This is made more difficult by the fact that the tumor defends itself against the immune system and tries to evade its surveillance by forming a "camouflage net". Tumor cells divide very quickly, often mutate spontaneously and permanently change their properties. In addition, there is often already a tolerance of the immune system to tumor antigens at the level of the CD4 and CD8 T cells. Tumors also produce cytokines such as TGF-β or IL-10, which reduce inflammation and induce tolerance to T cells, or they produce increased IDO (indoleamine-2,3-dioxygenate), which leads to tryptophan deficiency (which in turn impairs the function of the T cells affected) as well as FASL (ligand of TNF receptor superfamily member 6), which induces apoptosis of T cells.
University oncology is therefore trying to mobilize the immune system against larger tumors that are already visible, but so far this has only been unsuccessful because the immune system is apparently not able to attack or even destroy larger tumors.The oncologists hope, however, that at least micrometastases or tumor residues remaining after the basic therapy can be eliminated by an optimally functioning immune system. Tests are being carried out for this purpose, among other things, passive immunizations with monoclonal antibodies or activation of the complement system, NK cells or macrophages against components of tumor cells. Antibodies are also used to multiply T cells against tumor antigens and NK cells and to reduce VEGF (vascular endothelial growth factor), which promotes the formation of new blood vessels. The use of cytokines such as TNF-α, IL-2 or IFN-α, for example, is being tested for the late non-specific activation of the immune system in tumors that have already been identified.
However, it is probably not sufficient to strengthen the immune system of the already ill person in late therapy (i.e. at the time when university measures usually begin to take effect) with possibly additional stressful medication. Instead, if necessary, the immune system should be modulated long beforehand in prevention and in early therapy with gentle activities and, for example, the humoral and cellular immune system should be strengthened by means of an "immune building program" with micronutrients - to protect against degenerated cells and their later negative consequences.
e) energy balance and cancer
According to a theory by Warburg (1883-1970), which has since been confirmed several times, cancer cells can also gain their energy from the fermentation of sugar (aerobic glycolysis) in the cell cytosol. In this case, you largely do without the combustion of oxygen to form CO2 and H2O in the mitochondria and the use of fats or proteins as an energy source. Glycolysis can take place in two ways, via the so-called "Embden-Meyerhof pathway" and the pentose phosphate pathway, in which the enzyme transketolase-like-1 (TKTL1) plays a key role, because the pentose phosphate pathway is influenced by the quantities formed, among other things is controlled at TKTL1. The additional glycolysis via the pentose phosphate pathway enables the tumor cell to have a higher energy yield.
During fermentation, the cancer cell needs 20 to 30 times the amount of sugar compared to oxygen combustion in the mitochondria to generate sufficient amounts of energy. Unlike normal cells, which typically only use fermentation when there is a lack of oxygen, cancer cells actually use it even in the presence of oxygen. Because of the increased lactate formation with the predominant use of glycolysis, the tissue in the vicinity of the tumor becomes acidic, which on the one hand leads to a disruption of the entire metabolism and also to an improvement in the chances of survival for cancer cells and an increased risk of resistance to chemotherapy and radiotherapy.
An attempt should therefore be made to inhibit energy production by means of fermentation in tumor cells in order to slow down the growth of tumor cells and to make cancer cells more sensitive to therapy. In addition, inhibition of fermentation should be combined with inhibition of ATP formation in tumor cells in order to increase the chances of apoptosis and necrosis as well as sensitization with regard to other therapeutic measures.
Tumor-specific risk factors
In cancer prevention, it is important to have precise knowledge of the individual risks. In addition to the generally applicable risk factors, it seems necessary to know as many specific, recognized risk factors as possible for individual types of tumors, the presence of which makes early therapy seem sensible. These specific factors can e.g.can be looked up in the various oncological guidelines or at the German Cancer Aid (Blue Guide, your cancer risk). The most well-known of these factors are listed in the following tables.
Factor
colorectal carcinoma
breast cancer
prostate cancer
Lungs
Uterus (cervix, endometrium)
Frequency in % (Ø)
16
29w
24m
7w, 14m
3 or 6 w
Alcohol abuse
X
X
-
-
-
age
> 40 years
> 50 years
> 50 years
-
> 50 years
Anamnestic malignancies
X
X
-
X
-
Diabetes mellitus
-
-
-
-
X
Inflammatory diseases
Inflammation of the intestine
-
Prostatitis
-
-
Unbalanced diet, heavy on meat, low in fiber
X
-
X
-
-
Nutrition (more than 1 liter milk per day)
X
-
X
-
-
Genetics
Familial Polyposis
approx. 5% (mainly BRCA-1, BRCA-2)
approx. 5-10 %
X
approx. 5-10% (e.g.HNPCC syndrome)
Sex
-
X
X
-
X
Infections
-
-
-
-
Sexually transmitted HPV
immunosuppression
-
-
-
-
X
Childlessness
-
-
-
-
X
Medications
-
hormone replacement therapy, calcium antagonist
-
-
estrogens, tamoxifen, aromatase inhibitors
early menarche, late menopause
-
-
-
-
X
Nicotine abuse
X
X
-
XX
X
polyps, cysts
intestinal polyps
-
-
-
ovarian cysts
race
-
-
Black
-
-
pollution load
-
-
-
e.g. Asbestos
-
Shift work (especially with night work)
X
X
X
X
-
Sexual partner alternating
-
-
-
-
X
radiation exposure (e.g.through diagnostic or therapeutic medicine, profession)
-
X
-
X
X
Overweight
X
X
X
-
X
Factor
urinary bladder
Malignant melanoma (skin)
head neck tumors
pancreas
Non Hodgkin lymphoma
Leukemia
Frequency in % (Ø)
4w, 8m
1w, 3m
3
3
3
3
Alcohol abuse
-
-
X
-
-
-
Anamnestic malignancies
-
X
-
-
-
-
Diabetes mellitus
-
-
-
X
-
-
Inflammatory diseases
Inflammation of the bladder
-
-
Inflammation of the pancreas
-
-
Unbalanced diet, heavy on meat, low in fiber
X
-
-
-
-
-
Genetics
-
X
-
X
-
-
Skin nevi
-
X
-
-
-
-
immunosuppression
-
X
-
-
-
-
Infections
-
-
Eppstein Barr
-
Eppstein Barr
HTLV
Medications
cyclophosphamide, phenacetin
Arsenic
-
-
-
cytostatics, immunosuppressants
mouth hygiene lacking
-
-
X
-
-
-
Nicotine abuse
X
-
X
X
-
X
race
-
fairness
-
-
-
-
pollution load
e.g. aromatic amines
-
X
-
-
X
shift work (especially with night work)
X
-
-
X
X
X
radiation exposure (eg.through diagnostic or therapeutic medicine, profession)
-
UV light
X
-
-
X
Radiation exposure (living within 5 km to nuclear power plant)
X
Factor
Ovaries
Testicles
Liver
stomach
kidney
Frequency in % (Ø)
5w
2m
<1
4
4
Alcohol abuse
-
-
X
X
X
age
X
-
-
-
-
Anamnestic malignancies
-
X
-
-
-
Cystic kidney disease
-
-
-
-
X
Iron storage disease
-
-
X
-
-
Inflammatory diseases
-
-
-
stomach lining
-
Unbalanced diet, heavy on meat, low in fiber
-
-
-
-
X
birth weight low
-
X
-
-
-
Genetics
X
X
-
X
X
Sex
-
X
-
-
-
undescended testicles
-
X
-
-
-
Infections
-
-
hepatitis, moulds
Helicobacter pylori
-
Childlessness
X
-
-
-
-
Cirrhosis of the liver
-
-
X
-
-
Medications
-
-
-
-
painkillers
Nicotine abuse
-
-
-
X
X
Estrogen levels ↑ (mother or man)
-
X
-
-
-
reflux esophagitis
-
-
-
X
-
pollution load
-
-
X
X
X
Overweight
-
-
-
-
X
Factor
pharynx larynx
thyroid
Esophagus
Penis
Frequency in % (Ø)
1-2
2w, 1m
1w, 2m
<1
Alcohol abuse
X
-
X
-
Diabetes mellitus
-
-
-
-
Unbalanced diet, heavy on meat, low in fiber
X
-
-
-
Genetics
-
X
X
-
Infections
-
X
-
HPV
Oral hygiene lacking
X
-
-
-
Nicotine abuse
X
-
X
-
reflux esophagitis
-
-
X
-
pollution load
X
-
-
-
SD node cold
-
X
-
-
radiation exposure (e.gB by diagnostic or therapeutic medicine, profession)
-
X
-
-
Overweight
-
-
X
-
Cancer risk factors and types of cancer that trigger these factors preferentially
If, after knowing the basic data, we want to decide in the direction of "early cancer therapy" at a point in time when the tumor is still too small to be generally visible, tumor markers, ultrasound examinations or whole-body CT scans bring this at a very early stage Tumor stage often no reliable results. However, the laboratories in particular offer a large number of further diagnostic parameters, which are tables are listed.
Primarily measures the quality of the defense, says little about tumor-specific defense (since tumor cells are mostly camouflaged, at least initially )
Immune system advanced (tumour phase II)
lymphocyte differentiation, B cells, T cells, T helper cells, naive helper cells, memory cells, IL-2 expressing helper cells, T suppressor cells, NK cells, T-cytotoxic suppressor cells, activated killer cells, neopterin, CD 25, CD 69, TGFβ
Indication of tumor-associated changes in immune competence and help in therapy decisions, therapy monitoring
Inflammation screening
hsCRP, TNFα, histamine, IP-10 IL-1, IL-6, NFkB
Indications of acute or chronic inflammation
Detox Screening Detox advanced
GSH (intracellular) Paracetamol, caffeine metabolite test GSH/GSSG
Indications of the quality of the detoxification function
Screening of oxidative-nitrosative stress Oxidative-nitrosative stress advanced
Non-specific tumor marker, Independent of the primary tumor and generally applicable
mutation of the gene p53
capacity for apoptosis unspecific (prognostic factor for various tumors)
p53 autoantibody
Non-specific tumor marker positive in 10-30% of tumors (healthy cells are p53 autoantibody negative)
Apo10 antigen
Non-specific tumor marker (healthy cells are Apo10-negative), which indicates disturbances in apoptosis of tumor cells
Cyp1B1 enzyme (from the cytochrome p450 family)
Non-specific tumor marker (according to Dr. Dan Burke, healthy cells are Cyp1B1 negative)
Chemosensitivity test
Tumor tissue is treated with medication in order to find the most suitable substance for the tumor in question
CEA (carcinoembrional antigen) tumor associated antigen
Highly specific, especially for colon-Ca (80%) and less specific for pancreatic-Ca (60%), mamma-Ca (55%) and bile-duct and bronchial-Ca (50%) or similar tumors
PSA (prostate specific antigen) Tissue specific antigen
In suspected prostate Ca
TG (thyroglobulin), hCT (human calcitonin)
In suspected thyroid Ca
AFP (α1-fetoprotein)
In suspected liver Ca, teratoma
AFP and HCG (human chorionic gonadotropin)
In suspected germ cell tumors (testicles, ovary)
CA 72-4
In case of suspected stomach-Ca, breast-Ca
Monoclonal immunoglobulins and Bence Jones proteins
In suspected multiple fibroids
CA 19-9, CA 195, TPA
In suspected pancreas-.Ca
CA 15-3, CA 549, MCA (Mucin-like Carcinoma Associated Antigen)
In suspected mammary ca
CA 24, CA 50
In suspected intestinal Ca, pancreatic Ca
CA 125
In suspected gastric Ca
NSE (neuron-specific enolase)
In suspected bronchial Ca, neuroblastoma
CYFRA 21-1 (cytokeratin fragment)
In suspected bronchial Ca
Skeletal alkaline phosphatase (ostasis, bone AP)
In suspected bone metastasis11
SCC (squamous cell carcinoma antigen)
In V.a.Cervical Ca
Bence Jones proteins and beta-2 microglobulin
In suspected plasmacytoma
5-S-cysteinyldopa
In suspected malignant melanoma
neopterine, ß2-microglobulin
In suspected leukemia, lymphoma
BTA (bladder tumor antigen)
In suspected bladder Ca
M2-PK
In suspected renal cell carcinoma, colon and rectal carcinoma
5-HIES (5-hydroxyindoleacetic acid)
In suspected carcinoid (especially in the gastrointestinal tract)
protein S100
Prognostic factor in malignant melanoma
HER2-neu oncogene
Prognostic factor in mamma-Ca
BRCA 1+2 gene mutations
Indication of breast cancer risk
Approaches for meaningful backup diagnostics in practice (including common tumor markers)
Sample questionnaire for a "cancer check"
The below Of course, questionnaires do not replace medical diagnostics, but serve to raise awareness of one's own cancer risk by asking about some relevant cancer risk factors. Even if all questions are answered in the negative, this is of course not to be understood as meaning that there is no risk of cancer.
YES
Has one or more relatives in your family had any of the following cancers: breast cancer, colon cancer, ovarian cancer, uterine cancer, stomach cancer?
Have there been periods of prolonged alcohol abuse in your life?
Have you ever had cancer in the past?
Do you have diabetes mellitus?
Have you ever had an inflammatory disease (e.g. of the intestines, prostate, bladder, pancreas, gastric mucosa, reflux oesophagitis)?
Have or do you have colon polyps?
Have or do you have ovarian cysts (valid only for women)?
Are you childless (valid only for women)?
Did you or your mother have elevated estrogen levels (valid only for men)?
Have or do you have birthmarks?
Have or do you have cold thyroid nodules?
Have you had or do you have an iron storage disease?
Do you have cystic kidney disease?
Did you have a low birth weight?
Did you have or do you have undescended testicles?
Would you be able to say that your oral hygiene is inadequate?
Is your diet rather unbalanced, heavy on meat, low in fibre?
Do you drink more than 1 liter of milk per day?
Have or do you have conspicuous infectious diseases (e.g.STDs, HPV, Eppstein-Barr, HTLV, AIDS, hepatitis, mold, Helicobacter pylori)
Do you have a known weakness of the immune system or immunosuppression?
Is there childlessness (valid only for women)?
Did you take or do you take medication over a longer period of time, such as calcium antagonists, contraceptives, estrogens, tamoxifen, phenacetin, painkillers, cyclophosphamide, arsenic, cytostatics, immunosuppressants or so-called aromatase inhibitors?
Did your menarche occur rather early (valid only for women)?
If you have already had menopause, did it come on late (valid only for women)?
Do you smoke or have you smoked regularly for a long time?
Have you been or are you exposed to pollutants over a longer period of time (e.g. asbestos, mercury, aromatic amines)?
Shift work (particularly with night work)
Do you have frequently changing sexual partners?
Are you or were you exposed to increased radiation (e.g. from UV light, job, diagnostic or therapeutic medicine)?
Do you live - or have you lived - within a 5 km radius of a nuclear power plant?
Are you overweight?
If you answered "yes" to one or more of these questions, it is likely that you are at increased risk of cancer. In this case, be sure to discuss with your therapist what further steps should be taken.
Important micronutrient groups for general cancer prevention
micronutrient
Special features (general effects)
Antioxidants (e.g. Vit. C, Vit E, glutathione)
have an antioxidant effect (protect cells from damage caused by radicals), support detoxification, reduce the overall risk of cancer
Cave: Distance to inorganic selenium and in late therapy distance to free-radical-forming cytostatics and to radiation
Vitamin E (most effective as natural Vit E with all tocopherols)
Antioxidant, anti-inflammatory, has anticancer activity in its own right and inhibits growth and mitosis of cancer cells, probably only in high pharmacological doses
glutathione
Antioxidant, detoxifying, strengthens repair and apoptosis mechanisms, reduces cancer cell and tumor growth, improves tolerability of the basic therapy without damaging healthy cells In late therapy, possibly tumor cell protection factor (protection from therapeutic radicals) and possibly Multi-drug resistance (when levels ↑)
Antioxidant, anti-inflammatory, antiproliferative, Cave high-dose phytoestrogens in Re+ breast cancer (KI under hormone therapy)
selenium (inorganic) standard substance
reduces resistance and angiogenesis caveat: distance to Vit C
iron
Iron deficiency is common in cancer patients and must be optimally treated
zinc
Immune balancing, possibly inhibits tumor cell apoptosis (administration after basic therapy and in case of deficiency)
B vitamins
poss. B12 administration only after basic therapy and in case of deficiency as well as combined with Vit C (high doses of B12 may increase tumor cell growth), other B vitamins unproblematic
vitamin D
Anti-inflammatory, inhibits cell proliferation and angiogenesis, promotes apoptosis and cell differentiation, reduces tumor growth and metastasis
Lead substances in cancer therapy and a proven effect on certain types of cancer
Effect
substance
cytotoxic activity
Vit C (increases cytotoxicity in general, especially of doxorubicin, cisplatin, docetaxel, paclitaxel, dacarbazine, epirubicin, irinotecan, 5-FU, bleomycin, carboplastin and gemcitabine as well as that of arsenic trioxide in hematological diseases) selenium (increases cytotoxicity of taxol, doxorubicin, does not reduce cytotoxicity of radiation on cancer cells) quercetin (enhances cytotoxicity of cisplatin, busulfan) β-carotene (enhances cytotoxicity of 5-FU, adriamycin, etoposide, melphalan, cyclophosphamide) γ-linolenic acid and oleic acid (enhance cytotoxic effect of docetaxel, paclitaxel) Vit E (enhance cytotoxic effect of cisplatin)
Increase in response rate and prolongation of survival time
Vit C, Vit E and β-carotene (with paclitaxel, carboplatin), antioxidants (general), omega-3 fatty acids
Enhancement of tamoxifen effect
Genistein (in Re-neg breast cancer), Vit D, γ-linolenic acid, coenzyme Q10,Vit B2 and Vit B3
Increase in the number of therapy cycles
glutathione
Improvement of the operation success (e.g.Improvement of wound healing, reduction of infection risk and organ failure)
Antioxidants (such as Vit C, Vit E, glutathione) Selenium Zinc L-arginine, L-glutamine Omega-3 fatty acids Probiotics
improvement of radiation success
resveratrol, proteases, selenium
synergistic effects of micronutrients on the university basic therapy
The benefits of the above Micronutrients can be explained from their biochemical effects and from a large number of positive study results:
Antioxidant and detoxifying substances:
The various synergistically complementary antioxidants fulfill important functions in the primary prevention of cancer by detoxifying harmful radicals and other pollutants and make a significant contribution to preventing their fatal carcinogenic effects. The antioxidants that make sense here include vitamin C, vitamin E, vitamin A, glutathione, α-lipoic acid, coenzyme Q10 and phytochemicals (polyphenols, carotenoids) as well as cofactors of enzymatic antioxidants such as selenium, manganese, zinc or iron.
Anti-inflammatory and immune-modulating substances: Omega-3 fatty acids and vitamin D as well as zinc, selenium and secondary plant substances have proven their worth in this function. In addition to anti-inflammatory tasks, vitamin D, for example, has important functions for a balanced immune system (acts as a regulator in the immune system, activates macrophages and the formation of endogenous antibiotics) and for calcium metabolism.
In addition to these substances, other substances described in the above table are directly or indirectly involved in the optimization of metabolism, energy balance and repair mechanisms - such as Resveratrol:
Resveratrol
Using the example of the secondary plant substance resveratrol, some mechanisms of action of micronutrients for prevention (and possibly unavoidable later tumor therapy) will be described in more detail: Secondary plant substances such as resveratrol are active in all three phases of cancer formation and cancer development and can be used as a chemopreventive substances against cancer initiation, but also against cancer promotion and cancer progression for a wide use, which is why they can also be used in a complementary manner in the basic treatment of the disease.
Resveratrol initially has a primary preventive effect as a potent antioxidant and anti-inflammatory agent and has a positive effect on mitochondrial function and transcription factors. It blocks the activation of carcinogens and affects cancer initiation (phase I). It protects DNA from oxidative damage through its antioxidant effects and the promotion of the formation of antioxidant enzymes (e.g. catalase, superoxide dismutase and hemoxygenase-1). In connection with its anti-inflammatory effect, it alters gene expression and signal transduction pathways, e.g. by inhibiting transcription factors such as EGR-1, AP-1 and NFkB including a reduction in phosphorylation and degradation of the NFkB inhibitor IκBα. In addition, it probably prevents the activation of the aryl hydrocarbon receptor (AhR), which controls cell differentiation and cell growth.
Resveratrol influences numerous other transcription factors such as multi-drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and FlATPase as well as NFKB, STAT3, HIF-1α, β-catenin and PPAR-y.It blocks the transcription of the Cyp1A1 gene and reacts with the enzymes Cyp-1A1 and Cyp-1B1 (from the cytochrome p450 family) produced by mutant cells. These enzymes can have a pro-carcinogenic effect and create therapy resistance because they inactivate chemotherapeutic agents such as tamoxifen or docetaxel. The reaction of resveratrol with Cyp 1B1 also produces the resveratrol metabolite and tyrosine kinase inhibitor piceatannol, which activates apoptosis of tumor cells. The hypoxia-inducible transcription factor-1α (HIF-1α) is overexpressed in many human tumors and their metastases and is closely associated with an aggressive tumor phenotype. Resveratrol inhibits both basal levels and accumulation of the HIF-1α protein in cancer cells. It reduces the activities of the hypoxia-induced VEGF promoter and the release of VEGF as well as the activity of various protein kinases in cancer diseases, which also leads to a significant decrease in the accumulation of the HIF-1α protein and the activation of the VEGF transcription.
Resveratrol also significantly inhibits the invasiveness of cancer cells. In its role in detoxification processes, it inhibits phase I enzymes that can activate procarcinogens and promotes the formation of phase II enzymes that contribute to detoxification of carcinogens. It thereby improves DNA stability, influences cell differentiation and cell transformation and prevents the development of preneoplastic lesions and tumor formation in the mouse cancer model.
Resveratrol acts in secondary prevention or early therapy on various factors involved in tumor promotion and tumor progression and thereby inhibits tumor cell count, tumor growth and tumor spread. Here, too, it is initially involved in the downregulation of inflammatory processes in several ways. It inhibits synthesis and release of pro-inflammatory and carcinogenic substances such as TNF, COX-2, ornithine decarboxylase (key enzyme in polyamine biosynthesis), 5-LOX, VEGF, IL-1, IL-6, IL-8, AR, PSA, iNOS and CRP. It blocks activated immune cells, as well as nuclear factor B (NF-B) and AP-1, and it blocks AP-1-mediated gene expression.
Furthermore, resveratrol inhibits division and growth of tumor cells. It induces cell cycle arrest in S, G or M phase. It modulates cell cycle regulatory genes such as p53, Rb, PTEN, cyclin A, cyclin B1, cyclin E, Stat3-regulated cyclin D1 and CDK, while inducing p53-independent and p21 expression-mediated cell cycle inhibition.
Resveratrol suppresses angiogenesis, which is important for tumor growthby reducing the expression of VEGF and other angiogenic and pro-metastatic gene products (e.g. MMP's, cathepsin D and ICAM-1) . It inhibits DNA synthesis by blocking ribonucleotide reductase or DNA polymerase and altering biomarker expression.
Resveratrol promotes pro-apoptotic factors and induces programmed cell death (see figure), which is essential for protection against cancer and in which two main forms can be distinguished: "deadly" autophagy (programmed cell death type II ) and apoptosis (programmed cell death type I).
Factors affecting programmed cell death in cancer
Apoptosis is the better known form of programmed cell death and can be initiated either extrinsically or intrinsically.
The extrinsic pathway begins with the binding of a ligand (e.g. TNF or similar cytokines) to a receptor of the TNF receptor family (e.g. CD95), which triggers the caspase cascade and leads to apoptosis.
In the intrinsic pathway, DNA damage activates tumor suppressors such as p53.P53 stimulates substances of the pro-apoptotic Bcl-2 family (Bax, Bad), which release cytochrome C from mitochondria and thereby in turn trigger the caspase cascade and subsequent apoptosis
Apoptosis can be suppressed by anti-apoptotic substances of the Bcl-2 family (Bcl-2, Bcl-xL) and by protein kinase B and IAP (inhibitor of the apoptosis protein). The induction of programmed cell death by resveratrol occurs through expression of the pro-apoptotic proteins Bax, p53 and p21 as well as through depolarization of mitochondrial membranes and activation of CD95 independently Caspases (e.g. caspase-9, caspase-3).
Resveratrol also inhibits anti-apoptotic influences and inhibits various protein kinases in cancer cells such as IκBα kinase, src, JN kinase, MAP kinase, protein kinase B, protein kinase D as well as the COX-2 mRNA and TPA-induced protein kinase C and casein kinase 2. It represses the expression of anti-apoptotic genes and gene products such as Clap-2, Bcl-2, Bcl-xL and XIAP. It blocks the release of survivin by inhibiting survivin mRNA and activating sirtuin deacetylase. Survivin is produced by cancer cells and is one of the inhibitors of the apoptosis proteins that are secreted in most human cancers. It can inhibit mitochondria-dependent apoptosis and facilitate aberrant mitotic progression by inactivating the cell death protease caspase-9.
Resveratrol can also be used to support late cancer therapy. It sensitizes tumor cells to other therapies and shows its own cytotoxic activity. It can synergistically improve the effects of chemotherapy and radiation and can reduce both side effects and resistance to chemotherapy drugs.
In addition to resveratrol, a similar effect has been described for many other secondary plant substances, such as the epigallocatechin-3-gallate (EGCG) in green tea , which blocks an important enzyme in the proliferation of cancer cells. The less well-known phytochemicals include the protease inhibitors, which are mainly found in soybeans, legumes and various grains. They are also said to have a good anti-cancer effect, which is also reflected in the fact that synthetic protease inhibitors such as bortezomib are now being used in university oncology. Particularly interesting is the approach that resveratrol has a positive synergistic effect with other phytochemicals (e.g. quercetin) and that none of the processes influenced by resveratrol have any significant cytotoxicity towards healthy cells.
Selected studies on resveratrol in oncology
Resveratrol acts as a cancer chemopreventive agent. Here we discovered a new function of resveratrol: resveratrol is a potent sensitizer of tumor cells to tumor necrosis factor-dependent apoptosis-inducing ligand (TRAIL)-induced apoptosis through a p53-independent induction of p21 and linked to p21-mediated cell cycle inhibition with a depletion of survivin. Simultaneous analysis of cell cycle, survivin expression and apoptosis showed that resveratro-induced G(1) inhibition was associated with down-regulation of survivin expression and sensitization to TRAIL-induced apoptosis. Accordingly, G(1) inhibition by the cell cycle inhibitor mimosine or by overexpression of p21 t reduced survivin expression and sensitized cells to TRAIL treatment.Resveratrol-mediated cell cycle inhibition with subsequent survivin depletion and sensitization to TRAIL was impaired in p21-deficient cells. Down-regulation of survivin with survivin antisense oligonucleotides also sensitized cells to TRAIL-induced apoptosis. Importantly, resveratrol sensitizes various tumor cell lines, but not normal human fibroblasts, to dead receptor ligation or anticancer drug-induced apoptosis. This combined sensitizer (resveratrol) and inducer (e.g. TRAIL) strategy may be a new approach to improve the efficacy of TRAIL-based therapies in a variety of cancers. (Fulda S, Debatin KM ; Sensitization for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by the chemopreventive agent resveratrol; Cancer Res 2004; 64; 337-346)
Resveratrol is a chemopreventive agent against cancer. It has been shown to be anti-oxidant and anti-mutagenic, and thus an anti-initiation agent. Resveratrol selectively represses the activation of cytochrome P-450 1A1 transcription and inhibits the formation of carcinogen-induced preneoplastic lesions in the mouse model. It also inhibits the formation of 12-OTetradecanoylphorbol-13-Acetate (TPA) promoted skin tumors in the two-phase model. The enzymatic activity of COX-1 and -2 is inhibited in cell-free models and the COX-2 mRNA- and TPA-induced activation of protein kinase C and the AP-1-mediated gene expression are suppressed by resveratrol in mammary epithelial cells. In addition, resveratrol strongly inhibits the generation of nitric oxide and the expression of the iNOS protein. NFκB is closely associated with inflammatory and immune responses, and with oncogenesis in some models of carcinogenesis. Resveratrol suppresses the induction of this transcription factor. The mechanism also involves a decrease in phosphorylation and degradation of IκBα. At the cellular level, resveratrol induces apoptosis, cell cycle delay, or blockage of the G1→S transition phase in a variety of cell lines. (Bhat K, Pezzuto JM; Cancer Chemopreventive Activity of Resveratrol, Annals of the New York Academy of Sciences 2006; 957; 210-229)
Resveratrol works against inflammation and disease by modulating many different pathways. It binds to numerous cell signaling molecules such as multi-drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and Fl-ATPase. It activates various transcription factors (e.g. NFKB, STAT3, HIF-1α, β-catenin and PPAR-y), suppresses the expression of anti-apoptotic gene products (e.g. Bcl-2, Bcl-XL, XIAP and survivin) and of protein kinases ( e.g. src, PI3K, JNK and AKT), induces antioxidant enzymes (e.g. catalase, superoxide dismutase and hemoxygenase-1), suppresses the expression of inflammatory biomarkers (e.g. TNF, COX-2, iNOS and CRP), inhibits the expression of angiogenic and metastatic gene products (e.g. MMPs, VEGF, cathepsin D and ICAM-1) and modulates cell cycle regulatory genes (e.g. p53, Rb, PTEN, cyclins and CDK). Numerous animal studies have shown that resveratrol is effective against numerous age-related diseases including cancer, diabetes, Alzheimer's, cardiovascular and lung diseases. Efforts are also underway to improve its effects in vivo through structural modification and reformulation. (Harikumar KB et al.; Resveratrol: a multitargeted agent for age-associated chronic diseases; Cell Cycle 2008; 7; 1020 -1035)
Compelling evidence shows the positive effects of resveratrol on the nervous system, liver, cardiovascular system and cancer chemoprevention.In doing so, it blocks the different phases of carcinogenesis (tumor initiation, promotion and progression). One of the possible mechanisms for its biological activities includes downregulation of inflammatory responses by inhibiting the synthesis and release of pro-inflammatory mediators, altering eicosanoid synthesis, inhibition of activated immune cells of inducible nitric oxide synthase (iNOS) and of cyclooxygenase-2 (COX-2) via its inhibitory effect on nuclear factor B (NF-B) or activator protein-1 (AP-1). Recent data offer interesting insights into the effects of resveratrol on the lifespan of yeast and flies, demonstrating the potential of resveratrol as an anti-aging agent in the treatment of age-related diseases in humans. It must be mentioned that resveratrol has low bioavailability and rapid clearance from plasma. This article considers its potent anti-inflammatory activity and the plausibility of these mechanisms, and provides an update on resveratrol's bioavailability, pharmacokinetics and effects on lifespan. (De la Lastra CA, Villegas I; Resveratrol as an anti -inflammatory and anti-aging agent: mechanism and clinical implications; Molecular Nutrition and Food Research 2005; 49; 405-430)
Resveratrol inhibits growth, S-phase cell cycle arrest and changes in biomarker expression in human cancer cell lines. It differentially reduces the expression of cyclin B1, cyclin A, cyclin D1 and beta-catenin. It induces apoptosis. (Joe AK et al.; Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines. Cancer Res .2002;8, 893-903)
Resveratrol inhibits the growth of leukemia cells in culture. It induces leukemia cell differentiation, apoptosis, cell cycle arrest in S phase, inhibition of DNA synthesis by blocking ribonucleotide reductase or DNA polymerase. (Tsan MF et al.; Anti-leukemia effect of resveratrol.Leuk.Lymphoma 2002;43, 983-987)
Resveratrol reduces human colon cancer cell growth by 70%. The cells accumulated in the S/G2 phase transition of the cell cycle. Resveratrol significantly reduces the activity of ornithine decarboxylase (a key enzyme in polyamine biosynthesis involved in cancer growth). (Schneider Y et al.; Anti-proliferative effect of resveratrol, a natural component of grapes and wine , on human colonic cancer cells.Cancer Lett. 2000; 158, 85-91)
Resveratrol significantly reduces tumor growth in rapidly growing rat tumors and leads to an increase in the number of cells in the G2/M cell cycle phase. It induces apoptosis and leads to a decrease in cell numbers. (Carbo N et al; Resveratrol, a natural product present in wine, decreases tumor growth in a rat tumor model. Biophys. Res Commun 1999;254, 739-743)
Resveratrol induces apoptosis in more than 80% of CD95-sensitive and CD95-resistant acute lymphoblastic leukemia (ALL) cells by depolarizing mitochondrial membranes and by activating caspase-9, independent of CD-95 signaling. There is no significant cytotoxicity to normal peripheral blood cells. (Dorrie J et al.; Resveratrol induces extensive apoptosis by depolarizing mitochondrial membranes and activating caspase-9 in acute lymphoblastic leukemia cells. Cancer Res. 2001; 61, 4731-4739 )
Resveratrol (200 mcg/kg) significantly reduces carcinogenesis of colon cancer in rats. It significantly reduces cell number and alters bax and p21 expression. (Tessitore L et al.; Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21 (CIP) expression Carcinogenesis 2000; 21, 1619-1622)
Resveratrol develops antiproliferative activity. It inhibits proliferation and induces cytotoxicity and apoptosis in cells of Waldenstrom's macroglobulinemia (WM). Peripheral blood cells are not affected. Resveratrol shows synergistic cytotoxicity when combined with dexamethasone, fludarabine and bortzomib. (Roccaro AM et al.; Resveratrol Exerts Antiproliferative Activity and Induces Apoptosis in Waldenstrom's Macroglobulinemia; Clin. Cancer Res 2008; 14: 1849-1858)
Resveratrol acts on all three stages of carcinogenesis (initiation, promotion and progression) by altering signal transduction pathways that control cell division, cell growth, apoptosis, inflammation, angiogenesis and metastasis. Resveratrol's anti-cancer properties are supported by its ability to inhibit the proliferation of a variety of human tumor cells in vitro and in animal studies. In this review, data from preclinical in vivo studies and interventional studies on cancer and associated mechanisms of action are presented. In addition, bioavailability, pharmacokinetics and potential toxicity of resveratrol as well as its usefulness in cancer are discussed. (Bishayee A; Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials; Cancer Prev Res (Phila Pa) 2009; 2: 409-418)
Resveratrol significantly inhibits cell growth in pancreatic carcinoma cell lines (PANC-1 and AsPC-1) in a concentration- and time-dependent manner and induces cell apoptosis. (Ding XZ et al.; Resveratrol inhibits proliferation and induces apoptosis in human pancreatic cancer cells; Pancreas 2002; 25: e71-76)
Resveratrol has anti-cancer properties and suppresses the proliferation of a variety of tumor cells. The growth inhibitory effect is mediated by cell cycle inhibition with upregulation of p21(CIP1/WAF1), p53 and Bax and downregulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs and activation of caspases. Resveratrol suppresses the activation of transcription factors such as NFkB, AP-1 and EGR-1 and inhibits protein kinases including IkBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II. It downregulates COX2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities are responsible for the suppression of angiogenesis. Resveratrol also enhances the apoptotic effects of cytokines, chemotherapy drugs and radiation. It blocks carcinogen activation by inhibiting CYP1A1 expression and activity and suppresses tumor initiation, promotion and promotion. In addition to chemopreventive effects, resveratrol appears to have therapeutic effects against cancer. (Aggarwal BB et al.; Role of Resveratrol in prevention and therapy of cancer: preclinical and clinical studies; Anti-cancer Res 2004; 24; 2783-2840 )
Resveratrol influences (in addition to its protective function on the cardiovascular system) all three stages of cancer development (tumor initiation, promotion and progression). It also suppresses angiogenesis and metastasis. The anti-cancer effects of resveratrol appear to be closely related to its ability to interact with several molecular parameters involved in carcinogenesis while minimizing toxicity in healthy tissues. Therefore, resveratrol should be used in human cancer chemoprevention in combination with chemotherapeutic agents or cytotoxic factors for highly efficient treatment of drug-refractory tumor cells.The anti-carcinogenic potential of resveratrol for cancer chemoprevention and anti-cancer therapy represents, so to speak, a new explanation of the French paradox (Liu BL et al.; New enlightenment of French Paradox: resveratrol's potential for cancer chemoprevention and anti-cancer therapy; Cancer Biol Ther 2007;6:1833-1836)
Several studies have demonstrated the modulating effect of resveratrol on a variety of cell signaling and gene expression pathways. This article summarizes the effects of resveratrol in chemoprevention. (Goswami SK, Das DK; Resveratrol and chemoprevention; Cancer Lett 2009; 284: 1-6)
Resveratrol has a strong growth-inhibiting effect against various human cancer cells. Here, the inhibitory effect of resveratrol on experimental liver cancer is examined using a two-stage model in rats. Resveratrol 50-300 mg/kg body weight reduces the incidence, number, volume and multiplicity of visible hepatocyte nodules in a dose-dependent manner. It leads to a decrease in cell proliferation and an increase in apoptotic cells in the liver. It also induces expression of the pro-apoptotic protein Bax, reduces expression of the anti-apoptotic Bcl-2, and at the same time increases the Bax/Bcl-2 ratio. Due to its favorable toxicity profile, resveratrol has the potential to be developed as a chemopreventive drug against human hepatocellular carcinoma. (Bishayee A, Dhir N; Resveratrol-mediated chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis: inhibition of cell proliferation and induction of apoptosis; Chem Biol Interact 2009;179:131-44)
The aim of this study was to demonstrate interactions of ellagic acid and quercetin with resveratrol (polyphenols) in inducing apoptosis and reducing cell growth in human leukemia cells (MOLT-4). The combination of ellagic acid with resveratrol has a synergistic effect more than additive. Both substances alone and together induce significant changes in cell cycle kinetics. There are positive synergistic interactions between ellagic acid and resveratrol and between quercetin and resveratrol in inducing caspase-3 activity. The anticarcinogenic potential of foods with polyphenols can be enhanced through synergistic effects. (Mertens-Talcott SU, Percival SS; Ellagic acid and quercetin interact synergistically with resveratrol in the induction of apoptosis and cause translent cell cycle arrest in human lekemia cells; Cancer Lett 2005;218;141-151)
Resveratrol has a cancer-preventive effect and, in physiological doses, induces Bax-mediated and Bax-independent mitochondrial apoptosis in human HCT116 colon carcinoma cells. Both pathways limit the cells' ability to form colonies. (Mahyar-Roemer M et al.; Role of Bax in resveratrol-induced apoptosis of colorectal carcinoma cells; BMC Cancer 2002; 2; 27-36)
Interfering with multistep carcinogenesis by modulating intracellular signaling pathways may provide a molecular basis for phytochemical chemoprevention. Resveratrol has been extensively studied for its chemopreventive activity related to its ability to intervene in multistage carcinogenesis. Numerous intracellular signaling cascades converge with the activation of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), which act independently or coordinately to regulate expression of target genes. These ubiquitous eukaryotic transcription factors mediate pleiotropic effects on cellular transformation and tumor promotion.The aim of this review is to update the molecular mechanisms of resveratrol chemoprevention with particular attention to its effect on cellular signaling cascades mediated by NF-kappaB and AP-1.Resveratroldownregulates Survivin significantly in a dose- and time-dependent manner and the cell cycle, induces apoptosis and enhances the effects of chemotherapeutic agents in multidrug-resistant non-small cell lung cancer cells. (Zhao W et al.; Resveratrol down-regulates surviving and induces apoptosis in human multidrug-resistant SPC -A-1/CDDP cells; Oncology Reports 2010;23;279-286)
Resveratrol has antineoplastic activity. It inhibits the growth and induces the death of ovarian carcinoma cells (more via autophagy than via apoptosis), inter alia associated with caspase activation. It thus induces cell death via 2 different pathways: non-apoptotic and apoptotic (via release of the anti-apoptotic proteins Bcl-xL and Bcl-2) (Opipari AW et al.; Resveratrol-induced autophagy in the ovary Cancer Cells; Cancer Research 2004; 64, 696-703)
Resveratrol inhibits Src tyrosine kinase activity, thereby blocking activation of the constitutive signaling and transcription activator-3 (Stat3) protein in malignant cells. Analyzes of resveratrol-treated malignant cells harboring constitutively active Stat3 show irreversible cell cycle arrest of v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), human mammary (MDAMB-231), pancreatic (Panc-1 ) and prostate carcinoma (DU145) cell lines in G0-G1 or S phase human breast cancer (MDA-MB-468) and pancreatic cancer (Colo-357) cells, and loss of viability due to apoptosis. In contrast, cells treated with resveratrol but lacking aberrant Stat3 activity show reversible growth arrest and minimal loss of viability. Furthermore, in malignant cells that harbor constitutively active Stat3, including human prostate cancer DU145 cells and v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), resveratrol represses Stat3-regulated cyclin D1 as well as Bcl-xL and Mcl-1 genes, suggesting that resveratrol's anti-tumor cell activity is due in part to blockade of Stat3-mediated dysregulation of growth and survival pathways. Our study is among the first to identify Src-Stat3 signaling as a target of resveratrol, define the mechanism of resveratrol's antitumor cell activity, and demonstrate its potential for application to tumors with an activated Stat3 profile. (Kotha A et al.; Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein; Mol. Cancer Ther 2006; 5: 621 – 629)
Hypoxia-inducible factor-1α (HIF-1α) is overexpressed in many human tumors and their metastases and is closely associated with an aggressive tumor phenotype. In this study we investigated the effect of resveratrol on the accumulation of the hypoxia-induced HIF-1α protein and the expression of vascular endothelial growth factor (VEGF) in squamous cell carcinoma of the tongue and in hepatoma cells. Resveratrol markedly inhibits both basal levels and accumulation of hypoxia-induced HIF-1α protein in cancer cells, but not HIF-1α mRNA levels. Pretreatment of the cells with resveratrol markedly reduced the activities of the hypoxia-induced VEGF promoter and the release of VEGF at both the mRNA and protein level.The mechanism of resveratrol's inhibition of hypoxia-induced HIF-1α accumulation appears to involve a shortened HIF-1α protein half-life caused by increased degradation of proteins by the 26S proteasome system. In addition, resveratrol inhibits hypoxia-mediated HIF-1α accumulation Activation of extracellular signal-regulated kinase 1/2 and Akt, resulting in a marked decrease in accumulation of the hypoxia-induced HIF-1α protein and activation of VEGF transcription. Resveratrol also markedly inhibits the hypoxia-stimulated invasiveness of cancer cells. These data indicate that HIF-1α/VEGF could represent a promising target for resveratrol in the development of effective chemoprevention and therapy for human cancers. (Zhang Q et al.; Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1{alpha} and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells; Mol
Many recent studies have shown promising health benefits of red wine. This article provides an overview of some of the most important studies and the mechanisms for these beneficial effects. It has been shown that these positive effects are due to polyphenols in red wine, especially resveratrol in grape skins. These effects include a reduction of approximately 30% to 50%, 57%, and 50% in cardiovascular morbidity and mortality, lung cancer, and prostate cancer. Polyphenols possess antioxidant, superoxide scavenging, ischemia preconditioning, and angiogenesis properties. Some of these properties of polyphenols may explain their protective effects on the cardiovascular system and other organs of the body. Therefore, the United States Department of Health and Human Services recommended moderate alcohol consumption in their national health promotion and prevention initiative, Healthy People 2010. (Review; Vidavalur R et al.; Significance of wine and resveratrol in cardiovascular disease: French paradox revisited;Exp Clin Cardiol.2006;11:217-225)
Vitamin C
Vitamin C in particular plays an outstanding role in cancer therapy (see figure). Several different mechanisms of action of the substance come into play:
The antioxidant effect, for which there is sufficient evidence for use in supportive oncological therapy. In this way, vitamin C protects healthy cells and leads to a reduction in side effects as well as an improvement in the effect of usual therapy and an improvement in the quality of life
The cytotoxic effect on cancer cells especially with high-dose parenteral administration. As with radiation and some chemotherapeutic agents, it is mediated by the formation of H2O2 via anti-proliferative, but especially via pro-oxidative effects. With oral vitamin C administration, a cytotoxic effect was only found in early therapy, where it can also reduce the level of tumor markers, for example, but not in late therapy (e.g. Creagan, Moertel et al.; 1979) . This can be explained by the fact that with oral intake, the absorbed amounts of vitamin C are too low to achieve sufficiently high plasma levels over a longer period of time for a cytotoxic effect in the sense of apoptosis and autophagy in tumors that are already visible. On the other hand, there is sufficient evidence that parenteral vitamin C in pharmacological doses in late therapy achieves sufficient effective levels from approx. 25-30 mmol/l and, above all, in combination with other active substances, taking into account any possibleInteractions with chemotherapeutic agents and radiation in a wide variety of tumor forms in first-line chemotherapy is useful - without fear of systemic toxicity or damage to healthy cells
Vitamin C also has an anti-inflammatory effect, activates collagen formation, increases the cytotoxic potency of chemotherapeutic agents, reduces side effects such as pain, fatigue, vomiting or loss of appetite and contributes to improving the quality of life of tumor patients.
Antioxidant and prooxidative effects of vitamin C in oncology
selenium
Similar to vitamin C, selenium also plays a key role in the early and late treatment of malignant tumors.
It has antineoplastic and tumor-selective cytotoxic effects, inhibits tumor growth, invasion and angiogenesis and improves the detectability of tumor tissue
It promotes apoptosis of non-repairable cells (e.g. via activation of p53, p21, BAX and cytochrome C)
It increases the expression of selenium-dependent enzymatic antioxidants
It activates NK cells and potentiates the antitumor cytotoxicity of NK cell-based immunotherapies
It protects healthy cells and reduces side effects of basic therapy without loss of effectiveness
It has a prophylactic effect against lymphedema and erysipelas
It reduces the risk of resistance and sensitizes resistant tumor cells to therapy again
It reduces the risk of metastasis and recurrence as well as mortality
A selenium undersupply reduces the chances of success of basic university therapy, a good selenium supply and additional selenium doses increase it
Selected studies on selenium in oncology
CD94/NKG2A controls the activity of NK cells. Selenite reduces the expression of HLA-E on tumor cells and can potentiate the antitumor cytotoxicity of NK cell-based immunotherapies. (Enquist M et al.; Selenite induces posttranscriptional blockade of HLA-E expression and sensitizes tumor cells to CD94/NKG2A-positive N cells; J Immunol 2011; 187; 3546-3554)
Selenite oxidizes polythiols to corresponding disulfides and does not react with monothiols. It makes cancer cells more vulnerable to immune system surveillance and destruction. It activates NK cells and inhibits angiogenesis. (Lipinski B; Rationale for the treatment of cancer with sodium selenite; Med Hypotheses 2005; 64; 806-810)
Redox-active selenium inhibits the growth of cancer cells and has tumor-selective cytotoxic effects without resistance development. (Wallenberg M et al.; Selenium cytotoxicity in cancer; Basic & Clinical Pharmacology & Taxocology 2014; 1-10)
Low doses of selenium promote cell growth, high concentrations inhibit it. Selenium induces apoptosis of malignant cells and does not affect normal cells. (Björnstedt M, Fernandes AP; Selenium in the prevention of human cancers. EPMA J 2010;1: 389-95)
Low seleniumconcentrations are essential for cell growth, high concentrations selectively induce cell death in tumor cells. (Selenius M et al.; Selenium and the selenoprotein thioredoxin reductase in the prevention, treatment and diagnostics of cancer. Antioxid Redox Signal 2010;12:867-80)
Selenium can reduce cancer risk as well as progression and metastasis in all cancer types (and specifically in prostate, liver, gastrointestinal and lung cancer), especially in people with a low selenium status (there is a reduction in DNA damage and oxidative stress, among other things). (Rayman MP; Selenium in cancer prevention: a review of the evidence and mechanism of action; Proc Nutr Soc 2005; 64; 527-542)
Seleniumsupplementation increases antioxidant protection through increased expression of selenium-dependent GSHPeroxidase and thioredoxin reductase Selenium protects against cancer: it affects tumor metabolism, the immune system, cell cycle regulation and apoptosis. (Combs GF Jr; Chemopreventive mechanism of selenium; Med Klin 199; 94 Suppl 3; 18-24)
Enzymes
There are basically three main groups of enzymes to be distinguished in therapeutic use in cancer:
the antioxidant enzymes (see under antioxidants)
the detoxifying enzymes (see under detoxification)
the proteolytic enzymes (proteases)
Many of these enzymes require cofactors, coenzymes or co-substrates for their activities, such as B vitamins, iron, zinc, selenium, manganese, magnesium or polyphenols, which belong to the closest group of micronutrients.
The proteases belong to the hydrolases. In complementary oncology, the substances bromelain and papain as well as trypsin and chymotrypsin are mostly used in combination in enteric-coated preparations.
The proteases have an anti-inflammatory effect, for example, improve phagocytosis, stimulate the body's own defences, reduce immune and cytokine complexes as well as adhesion molecules and TGFβ, absorb edema and hematomas and contribute to the unmasking of tumor cells. They are mainly used in late cancer therapy, where they have a synergistic effect with basic university therapy and improve the quality of life. However, they can also be used in early therapy and to prevent metastases, as palliative treatment and in the case of malignant effusions.
Examples of studies and articles on the use of micronutrients in tumor diseases
PREVENTION
i) Risk of cancer in general
Chronic inflammation
Different effects of inflammatory processes on cancer have been described. Acute inflammation usually reduces the development of cancer, while chronic inflammation promotes it. For example, while IL-6 inhibits apoptosis and can promote cancer development, interferons can promote DNA repair and stabilize p53. They have an anti-oncogenic effect. (Philip M et al.; Inflammation as a tumor promoter in cancer induction; Semin Cancer Biol 2004; 14; 433-439)
Chronic inflammation is responsible for up to 20% of all cancers, e.g. inflammatory bowel diseases (Crohn's disease, ulcerative colitis), viral infections, bacterial infections (e.g. caused by Helicobacter pylori), parasitosis, exposure to asbestos , alcohol and nicotine abuse or overweight. They lead to radical overproduction and lipid peroxidation. These are responsible for DNA damage, tumor cell growth, tumor spread and activation of cancer genes. (Deutsches Ärzteblatt; how chronic inflammation leads to cancer; international expert meeting at the German Cancer Research Institute in Heidelberg; March 10, 2006)
Inflammation contributes to the development of about 15% of all cancers. Inflammation and inflammation-induced NFkB protein contribute to uncontrolled cancer cell growth, and macrophages produce substances that stimulate tumor growth, including TNFalpha, which boosts NFkB activity. Tumor cells produce substances such as CSF-1 (colony stimulating factor 1) and COX-2, which in turn promote inflammation. NSAIDs reduce the risk of cancer by reducing inflammation. Components of red wine and green tea act as NFkB inhibitors. (Marx J; Cancer research.Inflammation and cancer: the link goes stronger; Science 2004; 306; 966-968)
Antioxidants
Apples have a high antioxidant capacity, suppress cancer cell proliferation, reduce lipid oxidation and cholesterol. They contain various phytochemicals including quercetin, catechin or phloridzin. The content of phytochemicals varies greatly between different apples and there are also differences in phytochemical content during the ripening process. (Review; Boyer J et al.; Apple phytochemicals and their health benefits; Nutr J 2004; 3; 5)
After 7.5 years, antioxidants (beta-carotene 6 mg, zinc 20 mg, selenium 100 mcg, vitamin C 100 mg, vitamin E 30 mg) significantly reduce the risk of cancer (relative risk 0.69, 95% CI ) and all-cause mortality (risk ratio, 0.63, 95% CI) in males. Note: In women, the results were not available: men had lower blood levels of antioxidants. (Randomized, double-blind, placebo-controlled; 13017 participants; SU.VI.MAX; 2004; Serge Hercberg et al.; Arch Intern Med .2004;164;2335-2342)
All-cause mortality is associated with low levels of carotene and vitamin C (and retinol). Low vitamin E levels are associated with an increased risk of lung cancer and in smokers with an increased risk of prostate cancer. (2974 participants over 17 years; Eichholzer M et al.; Prediction of male cancer Mortality by plasma levels of interacting vitamins; 17-year follow-up of the prospective Basel Study; Int J of Can 1996; 66; 145-150; Stahelin HB et al.; Plasma antioxidant vitamins and subsequent cancer mortality in twelve-year follow-up of the prospective Basel Study. Amer J of Epidem 1991; 133; 766-775)
Vitamin and mineral supplementation (particularly with the combination of beta-carotene, vitamin E, and selenium) reduces the risk of cancer in the Linxian population (RR 0.91; 95% CI). (Randomized, 29584 participants; Blot W et al.; Nutrition intervention trials in Linxian, China: Supplementation with specific vitamin/mineral combinations, cancer incidences and disease-specific mortality in the general population. J of the Nat Can Inst; 1993; 85; 1483-1492)
Low alpha-tocopherol levels increase cancer risk 1.5-fold for various types of cancer, the correlation being strongest for gastrointestinal tumors and for cancers independent of nicotine abuse and for non-smokers with low selenium levels . (36265 participants over 8 years; Knekt P et al.; Vitamin E and cancer prevention; The Amer J of Clin Nutr 1991; 53; 283S-286S)
The risk of malignant melanoma is reduced at the highest versus lowest plasma levels of β-carotene (OR 0.9; 95% CI) and for total vitamin E ( OR 0.7; 95% CI). (452 participants; Stryker WS et al.; Diet, plasma levels of beta-carotene and alpha-tocopherol, and risk of malignant melanoma; Am J Epidemiol 1990; 131: 597-611)
Resveratrol
The inhibition of tumor initiation by resveratrol probably occurs by preventing the activation of the Ah receptor. Resveratrol also affects several factors involved in tumor promotion and progression. Because tumor-promoting agents alter the expression of genes whose products are implicated in inflammation, chemoprevention of cardiovascular disease, and cancer, common mechanisms may exist. This includes, above all, the modulation of the expression of growth factors and cytokines. Recently, chemopreventive properties of resveratrol have been linked to inhibition of NF-kappaB.This transcription factor is closely linked to inflammatory and immune responses and to the regulation of cell proliferation and apoptosis. It is therefore important for tumorigenesis and many other diseases such as atherosclerosis. Although the mechanisms by which resveratrol interferes with NF-κB activation are not clear, it appears that inhibition of its degradation, which is necessary for its cellular activation, is the most important target. Based on the amount and variety of data available on the biological activity of resveratrol, it must be considered as a very promising chemoprotectant and chemotherapeutic agent. (Ignatowicz E et al.; Resveratrol, a natural chemopreventive agent against degenerative diseases; Pol J; Pharmacol 2001; 53; 557-569)
Resveratrol has cancer chemopreventive activity at three key stages of carcinogenesis. It has antioxidant, antimutagenic and induces phase II drug-metabolizing enzymes (anti-initiation activity). It mediates anti-inflammatory effects and inhibits cyclooxygenase and hydroperoxidase functions (anti-promotional activity) and induces differentiation of human promyelocytic leukemia cells (anti-progressive activity). In addition, it prevents the development of preneoplastic lesions in carcinogen-treated mice and inhibits tumorigenesis in the mouse skin cancer model. These data suggest that resveratrol is a potential chemopreventive agent for human use. (Jang MS et al.; Cancer chemopreventive activity of reseveratrol, a natural product derived from grapes; Science; 1997; 275 ; 218-220)
Resveratrol is a chemoprotective substance against skin cancer and activates sirtuin deacetylase. It extends the lifespan of lower organisms and has protective effects against stress and disease. (Baur JA, Sinclair DA; Therapeutic potential of resveratrol: the in vivo evidence; Nature Reviews Drug Discovery 2006; 5, 493 -506)
selenium
In patients with a history of skin cancer, selenium 200 mcg versus placebo did not significantly affect the incidence of basal cell carcinoma and squamous cell carcinoma (RR 1.10 and RR 1.14, respectively; 95% CI). The patients receiving selenium had a non-significant reduction in all-cause mortality (RR 0.83; 95% CI) and a significant reduction in all-cause mortality (RR 0.50; 95% CI) and all-cause incidence (RR 0.63; 95% CI). (Double-blind, rendomized, placebo-controlled; 1312 participants over 8 years (1983-1991); Clark LC et al.; Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group; JAMA 1996; 276; 1957-1963)
Vitamin D
Low vitamin D levels are associated with an increased risk of cancer incidence and mortality in men, particularly in the gastrointestinal system. A 25 nmol/L increase in vitamin D levels is associated with a 17% reduction in overall cancer risk and a 45% reduction in gastrointestinal cancer mortality. (Prospective Cohort Study; Health Professionals Follow-Up Study with 47,800 participants over the age of 14. Giovannucci E et al.; Prospective Study of Predictors of Vitamin D Status and Cancer Incidence and Mortality in Men; JNCI Journal of the National Cancer Institute 2006 98(7):451 -459)
There is a clear association between vitamin D status and the risk of colon, breast, prostate and ovarian cancer. (30 colon, 13 breast, 26 prostate and 7 ovarian carcinomas from 63 clinical studies Garland CF et al.; The role of vitamin D in cancer prevention; Am J Public Health 2006; 96; 252-261)
Calcium
Calcium generally protects women from cancer With doses of more than 1300 mg, there is no increasing risk reduction. Dairy products (eg, 3 cups of low-fat or non-fat dairy products) and calcium dose-dependently protect men (RR 0.84) and women (RR 0.77) from gastrointestinal and especially colorectal cancer. Calcium intake does not correlate with the risk of breast, endometrial, ovarian, and prostate cancer. (Prospective National Institutes of Health-AARP Diet and Health Study (cohort study) over 7 years Park Y et al .; Dairy Food, Calcium, and Risk of Cancer in the NIH-AARP Diet and Health Study; Arch Intern Med 2009; 169; 391-401)
Calcium intake is associated with the overall cancer risk in women and decreases up to a calcium intake of 1300 mg/d. Higher doses do not lower the risk any further. Calcium intake is inversely associated with the risk of gastrointestinal cancer in males and females (RR 0.84; 95 CI in males and RR 0.77; 95% CI in females) and especially colorectal cancer. ( National Institutes of Health-AARP-Diet and Health Study Approximately 500,000 participants over the age of 7 Park Park et al Dairy Food, Calcium, and Risk of Cancer in the NIH-AARP Diet and Health Study Arch Intern Med 2009 169(4):391-401)
selenium
Selenium can activate the p53 tumor suppressor protein (through redox mechanisms) and the DNA repair arm of p53 in cancer prevention (Seo YR et al.; selenomethionine regulation of p53 by a ref1-dependent redox mechanism; Proc Natl Acad Sci USA 2002;99;14548-14553)
Selenium can reduce the risk of cancer as well as the progression and metastasis of all types of cancer (and especially prostate, liver, gastrointestinal and lung cancer), especially in people with low selenium status (there is a reduction DNA damage and oxidative stress). (Rayman MP; Selenium in cancer prevention: a review of the evidence and mechanism of action; Proc Nutr Soc 2005; 64; 527-542)
Low seleniumlevels increase cancer incidence compared to high levels (OR 1.95) cohort study with 4857 participants (Ujiie S et al.; Serum Selenium contents and the risk of cancer; Gan To Kagaku Ryoho 1998;25;1891-1897)
Selenium supplementation increases antioxidant protection through increased expression of selenium-dependent GSHPeroxidase and thioredoxin reductase. Selenium protects against cancer: it affects tumor metabolism, the immune system, cell cycle regulation and apoptosis. (Combs GF Jr; Chemopreventive mechanism of selenium; Med Klin 199; 94 Suppl 3; 18-24)
Selenium has a protective effect on cancer incidence (RR 0.76), particularly pronounced in people with low selenium levels and in high-risk patients. (meta-analysis; Lee EH et al.; Effects of selenium supplements on cancer prevention: meta-analysis of randomized controlled trials; Nutr Cancer 2011; 63; 1185-1195)
People with the lowest selenium levels have a 5.8-fold increased risk of fatal cancer compared to those with the highest selenium levels. It was increased 11.4 times in people with low selenium and low vitamin E levels. A reduced intake of vitamin A or provitamin A increases the risk of lung cancer in smokers with low selenium levels. (Salonen JT et al.; isk of cancer in relation to serum concentrations of selenium and vitamins A and E: matched case-control analysis of prospective data; Br Med J 1985; 290; 4127-420)
High selenium levels (between 130-150 ng/ml) greatly reduce all-cause mortality (HR 0.83), cancer mortality (HR 0.69) and cardiovascular mortality (HR 0.94). high selenium levels (> 150 ng/ml), on the other hand, slightly increase mortality. (13887 participants; Bleys J et al.; Serum selenium levels and all-cause, cancer and cardiovascular mortality among US adults; Arch Intern Med 2008;168;4040-410)
ii) Cancer risk for individual tumor types
Prostate
selenium
Men who are well supplied with selenium in the long term (measurement of the selenium content in toenails) have a lower risk of prostate cancer. (Prospective cohort study; 58279 participants; Geybels MS et al.; Advanced prostate cancer risk in relation to toenail selenium levels; J Natl Cancer Inst 2013; 105; 1394-1401)
There is a 63% lower risk of prostate Ca from selenium 200 mcg. (Randomized, double-blind, placebo-controlled; Clark LC et al.; Decreased incidence of prostate cancer with selenium supplementation; Br J Urol 1998; 730-734 (cf. original study evaluation from 1996 in JAMA 1996; 276; 1957-1963))
Selenium 200 mcg has a significant effect on the total prostate Ca incidence (RR 0.51; 95% CI ) (Randomised, placebo-controlled, double-blind; NPC trial; 1312 participants; Duffield-Lillico AJ et al.; Selenium supplementation, baselone plasma selenium status and incidence of prostate cancer; an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial; BJU international 2003; 91; 608-612)
Low selenium levels are associated with a 4-5-fold increased risk of prostate cancer. (case-control study; Baltimore Longitudinal Study of Aging; 148 participants; Brooks JD et al.; plasma sleenium level before diagnosis and the risk of prostate cancer development; The Journal of Urology; 2001; 166; 2034-2038)
Higher selenium levels are associated with a lower risk of advanced prostate cancer (OR 0.49; 95% CI for highest versus lowest levels). After additional control for family history for prostate cancer, BMI, calcium and saturated fat intake, vasectomy, and geographic region, the OR was 0.35 (95% CI). (Prospective Health Professionals case-control study; 51529 participants; Yoshizawa K et al.;Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer;J Natl Cancer Inst 1998;90:1219-1224)
Inorganic selenium in high doses significantly reduces the growth of primary hormone-refractory prostate carcinomas and the development of retroperitoneal lymph node metastases in the experimental mouse model. (Corcoran NM et al.; Inorganic selenium retards progression of experimental hormone refractory prostate cancer;J Urol 2004;171:907-910)
Selenium reduces the risk of prostate cancer (RR 0.74). (Review, meta-analysis Etminan M et al.; Intake of selenium in the prevention of prostate cancer: a systemic review and meta-analysis ; Cancer Causes Control 2005; 16; 1125-1131)
The risk of prostate cancer decreases with increasing seleniumlevels up to 170 ng/ml. (Hurst R et al.; Selenium and prostate cancer: systematic review and meta-analysis ; Am J Clin Nutr July 2012 vol. 96 no. 1 111-122)
Higher selenium intake reduces the risk of prostate cancer. (Van den Brandt PA et al.; Selenium levels and the subsequent risk of pro cancer state: a prospective cohort study; Cancer Epidemiol Biomerkers Prevent 2003; 12; 866-871)
Vitamin E
Vitamin E (+alpha-tocopheryl-succinate) and selenium (methylselenic acid) alone lead to a moderate inhibition of survival time and growth of human prostate cancer cells. A combination results in a dramatic increase in the Growth inhibition of prostate cancer cells. Apoptosis is induced, Bax, Bak and Bi proteins increase and Bcl-2 protein decreases. (Reagan-Shaw S et al.; Combination of vitamin E and selenium causes an induction of apoptosis of human prostate cancer cells by enhancing Bax/Bcl-2 ratio; Prostate 2008; 68: 1624-1634)
The incidence of prostate Ca is reduced by 1/3 with vitamin E 50 mg. (randomized, double-blind, placebo-controlled; ATBC study; Heinonen OP et al.; Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial;J Natl Cancer Inst 1998;90:440-446)
Smokers and ex-smokers who consume at least 100 IU vitamin E have a reduced risk of metastatic or fatal prostate. (RR 0.44; 95% CI). (47780 participants; Chan JM et al.; Supplemental Vitamin E Intake and Prostate Cancer Risk in a Large Cohort of Men in the United States; Cancer Epidemiology Biomarkers & Prevention 1999;8;893-899)
Supplementation with vitamin E 400 IU hardly reduced the overall prostate carcinoma risk (HR 0.86; 95% CI). The risk of advanced prostate carcinoma (regionally invasive or metastatic) decreased significantly in relation to the dose of vitamin E (HR 0.43; 95% CI). There was no stronger association between the administration of selenium (<50 mcg) and the risk of prostate carcinoma (HR 0.90; 95% CI) (Prospective cohort study; 35242 participants over 10 years; Peters et al .; Vitamin E and selenium supplementation and risk of prostate cancer in the Vitamins and lifestyle (VITAL) study cohort; Cancer Causes Control 2008; 19: 75-87)
Vitamin K2
There is a non-significant relationship between prostate cancer incidence and vitamin K2. The reduction in risk is 35% (RR 0.65), the risk of advanced prostate ca. is reduced by 63% (RR 0.37). The association with menaquinone from dairy products is more pronounced than with meat-based vitamin K2. Vitamin K1 (phylloquinone, mainly from leafy vegetables and vegetable oil) shows no correlation. (EPIC study, 11319 participants over 8.6 years; Nimptsch K et al.; Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg); Am J Clin Nutr 2008; 87; 985-992)
Tomatoes
The risk of prostate cancer is reduced with a high intake of raw tomatoes (RR 0.89; 95% CI) and higher with cooked tomato products (RR 0.81; 95% CI). (Meta-analysis from 11 case control studies and 10 cohort studies; Etminan M et al.; The Role of Tomato Products and Lycopene in the Prevention of Prostate Cancer: A MetaAnalysis of Observational Studies; Cancer Epidemiology Biomarkers & Prevention 2004; 13; 340-345 )
Soy
Soy isoflavones can reduce the risk of prostate cancer in 2 studies (RR 0.49; 95% CI). (Van Die MD et al.; Soy and soy isoflavones in prostate cancer : a systematic review and meta-analysis of randomized controlled trials.)
Japanese have 7-110 times higher isoflavonoid levels than Finns.The high levels of phyto-oestrogens may inhibit the growth of prostate cancer in Japanese and explain the low mortality from prostate cancer in Japan (Adlerkreutz H et al.; Plasma concentrations of phyto-oestrogens in Japanese men; Lancet 1993; 342; 1209-1210)
Fish (omega 3 fatty acids EPA and DHA)
Fish intake more than 3 times per week reduces the risk of prostate cancer and particularly the risk of metastatic carcinoma (RR 0.56; 95% CI). Each 0.5 g intake of fish oil is associated with a 24% risk reduction for metastatic prostate cancer (Health professionals follow-up study; 47882 participants over 12 years; Augustsson K et al.; A Prospective Study of Intake of Fish and Marine Fatty Acids and Prostate Cancer; Cancer Epidemiology Biomarkers & Prevention 2003;12;64-67)
Men who do not eat fish have a 2-3 times higher risk of prostate cancer than men who eat moderate or high amounts of fish. (Prospective cohort study; 6272 participants over 30 years old; Terry P et al.; Fatty fish consumption at risk of prostate cancer; The Lancet 2001; 357; 1764)
Gynecological tumors / breast carcinoma
Western lifestyle
Asian American women who were born in the West and practice Western lifestyleshave at least a 60% greater risk of breast cancer than Eastern-born controls, regardless of whether the ancestors were born in the West or East. Among eastern-born emigrants, those from urban areas have a 30% higher risk than emigrants from rural areas. (A up to 6-fold increased risk of breast cancer due to migration has been observed). (Case-control study; 1563 participants; Ziegler RG et al.; Migration patterns and breast cancer risk in Asian-American women; JNCI 1993 ;85;1819-1827)
Body weight / obesity
The risk of breast cancer increases by 45% in women who have gained at least 25 kg weight after the age of 18 - and by 18% in women who gained approx. 11 kg after menopause. 15% of all breast cancer cases can be traced back to a weight gain of at least 2 kg after the 18th year and 4.4% of the cases to a weight gain of at least 2 kg after the menopause. Women who lost at least 11 kg after menopause have a 57% reduced risk of breast cancer. (Prospective cohort study; Nurses Health Study; 87143 participants; Eliassen AH et al.; Adult Weight Change and Risk of Postmenopausal Breast cancer; JAMA 2006; 296; 193-201)
High-fat diet (with little bread and fruit juices) significantly doubles the risk of breast cancer compared to low-fat consumption (HR 2.0; 95% CI). (EPIC study; 15351 participants; Schulz M et al.; Identification of a dietary pattern characterized by high-fat food choices associated with increased risk of breast cancer: the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study; British Journal of Nutrition 2008; 100; 942 -946)
Carotenoids
Carotenoids: There was no general relationship between total postmenopausal breast cancer and micronutrient intake. Dietary beta-carotene reduces risk of lobular breast cancer (IRR 0.72). Dietary vitamin E reduces risk of estrogen receptor- and progesterone receptor-positive breast cancer (IRR 0.50). Dietary folic acid potentially increases risk of estrogen receptor and progesterone receptor positive breast cancer (IRR 1.27). (Prospective cohort study; 26224 participants; Roswall N et al.; Micronutrient intake and breast cancer characteristics among postmenopausal women; Eur J Cancer Prev 2010; 19: 360-365)
Carotenoids: Dietary alpha- (RR 0.83) and beta-carotene (RR 0.78) as well as lycopene (RR 0.85) are inversely correlated with the risk of estrogen- and progesterone-receptor-positive breast cancer vitamin E does not correlate with breast cancer risk. Vitamin C intake has a weak positive association with breast cancer in general. (84,805 participants; Cuii Y et al.; Selected antioxidants and risk of hormone receptor-defined invasive breast cancers among postmenopausal women in the Women's Health Initiative Observational Study;Am J Clin Nutr.2008;87:1009-1018)
Carotenoids: Dietary carotenoids do not correlate with the overall risk of breast cancer. Dietary alpha- and beta-carotene are inversely correlated with the risk of estrogen- and progesterone-receptor-negative breast cancer in smokers (RR 0.32 and RR 0.35, respectively) and in women who do not take supplements. (cohort study; 36664 participants over 9.4 years; Larsson SC et al.; Dietary carotenoids and risk of hormone receptor-defined breast cancer in a prospective cohort of Swedish women; Eur J Cancer 2010; 46: 1079-1085)
Carotenoids: The concentrations of total carotenoids, beta-carotene, lycopene and lutein were significantly lower in cancer than in healthy controls. Breast cancer risk was greatly reduced for beta-carotene (OR 0.41), lycopene (OR 0.55), and total carotenoids (OR 0.55) between peak and trough blood levels. (case control study; 590 participants; Sato R et al.; Prospective study of carotenoids, tocopherols, and retinoid concentrations and the risk of breast cancer; Cancer Epidemiol Biomarkers Prev 2002; 11: 451-457)
folic acid
Low folate levels are associated with increased risk of prostate cancer (HR 4.79) as well as increased risk of breast cancer (HR 6.46). (cohort study; 1988 participants over more than 20 years; Rossi E et al.; Folate levels and cancer morbidity and mortality: prospective cohort study from Busselton, Western Australia; Ann Epidemiol 2006; 16; 206-212)
Higher intake of folate, B12 or methionine is associated with a reduced risk of ER breast cancer (ER = estrogen receptor negative). (Yang D et al.; Dietary intake of folate, B-vitamins and methionine and breast cancer risk among Hispanic and non-Hispanic white women.PLoS One.2013;8(2):e54495.)
The excessive risk of breast cancer associated with increased alcohol consumption is reduced by adequate intake of folic acid (RR for 600 mcg folic acid per day versus 150-299 mcg per day was 0.55, 95% CI). (Prospective cohort study over 16 years; 88818 participants from the Nurses Health Study; Zhang S et al.; A Prospective Study of Folate Intake and the Risk of Breast Cancer; JAMA 1999; 281; 1632-1637)
Cysteine
High levels of cysteine (precursor to glutathione) or NAC are dose-dependently significantly associated with a reduced risk of breast cancer (RR 0.44; 95% CI for highest versus lowest levels) (Prospective Nurses Health Study; 32826 participants; Zhang SM et al.; A prospective study of plasma total cysteine and risk of breast cancer; Cancer Epidemiol Biomarkers Prev 2003; 12: 1188-1193)
Omega 3 fatty acids (EPA and DHA)
There is clear evidence of an inverse relationship between the intake of omega 3 fatty acids and the risk of breast cancer. Omega 3 fatty acids reduce the risk by 14%. The risk decreased by 5% for every 0.1 g increase in O3-FA intake. (meta-analysis from 26 publications with 883585 participants; Zheng JS et al.; Intake of fish and marine n-3-polyunsaturated fatty acids and risk of breast cancer: metaanlysis of datafvrom 21 independent prospective cohort studies; BMJ 2013; 346; f37062)
Fish oil reduces the risk of ductal (HR 0.68) but not lobular breast cancer (cohort study; 35016 participants over 3 years; Brasky TM et al.; Specialty supplements and breast cancer risk in the VITamins And Lifestyle (VITAL) Cohort; Cancer Epidemiol Biomarkers Prev 2010;19: 1696-1708)
Soy / isoflavones
Increased soy intake significantly reduces the risk of breast cancer in Asians: with intake of > 19 mg isoflavones OR = 0.71 (29% reduction) and with intake of approx. 10 mg OR = 0.88 versus an intake of < 5 mg. The risk decreases by about 16% per 10 mg isoflavone intake - in pre- and postmenopausal cancer. (In 11 studies with western population and low soy intake of 0.8-0.15 mg isoflavones per day there is no correlation between soy intake and breast cancer risk ). (meta-analysis from 1 cohort and 7 case control studies; Wu AH et al.; Epidemiology of soy exposures and breast cancer risk; British Journal of Cancer 2008; 98, 9-14; doi:10.1038/sj .bjc.6604145)
Frequent intake of miso soup and isoflavones is associated with a lower risk of breast cancer in Japanese women (OR 0.46; 95% CI comparing the lowest versus the highest intake), particularly in postmenopausal women. (Prospective JPHC cohort study; 21852 participants; Yamamoto S et al.; Soy, Isoflavones, an Breast Cancer Risk in Japan; Journal of the National Cancer Institute 2003; 95; 906-913)
Adolescent soy intake levels are inversely associated with breast cancer risk in both pre- and postmenopausal Chinese women (OR 0.51; 95% CI for the highest versus the lowest intake). (case control study; 3015 participants; Shu XO et al.; Soyfood Intake during Adolescence and Subsequent Risk of Breast Cancer among Chinese Women; Cancer Epidemiology, Biomarkers & Prevention; 2001; 10; 483- 488)
Excretion of isoflavonoids and lignans is significantly lower in women with breast cancer compared to controls. The risk of breast cancer decreases with increasing excretion of isoflavonoids and lignans (OR 0.62, 0.40 and 0.28, respectively; 95% CI at the highest versus lowest intake for isoflavonoids, lignans, and isoflavonoids and lignans, respectively) (Case control study; Shanghai Breast Cancer Study; 250 participants; Dai Q et al.; Urinary Excretion of Phytoestrogens and Risk of Breast Cancer among Chinese Women in Shanghai; Cancer Epidemiology, Biomarkers & Prevention 2002; 11; 815-821)
There is a significant risk reduction in women due to a high intake of phytoestrogens (isoflavones, lignans). (Randomized case-control study; Ingram D. et al.; case-control study of phyto-oestrogens and breast cancer; Lancet. 1997;350;990-994)
Soy isoflavones reduce free estradiol and estrone levels in premenopausal women (in 53.9% of cases versus 37.5% in controls). SHBG increases (by 41.4% vs. 37.5% in controls). The menstrual cycle lengthens by 3.5 days compared to controls and the follicular phase by 1.46 days. Longer cycles or fewer cycles are associated with a lower risk of breast cancer. (Double-blind, placebo-controlled; 66 participants; Kumar NB et al.; The specific role of isoflavones on estrogen metabolism in premenopausal women; Cancer 2002; 94; 1166-1174)
Soy and its components can reduce the risk of breast cancer if consumed regularly (regarding soy protein OR 0.39 for premenopausal and OR 0.22 for postmenopausal women and regarding tofu OR 0.23 for premenopausal women; each 95% CI) (Kim MK et al.; Dietary intake of soy protein and tofu in association with breast cancer risk based on a casecontrol study; Nutr Cancer 2008; 60: 568-576)
In postmenopausal American women, breast cancer risk decreases with flavonoid intake, most notably flavonols (OR=0.54; 95% CI), flavones (OR=0.61), flavan-3-ols (OR=0 .74) and lignans (OR=0.69) (case control study; 2874 participants; Fink BN et al.; Dietary flavonoid intake and breast cancer risk among women on Long Island; Am J Epidemiol 2007; 165: 514-523)
In pre- and postmenopausal American breast cancer patients, general mortality decreases with high intake of flavonoids compared to low intake, most notably for flavones (OR=0.63; 95% CI), anthocynidins (OR= 0 .64) and isoflavones (OR=0.52). Similar results are found for cancer-specific mortality. (Cohort study; 1210 participants over more than 5 years; Fink BN et al.; Dietary Flavonoid Intake and Breast Cancer Survival among Women on Long Island; Cancer Epidemiology Biomarkers & Prevention 2007;16, 2285-2292)
Green tea
Women who regularly drink green tea have a significantly reduced risk of breast cancer, which is clearly inversely correlated with the amount of tea drunk. (case-control study; 2018 participants; Zhang M et al.; Green tea and the prevention of breast cancer: a case-control study in southeast china; Carcinogenesis 2007; 28; 1074-1078)
Carotenoids
The risk of breast cancer in the group with the highest intake of beta-carotene, lycopene and total carotenoids was about half that in the group with the lowest intake. (Prospective Case-control study; 590 participants; Sato R et al.; Prospective Study of Carotenoids, Tocopherols, and Retinoid Concentrations and the Risk of Breast Cancer; Cancer Epidemiology Biomarkers & Prevention 2002; 11; 451-457)
The combined high intake of carotenoids (OR 0.57; 95% CI for beta-carotene in women not taking HRT) and theomega 3 fatty acidDHA Docosahexaenoic acid (OR 0.52; 95% CI in postmenopausal women) reduces the risk of breast cancer. (case control study; 843 participants; Nkondjock A et al.; Intake of specific carotenoids and Essential fatty acids and breast cancer risk in Montreal, Canada; Am J Clin Nutr 2004; 79; 857-864)
High levels of alpha and beta carotene, lutein, zeaxanthin, lycopene and total carotenoids reduce the risk of breast cancer. For some carotenoids (e.g. beta-carotene) the associations are stricter for estrogen receptor-negative than for estrogen receptor-positive tumors. (Eliassen AH et al.; Circulating carotenoids and risk of breast cancer: pooled analysis of eight prospective studies.J Natl Cancer Institute 2012;104(24):1905-16.)
Calcium and vitamin D
In women who have not previously taken calcium or vitamin D, calcium and vitamin D together significantly reduce the risk of breast and colorectal cancer. (15,646 women in the GHI Study; Bolland MJ et al.; Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set.Am J Clin Nutr 2011; 94: 1144-9) There is a significant inverse relationship between vitamin D levels or calcium levels and breast cancer risk (meta-analysis ; Chen P et al.; Meta-analysis of vitamin D, calcium and the prevention of breast cancer; Breast Cancer Res Treat 2010; 121; 469-477)
The calcium intake correlates significantly inversely with the risk of estrogen and progesterone receptor-negative breast cancer (RR 0.66). (Prospective cohort study; 61433 participants over 17.4 years ; Larsson SC et al.; Long-term dietary calcium intake and breast cancer risk in a prospective cohort of women; Am J Clin Nutr 2009; 89: 277-282)
choline / betaine
In China, there is a significant inverse association between the intake of choline and betaine and the risk of breast cancer, especially in women with low folate levels. (Zhang CX et al.; Choline and betaine intake is inversely associated with breast cancer risk: a two-stage casecontrol study in China. Cancer Sci. 2013; 104(2):250-8.)
selenium
Lower selenium concentrations are found in women with breast cancer than in healthy individuals (81.1 mcg/l versus 98.5 mcg/l). (Lopez-Saez Jb et al .; Selenium in breast cancer; Oncology 2003; 64; 227-231)
Women with BRCA1 mutations have an increased risk of breast and ovarian cancer. This BRCA1 increases susceptibility to DNA breaks. Seleniumsupplementation reduces the number of DNA breaks in mutation carriers to the level of non-carrier controls. (Kowalska E et al.; Increased rates of chromosome breakage in BRCA1 carriers are normalized byoral selenium supplementation; Cancer Epidemiol Biomarkers Prev 2005;14;1302-1306)
Zinc
Zinc has a significant positive effect in premenopausal breast cancer when supplemented > 10 years. Multivitamins and vitamin C, E and beta-carotene have a significant positive effect when supplemented > 10 years in postmenopausal breast cancer. (retrospective case control study; 7824 participants; Pan SY et al Antioxidants and breast cancer risk – a population-based case-control study in Canada BMC Cancer 2011;11:372)
lungs
Carotenoids and vitamin A
Intake of green vegetables, beta-carotene-rich vegetables, watermelon, vitamin A, and carotenoids is inversely associated with the risk of lung cancer (HR 0.72 for the highest vs. the lowest intake). (Takata Y et al.; Intakes of fruits, vegetables, and related vitamins and lung cancer risk: results from the Shanghai Men's Health Study (2002-2009). Nutr Cancer. 2013; 65(1):51-61)
folic acid and vitamin C
Significant protective effects were found for folic acid and vitamin C. (cohort study over 6.3 years; 58279 participants; Voorrips LE et al.; A Prospective Cohort Study on Antioxidant and Folate Intake and Male Lung Cancer Risk; Cancer Epidemiology Biomarkers & Prevention 2000; 9, 357-365)
Vitamin B6
High vitamin B6 levels reduce the risk by half (odds ratio 0.51; 95% CI). (case control study; Hartman TJ et al.; Association of the B-Vitamins Pyridoxal 5'-Phosphate (B6), B12, and Folate with Lung Cancer Risk in Older Men; Am J Epidemiol 2001; 153; 688-694)
selenium
With the administration of 200 mcg selenium (selenium yeast) there is a significant reduction in lung cancer incidence by 45% (95% CI) (Randomised; multicentre, double-blind, placebo-controlled: 1312 Participants over 8 years Clark LC et al.; Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin A randomized controlled trial. Nutritional Prevention of Cancer Study Group; JAMA 1996; 276; 1957-1963)
A low seleniumstatus is associated with an increased risk of lung cancer. (Cohort study, 500 participants; Hartman TJ et al.; Selenium concentration and lung cancer in male smokers; Cancer causes Control 2002 ;123;923-928)
Low selenium levels are associated with an increased risk of lung cancer. (120 participants; Zhuo H et al.; Serum and lung tissue selenium measurements in subjects with lung cancer from Xuanwei, China ; Zhogguo Fei Al Za Zhi 2011;14;39-42)
Selenium has a preventive effect against lung cancer in people with low selenium levels. It reduces cisplatin-induced nephrotoxicity and side effects of radiation in lung cancer patients. (Review; Fritz H et al.; Selenium and lung cancer: a systemic review and meta analysis; PLoS One 2011; 6; #26259)
People with the lowest selenium levels have a 5.8-fold increased risk of fatal cancer compared to those with the highest selenium levels. It was increased 11.4-fold in people with low selenium and low vitamin E levels. A reduced intake of vitamin A or provitamin A increases the risk of lung cancer in smokers with low selenium levels. (Salonen JT et al.; isk of cancer in relation to serum concentrations of selenium and vitamins A and E: matched case-control analysis of prospective data; Br Med J 1985; 290; 4127-420)
Red wine
The risk of lung cancer decreased by 60% in smokers if they smoked moderate red wine once a day Consumption of beer, white wine or liqueur did not reduce the risk. (California Men' 's Health Study with 84,170 participants; Chao C et al.; Alcoholic Beverage Intake and Risk of Lung Cancer: The California Men's Health Study; Cancer Epidemiol Biomarkers Prev 2008; 17: 2692-2699)
phytoestrogens (e.g. ashwagandha)
The risk of lung cancer decreases with increasing intake of phytoestrogens (more significant for isoflavones than for phytosterols) in food by up to 46% (95% CI). (Case control study; 3409 participants over 8 years; Schabath MB et al; Dietary Phytoestrogens and Lung Cancer Risk; JAMA 2005; 294:1493-1504)
flavones and proanthocyanidins
For the occurrence of lung cancer in postmenopausal women, there was an inverse correlation between the intake of flavanones and proanthocyanidins. Smokers and former smokers with a very high intake of flavanones and proanthocyanidins had a significantly lower incidence of lung cancer than smokers and former smokers with a very low intake. Women who consumed higher amounts of isoflavones were less likely to develop cancer. (34,708 participants aged 18+; Cutler GJ; Dietary flavonoid intake and risk of cancer in postmenopausal women: the Iowa Women's Health Study; Int J Cancer .2008 Aug 1;123(3):664-671)
gastrointestinal tract (incl. liver and pancreas)
Apples
The odds ratio of the incidence of cancer of the oral cavity and pharynx is 0.79 for intake of > 1 apple/day versus < 1 apple/day and 0.75 for esophagus, 0.80 for colon and rectum, 0.58 from larynx, 0.82 from breast, 0.85 from ovary and 0.91 from prostate (95% CI each). (case-control study; 14138 participants over 11 years; Gallus S et al.; Does an apple a day keep the oncologist away? Annals of Oncology 2005; 16: 1841-1844)
Fresh apple 100g has the same antioxidant activity as 1500 mg vitamin C and extract from whole apples dose-dependently inhibits the growth of colon and liver cancer in vitro (Eberhardt MV et al. ; Antioxidant activity of fresh apples; Nature 2000;405:903-904)
flavonoids
flavonoids (apagenin 20 mg and epigallocatechin gallate 20 mg) reduce the recurrence rate after curative colorectal cancer surgery (0% versus 20% in the control group; evidence level 2B). (87 participants over 3 -4 years; Hoensch H et al.; Prospective cohort comparison of flavonoid treatment in patients with resected colorectal cancer to prevent recurrence; World J Gastroenterol 2008; 14; 2187-2193)
Tomatoes
Intake of larger amounts of tomatoproducts reduces the risk of gastric cancer. (Yang T et al.; The role of tomato products and lycopene in the prevention of gastric cancer: a meta -analysis of epidemiologic studies.Med Hypotheses.2013;80(4):383-8)
Carotenoids
The risk of gastric cancer is inversely correlated with blood levels of the antioxidants beta-carotene (R 0.31), vitamin E (R 0.89), alpha-carotene (R 0.67), lycopene (R 0.56) and vitamin C (R 0.61). (634 participants; Tsubonon Y et al.; Plasma antioxidant vitamins and carotenoids in five Japanese populations with varied mortality from gastric cancer; Nutr Cancer 1999;34;56-61)
Lycopene results in a 31% significant reduction in the risk of pancreatic carcinoma (OR 0.69; 95% CI). Beta-carotene (OR 0.57; 95% CI) and total carotenoids (OR 0.58; 95% CI) significantly reduce the risk only in non-smokers. (Case control study with 5183 participants over 3 years; Nkondjock A et al.; Dietary intake of lycopene is associated with reduced pancreatic cancer risk; Nutr 2005; 135: 592-597)
Vitamins A and C
Patients taking supplements containing vitamin A have a reduced risk of gastric cancer (RR = 0.4; 95% CI). There is an inverse relationship between vitamin C intake and gastric cancer (RR 0.7; 95% CI for highest versus lowest intake) (Netherlands Cohort Study; 120852 participants over 6.3 years; Botterweck AA et al.; Vitamins, carotenoids, dietary fiber, and the risk of gastric carcinoma: results from a prospective study after 6.3 years of follow-up; Cancer 2000; 88; 737-748)
Magnesium
Magnesium significantly reduces the risk of colon carcinoma. (Prospective study with 35196 participants over 17 years; Folsom AR et al.; Magnesium Intake and Reduced Risk of Colon Cancer in a Prospective Study of Women; Am J Epidemiol 2006; 163; 232-235)
selenium
With the administration of 200 mcg selenium (selenium yeast) there is a significant reduction in the incidence of colon carcinoma by 58% (95% CI). (Randomized; multicentric, double-blind, placebo-controlled: 1312 participants over 8 years; Clark LC et al.; Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group; JAMA 1996; 276; 1957-1963)
There is an inverse relationship between seleniumlevels and risk of esophageal and gastric cancer. (Prospective cohort study; 120,852 participants; Steevens J et al.; Selenium status and the risk of Esophageal and gastric cancer subtypes: the Netherlands cohort study; Gastrenterology 2010; 138; 1704-1713)
High selenium levels reduce the risk of exocrine pancreatic cancer (high levels of cadmium, arsenic and lead increase it). (517 participants; Amarai AF et al; Pancreatic cancer risk and levels of trace elements; Gut 2011)
500 mcg selenium over 3 years increases selenium levels and GPx activity and significantly reduces liver cancer incidence in high-risk patients. (placebo-controlled; 2065 participants; Li H et al.; The prevention of liver Cancer by selenium in high-risk populations;Zhonghua Yu Fang Yi Xue Za Zhi 2000;34;696-703)
Men with low seleniumstatus have an increased risk of colorectal cancer (OR for highest versus lowest levels = 0.68; 95% CI). (case control study; 1609 participants; Takata X et al.; Serum selenium, genetic variation in selenoenzymes, and risk of colorectal cancer: primary analysis from the woman's health initiative Observational study and meta-analysis; Cancer Epidemiol Biomarkers Prev 2011; 20; 1822-1830)
selenium and vitamin C
Low serum levels of selenium, zinc, manganese, vitamin C and vitamin E increase the risk of gallbladder cancer. (Shukla VK et al.; Micronutrients, anbtioxidants, and carcinoma of the gallbladder; J Surg Oncol 2003; 84; 31-35)
High vitamin C intake reduces the risk of pankeas carcinoma (OR 0.45; 95% CI), high cholesterol significantly increases it. (109 participants; Lin Y et al .; Nutritional factors and risk of pancreatic cancer: a population-based case-control study based on direct interview in Japan; J Gastroenterol 2005; 40: 297-301)
folic acid
The intake of folic acid 71-660 μg/day (via preparations or food) is not associated with an increased risk of colon cancer folic acid reduces the risk by 19%. (Cancer Prevention Study II Nutrition Cohort; 99521 participants; Stevens VL et al.; High Levels of Folate, from Supplement and Fortification, are not associated with increased risk of colorectal cancer; Gastroenterology 2011; published ahead of print; doi: 10.1053/j .gastro.2011.04.004)
Colorectal tumors: The risk in women is inversely proportional to the intake of iron, folic acid and vitamin C. Folic acid is the best protective factor. In men , high intakes of calcium and vitamin E were associated with a reduced risk, with vitamin working best (RR 0.35; 95% CI). (Case control study; Tseng M et al.; Micronutrients and the risk of colorectal adenomas; American Journal of Epidemiology, Vol 144, Issue 11 1005-1014)
Low levels of folatein cell cultures increase the risk of DNA damage to colon cells (and the increase in proteins such as Nit2 and COMT) and thus the risk of colon cancer.
High dietary folic acid intake significantly reduces the risk of pancreatic carcinoma (multivariable rate ratio 0.25; 95% CI). (81,922 participants over 6.8 years of age; Larsson SC et al.; Folate intake and pancreatic cancer incidence: a prospective study of Swedish women and men; J Natl Cancer Inst 2006; 98: 407-413) (Duthie SJ et al.; The Response of human coloncytes to folate deficiency in vitro: functional and proteomic analyses; J Proteome Res 2008; 7; 3254-3266)
Calcium and vitamin D
In women who have not previously taken calcium or vitamin D, calcium and vitamin D together significantly reduce the risk of breast and colorectal cancer. (15,646 women in the GHI Study Bolland MJ et al.; Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am J Clin Nutr 2011; 94: 1144-9)
Colorectal adenomas: There is evidence that calcium and vitamin D intake is inversely related to the frequency of colorectal adenomas. (Randomized multicenter study; polyp pervention trial; 1st .905 participants; Hartman TJ et al; The Association of Calcium and Vitamin D with Risk of Colorectal Adenomas; J Nutr 2005; 135: 252-259)
Vitamin D
25(OH)D (= vitamin D) levels are inversely related to the risk of colorectal cancer (an increase of 20ng/ml reduces the risk by 43%). ( Meta-analysis; Yin L et al.; Meta-analysis: longitudinal studies of serum vitamin D and colorectal cancer risk; Aliment Pharmacol Ther 2009; 30; 113-125)
A high intake of vitamin D (over 25 mcg/day) or a vitamin D serum level of 33 ng/ml reduces the risk of colon cancer by 50% (note: vitamin D increases calcium absorption in the intestine) . (Gorham ED et al.; Vitamin D and prevention of colorectal cancer; J Steroid Biochem Mol Biol 2005; 97; 179-194)
High intake and serum levels of vitamin D are associated with a significant reduction in the risk of colorectal cancer. (Research of epidemiological studies; Grant WB et al; A critical review of studies on vitamin D in relation to colorectal cancer.Nutrition and Cancer 2004;48:115-123)
The risk of colorectal cancer is reduced by half when 25-hydroxyvitamin D levels are above 33 ng/mL compared to levels below 2 ng/mL (RR 0.49; 95% CI). (Meta-analysis from 5 studies; Gorham ED et al. "Optimal Vitamin D Status for Colorectal Cancer Prevention: A Quantitative Meta Analysis." Am J Prev Med 2007; 32: 210-216 )
Vitamin D intake and levels are inversely associated with the risk of colorectal cancer. (Ma Y et al.; Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies J Clin Oncol 2011;29(28):3775-82)
Rectal carcinoma: The risk is strongly dependent on calcium intake (RR 0.59 with high calcium intake versus RR 1.00 with low intake) and vitamin D3 -Intake (RR 0.76 vs. RR 1.00 at low intake). For calcium and vitamin D3 together, the risk reduction was 45% (RR 0.55). (9-year cohort study; 34,702 postmenopausal women; Zheng W et al.; A prospective cohort study of intake of calcium, vitamin D, and other micronutrients in relation to incidence of rectal cancer among postmenopausal women;Cancer Epidemiol Biomarkers Prev.1998;7:221-225)
Vitamin D affects the pathogenesis of pancreatic carcinoma (RR 0.59 at the highest versus the lowest intake). (Health Professionals Follow-up Study with 46,771 men; Nurses'''' Health study with 75,427 women; Skinner HG et al.; Vitamin D intake and the risk for pancreatic cancer in two cohort studies; Cancer Epidemiol Biomarkers Prev 2006; 15: 1688-1695)
Vitamin K2
Vitamin K2 beneficial in the prevention of hepatocellular carcinoma in women with viral cirrhosis (OR 0.13; 95% CI). (Habu D et al.; Role of vitamin K2 in the Development of hepatocellular carcinoma in women with viral cirrhosis of the liver JAMA 2004 Jul 21;292(3):358-61.)
Methionine
Higher intake of methionine significantly reduces the risk of pancreatic carcinoma (multivariate rate ratio 0.44; 95% CI). (81,022 participants over 7.2 years; Larsson SC et al.; Methionine and vitamin B6 intake and risk of pancreatic cancer: a prospective study of Swedish women and men; Gastroenterology 2007; 132: 113-118)
Intake of folate or methionine is inversely associated with the risk of colorectal cancer. (Razzak AA et al.; Associations between intake of folate and related micronutrients with molecularly defined colorectal Cancer risks in the Iowa Women's Health Study. Nutr Cancer.2012;64(7):899-910)
glutathione
Glutathione from food reduces the risk of oral and pharyngeal carcinomas by 50% (Jones DP; Glutathione distribution in natural products: absorption and tissue distribution; Methods in Enzymology 1995; 25; 3 -13)
Fish (omega 3 fatty acids EPA and DHA)
The amount of fish consumption is inversely associated with colorectal cancer. (Wu S et al.; Fish consumption and colorectal cancer risk in humans: a systematic review and meta-analysis. Am J Med 2012;125(6):551-9.e5)
Urology
Carotenoids
Taking into account various influencing factors such as smoking and age of the participants, the odds ratio of bladder cancer with carotenoids as protective substances was determined: alpha-carotene 0.22, lutein 0.42, lycopene 0.94 and beta-cryptoxanthine 0.90. Regarding the combined effect of plasma carotenoids and smoking, the odds ratio for smokers with low lutein levels was 6.22 and low zeaxanthin levels was 5.18. The results of the study suggest that carotenoids protect against bladder cancer. Smokers in particular could benefit from a higher carotenoid intake. (case control study; 448 participants over 4 years; Hung RJ et al.; Protective effects of plasma carotenoids on the risk of bladder cancer; J Urol 2006; 176: 1192- 1197)
Fish (omega 3 fatty acids EPA and DHA)
Fatty sea fish (such as mackerel, herring, sardines, salmon) with lots of omega-3 fatty acids and vitamin D at least once a week reduces the risk of kidney cancer significantly (OR 0.56) compared to the control group. If the diet lasted more than 10 years, the risk decreases even further (OR 0.26). (Cohort study with 61433 participants over 15 years; Wolk A et al.; Long-term Fatty Fish Consumption and Renal Cell Carcinoma Incidence in Women;JAMA 2006;296:1371-1376)
There is an inverse connection between the consumption of fatty fish and a risk of renal cell carcinoma (risk 0.26 with regular consumption of oily fish compared to no fish intake), but no connection with the consumption of lean types of fish.(Swedish Mammography Cohort Study; 61,433 participants over 10 years; Wolk A et al.; Long-term fatty fish consumption and renal cell carcinoma incidence in women; JAMA 2006; 20; 296: 1371-1376)
selenium
There is an inverse relationship between selenium concentration and bladder cancer risk. (case-control study; 540 participants; Kellen E et al.; Selenium is inversely associated with bladder cancer risk ; a report form the Belgian case-control study on bladder cancer; Int J Urol 2006; 13; 1180-1184)
seleniumconcentration is inversely related to bladder cancer risk in women (case control study; 679 participants; Michaud DS et al.; Toenail selenium concentrations and bladder cancer risk in woman and men; Brit J Cancer 2005;93;443-458)
There is an inverse relationship between selenium levels and bladder cancer risk. (Prospective cohort study; 120,852 participants; Zeegers MP et al.; Prediagnostic toenail selenium and risk of bladder cancer; Cancer Epidemiol Biomarkers Prev 2002;11;1292-1297)
People with high levels of selenium have a lower risk of bladder cancer. Folic acid or a high intake of fruit reduce the risk in smokers. (Altwein JE; Primary prevention of bladder cancer; What's new? Urologe A 2007; 46; 616-621)
High selenium status significantly reduces bladder cancer risk by 39% (Or 0.61; 95% CI). (meta-analysis from 7 epidemiological studies; Amarai M et al; Selenium and bladder cancer risk: a meta-analysis; Cancer Epidemiol Biomarkers Prev 2010; 19; 2407-2415)
Selenium protects risk groups such as smokers, women and people with a mutation in the p53 gene from bladder cancer. (1,875 participants; Wallace K et al.; Selenium and risko of bladder cancer: a population- based case-control study; Cancer Prev Res 2009;2;70-73)
Hematology
Carotenoids and glutathione
Leukemia (hematological neoplasia): The intake amount of vegetables (OR 0.53; 95% CI), protein sources (OR 0.40; 95% CI) and fruits (OR 0.71; 95% CI) and especially < Maternal t1>carotenoids (OR 0.65; 95% CI) and antioxidant glutathione (OR 0.43; 95% CI) is inversely associated with acute lymphoblastic leukemia (ALL) in children (ALL may arise in utero). (Population-based Northern California Childhood Leukemia Study; 276 participants; Jensen CD et al.; Maternal dietary risk factors in childhood acute lymphoblastic leukemia; Cancer Causes and Control 2004; 15; 559 -570)
Iron and folic acid
Acute lymphoblastic leukemia (haematological neoplasia): In children aged 0-14 years, there is a connection between iron or folic acid supplementation during pregnancy and the development of ALL in the child (OR 0.37; 95% CI). For iron alone, the odds ratio is 0.75. (249 participants over 10 years; Thompson JR et al.; The Lancet 2001; 358; 9297)
Polyunsaturated fatty acids and vitamin D
There is an inverse relationship between the risk of non-Hodgkin's lymphoma (hematological neoplasia) and the intake of polyunsaturated fatty acids, linoleic acid and vitamin D (OR 0.6 each; 95% CI). The effect is stronger in women. (Case control study; 674 participants over 3 years; Polesel J et al.; Linoleic acid, vitamin D and other nutrient intakes in the risk of non-Hodgkin lymphoma: an Italian case-control study; Ann Oncol 2006;17:713-718)
selenium
The anti-leukemic effect of selenite is linked to the inhibition of DNA replication, transcription and translation. (Jiang XR et al.; The anti-leucaemic effects and the mechanism of sodium selenite; Leuk Res 1992; 16; 347-352)
Individual tumor types
A) Prostate
Fish / Omega 3 fatty acids
Arachidonic acid and its metabolite, prostaglandin E2, promote the migration of cancer cells, driving invasion into the bone marrow. Omega-3 fatty acids inhibit the migration of prostate cancer cells into the bone marrow when they are present in half the concentration of omega-6 fatty acids. The omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid can prevent prostate cancer cells from reaching the bone marrow. (Brown MD et al.; Promotion of prostatic metastatic migration towards human bone marrow stoma by Omega 6 and its inhibition by omega 3 PUFAs; Br J Cancer 2006;27;94:842-853)
There is no association between fishintake and prostate cancer, but (in studies with 49,641 participants) a significant reduction in prostate cancer-specific mortality (RR 0.37). (meta-analysis ( including 12 case control studies with 15,582 participants and 12 cohort studies with 445,820 participants); Szymanski KM et al.; Fish consumption and prostate cancer risk: a review and meta-analysis; Am J Clin Nutr 2010; 92: 1223-1233)
Prostate carcinoma: fat content of food and fat type have a significant influence on cancer cell growth: A fat-modified diet, in contrast to a western diet rich in fat, leads to a significant inhibition of prostate Cancer cell growth (randomized, prospective; Aronson WJ et al. "growth inhibitory effects of a low fat diet on prostate cancer cells in vitro: results of a prospective randomized dietary intervention trial in men with prostate cancer". AUA 2005 , Abstr. 1417)
Vitamin E
Prostate carcinoma: Mortality is significantly reduced by 41% with alpha-tocopherol (vitamin E) 50 mg. (Randomized, double-blind; 29,133 smokers; Heinonen OP et al .;ATCB study;J Natl Cancer Inst 1998;90;440-446)
Long-term vitamin E supplementation of 400 IU and more is associated with a reduced extent (locally invasive and/or metastatic) of existing prostate Ca by 57% (HR = 0.43; 95 % CI). (Prospective cohort study; 35,242 participants; Peters U et al.; Vitamin E and selenium supplementation and risk of prostate cancer in the Vitamins and lifestyle (VITAL) study cohort; Cancer Causes Control 2008; 19 : 75-87)
Prostate carcinoma: Vitamin E suppresses the release of PSA and androgen receptors. Combined use of vitamin E and antiandrogen flutamide inhibits LNCaP cell growth significantly more. Selenomethionine also shows an inhibitory effect on LNCaP cell growth. (Yu Zhang et al.; Vitamin E succinate inhibits the function of androgen receptor and the expression of prostate-specific antigen in prostate cancer cells; Proc Natl Acad Sci U S A 2002;99;7408-7413)
Soy
Soy isoflavone supplementation 60 mg in early stage prostate cancer affects surrogate markers for cancer proliferation such as PSA and free testosterone. (76 participants over 12 weeks; Kumar NB et al .; The Specific Role of Isoflavones in Reducing Prostate Cancer Risk; The Prostate 2004; 59; 141-147)
Broccoli (sulforaphane)
Broccoli (or the ingredient sulforaphane) makes aggressive and resistant pancreatic stem cells (pancreatic carcinomas contain about 10% of these cells) vulnerable and slows down metastasis of the pancreas (in Germany approx. 12650 cases of pancreatic ca.) (Kallifatidis G, Herr I et al.; Sulforaphane targets pancreatic tumor-initiating cells by NF-kB-induced antiapoptotic signaling. GUT 2008 , in press)
selenium
Selenite significantly increases p53 in prostate cancer cells. This is important for the activation of caspase-mediated apoptosis of cancer cells (involving the caspase-8 and caspase-9 pathway). (Jiang C et al.; Selenite-induced p53 Ser-15 phosphorylation and caspase -mediated apoptosis in LNCaP human prostate cancer cells; Mol Cancer Ther 2004; 3; 877-884)
B) Gynecological tumors
Antioxidants
Breast cancer and antioxidants: Levels of ROS, MDA and antioxidant enzyme activities are significantly higher in patients with breast cancer than in controls. The levels of vitamin C, GSH, GSSG (oxidized glutathione) and GSH/GSSG ratio are significantly lower. (Yeh CC et al.; Superoxide anion radical, lipid peroxides and antioxidant status in the blood of patients with breast cancer; Clinica Chimica Acta 2005; 361; 104-111)
Vitamin D
Women with early breast cancer have significantly higher vitamin D levels than women with advanced or metastatic breast cancer Vitamin D affects cell cycle regulation and may delay tumor growth. (558 Participants; Palmieri C et al.; Serum 25-hydroxyvitamin D levels in early and advanced breast cancer; J Clin Pathol 2006; 59; 1334-1336)
Vitamin E
Cervical cancer and vitamin E: The plasma levels of alpha-tocopherol and alpha-tocopheryl-quinone (oxidized alpha-tocopherol) are significantly reduced in the study group compared to controls. ( 72 participants; Palan PR et al.; [alpha]-tocopherol and [alpha]-tocopheryl quinone levels in cervical intraepithelial neoplasia and cervical cancer; American Journal of Obstetrics & Gynecology. 2004; 190; 1407-1410 )
Resveratrol
Resveratrol induces S-phase arrest in human ovarian carcinoma Ovcar-3 cells via Tyr15 phosphorylation of Cdc2. Overexpression of Cdc2AF, a mutant resistant to Thr14 and Tyr15 phosphorylation, reduced resveratrol-induced S-phase arrest. Resveratrol causes phosphorylation of cell division cycle 25C (CDC25C) tyrosine phosphatase via activation of checkpoint kinases Chk1 and Chk2, which in turn were activated via ATM (ataxia telangiectasia mutated) / ATR (ataxia telangiectasia Rad3-related ) kinase in response to DNA -Damage. Resveratrol also increases phospho-H2A.X (Ser139), which is phosphorylated by ATM/ATR in response to DNA damage. The involvement of these molecules in resveratrol-induced S-phase was also confirmed in studies showing that addition of the ATM/ATR inhibitor caffeine reduced resveratrol-induced activation of ATM/ATR Chk1/2 and phosphorylation of CDC25C, Cdc2 and H2A. X and reverses the S-phase arrest. Resveratrol also induces S-phase arrest and H2A.X (Ser139) phosphorylation in ovarian cancer cell lines PA-1 and SKOV-3 (albeit at different levels), while it does not in normal human foreskin fibroblasts detectable levels of Phospho-H2A.X (Ser139) showed only marginal S-phase arrest. Resveratrol establishes Cdc2-tyr15 phosphorylation via the ATM/ATR-Chk1/2-Cdc25C pathway as a central mechanism for DNA damage and S-phase arrest selectively in ovarian carcinoma cells and provides rationale for the potential efficacy of ATM/ATRA gonists in in cancer prevention and intervention. (Tyagi A et al.; Resveratrol causes Cdc2-tyr15 phosphorylation via ATM/ATR-Chk1/2-Cdc25C pathway as a central mechanism for S phase arrest in human ovarian carcinoma Ovcar -3 cells; Carcinogenesis 2005;26:1978-1987)
Resveratrol has antineoplastic activity. It inhibits the growth and induces the death of ovarian carcinoma cells (more via autophagy than via apoptosis), inter alia associated with caspase activation. It thus induces cell death in two different ways: non-apoptotic and apoptotic (via release of the anti-apoptotic proteins Bcl-xL and Bcl-2) (Opipari AW et al.; Resveratrol-induced autophagocytosis in ovarian cancer cells ; Cancer Research 2004; 64, 696-703)
selenium
Selenium is an important cofactor in the production of antioxidant enzymes. Selenium reduces cancer mortality in intervention studies. Selenium intake (in subjects with low selenium intake) prior to breast cancer diagnosis is inversely associated with breast cancer-specific mortality (HR 0.69) and all-cause mortality (Harris HR et al.; Selenium intake and breast cancer mortality in a cohort of Swedish women Breast Cancer Res Treat. 2012; 134(3):1269-77)
Increased selenium intake leads to a significant reduction in VEGF and the intratumoral density of microvessels in breast cancer. Selenium thus reduces angiogenesis. (Jiang C et al.; Selenium induced inhibition of angiogenesis in mammary cancer at chemopreventive levels of intake; Mol Carcinog 1999; 26; 213-225)
C) Gastrointestinal tract and pancreas
Antioxidants
5-FU has a responder rate of only 20% in colorectal cancer, but it remains the single most effective therapy. Antioxidants (such as Vit E) induce apoptosis in CRC cells via activation of p21 WAF1/CIP1, a potent cell cycle inhibitor (with incorporation of C/EBPbeta, a member of the CCAAT enhancer-binding protein family of transcription factors) - independent of p53 . Antioxidants significantly increase tumor growth inhibition by cytostatic therapy with 5 FU (and doxorubicin). The combination of chemotherapy and antioxidants provides a new therapy for CRC. (Chinery R et al.; Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21 via C/EBP-beta; Nat Med 1997;3;1233-1241)
Supplementation of vitamin C alone and in combination with beta-carotene leads to a reduced number of advanced ductular lesions in rat pancreatic carcinoma. Vitamin E and/or selenium have no effect. (Appel MJ et al.; Lack of inhibitory effects of beta-carotene, vitamin C, vitamin E and selenium on development of ductular adenocarcinomas in exocrine pancreas of hamsters; Cancer Lett 1996;103:157-162)
Vitamin E significantly inhibits cell growth in human pancreatic cancer cell lines. (Heisler T et al.; Peptide YY augments gross inhibition by vitamin E succinate of human pancreatic cancer cell growth; J Surg Res 2000; 88: 23-25)
Treatment with vitamin C, vitamin E and selenium significantly reduces deaths from gastric and esophageal cancer (Randomised, placebo-controlled; 3365 participants; Ma Jl et al.; Fifteen year effects of Helicbacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality; J Natl Cancer Inst 2012; 104; 488-492)
Vitamin D
Vitamin D decreased in patients with kolonka. significantly the mortality for all causes of death (HR 0.52 for highest versus lowest levels). For colonca mortality, the reduction is 39%. (304 participants (Nurses Health Study, Health Professionals Follow Up Study); Ng K et al.; Circulating 25-Hydroxyvitamin D Levels and Survival in Patients With Colorectal Cancer; Journal of Clinical Oncology 2008, 26, 2984-2991)
Calcium
Colorectal adenomas: With supplementation with calcium (calcium carbonate or calcium gluconolactate), the number of adenoma recurrences was significantly lower than in the randomized comparison group (RR: 0.80, CI: 0.68, 0.93) (Meta-analysis from 3 studies with 1485 participants; Shaukat A et al.; Role of supplemental calcium in the recurrence of colorectal adenomas: a metaanalysis of randomized controlled trials; Am J Gastroenterol. 2005; 100; 390-294)
Alpha lipoic acid
There is evidence that alpha-lipoic acid or the reduced form dihydrolipoic acid effectively induces apoptosis in human HAT-29 colon cancer cells through a pro-oxidative (mitochondrial) mechanism. (Wenzel U et al:; alpha-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2-*-generation; Apoptosis 2005 Mar; 10(2):359-368)
Lycopene
Lycopene inhibits cell proliferation in human colon carcinoma cells and activation of phosphoinositide-2-kinase/Akt signaling pathway (regulates cancer cell survival) (Tang FY et al.; Lycopene inhibits growth of human colon cancer cells via suppression of the Akt signaling pathway; Mol Nutr Food Res 2008; 52; 646-654)
Resveratrol
Resveratrol 25 microM reduces human colon cancer cell growth by 70%. The cells accumulated in the S/G2 phase transition of the cell cycle. Resveratrol significantly reduces the activity of ornithine decarboxylase (a key enzyme in polyamine biosynthesis involved in cancer growth). (Schneider Y et al.; Anti-proliferative effect of resveratrol, a natural component of grapes and wine , on human colonic cancer cells.Cancer Lett. 2000; 158, 85-91)
Resveratrol 200 mcg/kg significantly reduces carcinogenesis of colon cancer in rats. It significantly reduces cell number and alters bax and p21 expression. (Tessitore L et al.; Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21 (CIP) expression. Carcinogenesis 2000;21, 1619-1622)
Resveratrol 100 mcmol/l significantly inhibits cell growth in pancreatic carcinoma cell lines (PANC-1 and AsPC-1) in a concentration- and time-dependent manner and induces cell apoptosis. (Ding XZ et al.; Resveratrol inhibits proliferation and induces apoptosis in human pancreatic cancer cells; Pancreas 2002; 25: e71-76)
Alcohol consumption (wine vs other alcohols)
There is a dose-response relationship between alcohol and rectal carcinoma. More than 41 drinks per week conferred a relative risk of rectal cancer of 2.2 (95% CI) compared to non-drinkers. More than 14 drinks of beer and spirits - but not wine - per week resulted in an RR of 3.5 for rectal cancer compared to non-drinkers, while those who drank the same amount of alcohol but consumed more than 30% than We had an RR of 1.8 for rectal cancer. No association was found between alcohol and colon cancer when examining the effects of the total amount of alcohol in beer, wine and spirits and the proportion of wine in total alcohol consumption. Alcohol intake is associated with a significantly increased risk of rectal cancer, but the risk appears to be reduced when wine is included. (Randomised, population-based cohort study (Copenhagen, Danish Cancer Registry); 29,132 participants over 14.7 Years; Pederson A, Johansen C, Groenbaek M; Relations between amount and type of alcohol and colon and rectal cancer in a Danish population based cohort study; Gut 2003;52:861-867)
Overall, alcoholconsumption itself is not associated with gastric cancer, but the type of alcohol appears to influence risk. Compared to non-wine drinkers, participants who drank 1-6 glasses of wine per week had a relative risk of 0.76 (95% CI), while those who drank more than 13 glasses of wine per week had an RR of 0.16 (95% CI). There is a significant association with an RR of 0.60 (95% CI) for each glass of wine consumed per day. There was no association between beer or spirits and gastric cancer. (3 prospective population-based studies; 28463 participants; Barstad B, Groenbaek M et al.; Intake of wine, beer and spirits and risk of gastric cancer; European Journal of Cancer Prevention 2005; 14; 239-243)
Broccoli (sulforaphane)
Treatment-resistant tumor stem cells play an important role in the pathogenesis of pancreatic cancer Substances such as the broccolicomponent sulforaphane inhibit NFkB, apoptosis inhibitors and angiogenesis and induce apoptosis. Combination with TRAIL (tumor necrosis factor-dependent-apoptosis-inducing ligand) enhances apoptosis in tumor stem cells. (Kallifatidis G et al.; Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB-induced antiapoptotic signalling. Good 2009;58:949-63)
Resveratrol
Resveratrol has a strong growth-inhibiting effect against various human cancer cells. Here, the inhibitory effect of resveratrol on experimental liver cancer is examined using a two-stage model in rats. Resveratrol 50-300 mg/kg body weight reduces the incidence, number, volume and multiplicity of visible hepatocyte nodules in a dose-dependent manner. It leads to a decrease in cell proliferation and an increase in apoptotic cells in the liver. It also induces expression of the pro-apoptotic protein Bax, reduces expression of the anti-apoptotic Bcl-2, and at the same time increases the Bax/Bcl-2 ratio. Due to its favorable toxicity profile, resveratrol has the potential to be developed as a chemopreventive drug against human hepatocellular carcinoma. (Bishayee A, Dhir N; Resveratrol-mediated chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis: inhibition of cell proliferation and induction of apoptosis; Chem Biol Interact 2009;179:131-44)
Resveratrol has a cancer-preventive effect and induces Bax-mediated and Bax-independent mitochondrial apoptosis in human HCT116 colon carcinoma cells at physiological doses. Both pathways limit the cells' ability to form colonies. (Mahyar-Roemer M et al.; Role of Bax in resveratrol-induced apoptosis of colorectal carcinoma cells; BMC Cancer 2002; 2; 27-36)
Quercetin
Quercetin inhibits the growth of human gastric cancer cells. DNA synthesis and cell progression from G1 to S phase of mitosis are suppressed (Yoshida M et al.; The effect of quercetin on cell cycle progression and growth of human gastric cancer cells; FEBS Lett 1990;260;10-13)
Zinc
Zinc inhibits the growth of pancreatic carcinoma cells more effectively than gemcitabine (gold standard of chemotherapy). (Donadelli M etal.; Intracellular zinc increase inhibits p53(-/-) pancreatic adenocarcinoma cell growth by ROS/AIF-mediated apoptosis (Biochim Biophys Acta. 2008)
Omega 3 fatty acids
Polyunsaturated fatty acids (especially the omega 3 fatty acid EPA) have a significant inhibitory effect on the growth of human pancreatic carcinoma cell lines. (Falconer JS et al.; Effect of eicosapentaenoic acid and other fatty acids on the growth in vitro of human pancreatic cancer cell lines;Br J Cancer 1994;69:826-832)
D) Hematology
Vitamin K2
Myeloma cells and B-cell lymphomas (hematological neoplasms) are sensitive to vitamin K2. Growth inhibition occurs, among other things, via apoptosis and activation of caspase-3. K2 represents a good treatment for myeloma patients, particularly those who are unsuitable for intensive cell-reducing chemotherapy due to age or complications. (Tsujioka T et al; The mechanisms of vitamin K2-induced apoptosis of myeloma cells; Haematologica 2006; 91: 613-619)
Vitamin D
Vitamin D levels are seasonal The season of diagnosis is also a strong prognostic factor for Hodgkin's disease (hematological neoplasia), with approximately 20% fewer fatal cases in autumn versus winter (RR 0.783; 95% CI ). Survival time is increased by more than 60% in autumn patients under 30 years (RR 0.364; 95% CI). The increased vitamin D levels have a beneficial effect on conventional therapy. (Epidemiological study over 36 years; Porojnicu AC et al.; Season of diagnosis is a prognostic factor in Hodgkin's lymphoma: a possible role of suninduced vitamin D;Br J Cancer 2005;93:571-574)
Magnesium and Zinc
In children with acute lymphocytic leukemia ALL and malignant lymphoma (hematological neoplasia), there are lower levels of magnesium (significant only in T-cell ALL) and significantly lower levels of Zinc. The serum zinc levels are also reduced. (58 participants; Sahin G et al.; High prevelance of chronic magnesium deficiency in T cell lymphoblastic leukemia and chronic zinc deficiency in children with acute lymphoblastic leukemia and malignant lymphoma; Leuk Lymphoma 2000;39:555-562)
selenium
In patients with aggressive B-cell non-Hodgkin's lymphoma (hematological neoplasia) receiving anthracycline-based chemotherapy and/or radiation, serum selenium levels correlate positively with response rate (OR 0.62; 95% CI) and long-term remission after initial treatment and overall survival time (HR 0.76 for 0.2 mcmol/l increase; 95% CI). (Last KW et al.; Presentation serum selenium predicts for overall survival, dose delivery , and first treatment response in aggressive non-Hodgkin's lymphoma;J Clin Oncol 2003;15;2:2335-2341)
Grape seed extract (OPC)
Grape seed extract (OPC) induces apoptosis in human leukemia cells in a dose- and time-dependent manner (via activation of the c-Jun NH2-terminal kinase). (Gao N et al.; Induction of apoptosis in human leukemia cells by grape seed extract occurs via activation of c-Jun NH2-terminal kinase Clinical Cancer Research 15, 140, January 1, 2009. doi: 10.1158/1078-0432.CCR-08-1447)
Resveratrol
Resveratrol induces downregulation in survivin expression and apoptosis and inhibition of cell growth in T-cell leukemia cell lines. (Hayashibara T et al.; Resveratrol induces downregulation in survivin expression and apoptosis in HTLV- 1-infected cell lines: A prospective agent for adult T cell leukemia chemotherapy; Nutrition and cancer 2002, 44, 192-201)
Resveratrol inhibits the growth of leukemia cells in culture. It induces leukemia cell differentiation, apoptosis, cell cycle arrest in S phase, inhibition of DNA synthesis by blocking ribonucleotide reductase or DNA polymerase. (Tsan MF et al.; Anti-leukemia effect of resveratrol.Leuk.Lymphoma 2002;43, 983-987)
Resveratrol 50 microM induces apoptosis in more than 80% of CD95-sensitive and CD95-resistant acute lymphoblastic leukemia (ALL) cells by depolarizing mitochondrial membranes and by activating caspase-9, independent of CD-95 signaling . There is no significant cytotoxicity to normal peripheral blood cells. (Dorrie J et al.; Resveratrol induces extensive apoptosis by depolarizing mitochondrial membranes and activating caspase-9 in acute lymphoblastic leukemia cells. Cancer Res. 2001;61, 4731-4739)
Resveratrol develops antiproliferative activity.It inhibits proliferation and induces cytotoxicity or apoptosis of cells in Waldenstrom's macroglobulinemia (WM) lymphoma malignancy. Peripheral blood cells are not affected. Resveratrol shows synergistic cytotoxicity when combined with dexamethasone, fludarabine and bortzomib. (Roccaro AM et al.; Resveratrol Exerts Antiproliferative Activity and Induces Apoptosis in Waldenstrom's Macroglobulinemia; Clin. Cancer Res 2008; 14: 1849-1858)
The aim of this study was to investigate interactions of ellagic acid and quercetin with resveratrol (polyphenols) in the induction of apoptosis and reduction of cell growth in the human leukemia cells (MOLT-4). The combination of ellagic acid with resveratrol has a synergistic effect more than additive. Both substances alone and together induce significant changes in cell cycle kinetics. There are positive synergistic interactions between ellagic acid and resveratrol and between quercetin and resveratrol in inducing caspase-3 activity. The anticarcinogenic potential of foods with polyphenols can be enhanced through synergistic effects. (Mertens-Talcott SU, Percival SS; Ellagic acid and quercetin interact synergistically with resveratrol in the induction of apoptosis and cause translent cell cycle arrest in human lekemia cells; Cancer Lett 2005;218;141-151)
E) SKIN
Vitamin C
Vitamin C induces apoptosis of melanoma cells in vitro. (Kang JS et al.; Sodium ascorbate (vitamin C) induces apoptosis in melanoma cells via the down-regulation of transferrin receptor dependent iron uptake; J Cell Physiol 2005;204:192-197)
Vitamin E
Vitamin E promotes quiescence and inhibits angiogenesis in melanoma cells in vitro. It also significantly suppresses the expression of VEGF (endothelial growth factor), VEGF receptor 1 and VEGF receptor 2 in melanoma. (Malafa MP et al.; Inhibition of angiogenesis and promotion of melanoma dormancy by vitamin E succinate; Ann Surg Oncol 2002;9:1023-1032)
Vitamin D
Low vitamin D levels are significantly associated with greater tumor thickness (according to Berslow) in malignant melanoma and an advanced stage. 564 patients had 25-OH-D levels < 20 ng/mL, 145 had levels of 20-30 ng/mL and only 55 had normal range levels of at least 30 ng/mL. (764 participants; Gambichler T et al.; Serum-25-hydroxyvitamin D serum levels in a large German cohort of patinets with melanoma; Br J Dermatol 2013; 168; 625-628)
Vitamin D receptor gene polymorphisms are associated with susceptibility and prognosis for malignant melanoma (MM). The data suggest that the antiproliferative calcitriol (1,25(OH)2D3), the ligand of VDR, has a protective effect against MM. (case control study; 424 Participants; Hutchinson PE et al.; Vitamin D receptor polymorphisms are associated with altered prognosis in patients with malignant melanoma; Clin Cancer Res 2000; 6: 498-504)
selenium
In malignant melanomas and cutaneous T-cell lymphomas (CTCL) there are reduced serum selenium levels depending on the stage of the disease: they are significantly lower in tumor recurrences than in tumors without recurrence.(251 participants; Deffuant C et al.; Serum selenium in melanoma and epidermotropic cutaneous T-cell lymphoma; Acta Derm Venereol 1994; 74: 90-92)
Patients with malignant melanoma have significantly lower selenium levels (increasing with severity) than controls. (101 participants; Reinhold U et al.; Serum selenium levels in patients with malignant melanoma; Acta Derm Venereol 1989; 69: 132-136)
Resveratrol
Solar radiation covers a large electromagnetic spectrum including UV radiation, which is potentially harmful to normal cells, and ionizing radiation, which is therapeutically useful in destroying cancer cells responsible for keratosis. Chemoprevention of UV damage via non-toxic substances, especially plant antioxidants, is an approach to prevent photodamage including photocarcinogenesis. In this paper, the photoprotective effects of resveratrol against UVB exposure-mediated damage are discussed. In addition, we also discussed studies showing that resveratrol can enhance the therapeutic effects of ionizing radiation on cancer cells. Based on literature data, resveratrol may be useful in preventing UVB-mediated damage, including skin cancer, and in enhancing the efficacy of radiation therapy against hyperproliferative, precancerous, and neoplastic conditions. (Reagan-Shaw S et al.; Resveratrol imparts photoprotection of normal cells and enhances the efficacy of radiation therapy in cancer cells; Photochem Photobiol 2008; 84: 415-421)
Non-melanoma skin cancer is the most commonly diagnosed malignancy in the United States. The main cause is multiple exposure to the sun's ultraviolet (UV) radiation (particularly the UV-B component, 290-320 nm). Chemoprevention by naturally occurring agents is considered a newer dimension in the management of neoplasia (including skin cancer). We have shown that resveratrol mediates protection against acute UVB-mediated cutaneous damage in SKH-1 hairless mice. Understanding this mechanism is important. We have previously shown that resveratrol has chemopreventive effects against a range of UV exposure-mediated changes in the cki-cyclin-CDK network, and the mitogen-activated protein kinase (MAPK) signaling pathway. In this study, the skin of SKH-1 nude mice was irradiated with UV-B on alternate days. Topical pretreatment with resveratrol significantly inhibited a UV-B exposure-mediated increase in cell proliferation (Ki-67 immunostaining), epidermal cyclooxygenase-2 and ornithine decarboxylase, established markers of tumor promotion, protein and messenger RNA -Levels of survivin and phosphorylation of survivin in mouse skin. Resveratrol pretreatment also reversed the UV-B-mediated decrease in Smac/DIABLO and the increase in UV-B-mediated induction of apoptosis in mouse skin and increased UV-B-mediated induction of apoptosis in the mouse skin. Overall, our study shows that resveratrol has chemopreventive effects against UV-B exposure-mediated damage in the skin of SKH-1 hairless mice via inhibition of survivin and associated events. (Aziz MH et al.; Prevention of ultraviolet-B radiation damage by resveratrol in mouse skin is mediated via modulation in surviving; Photochem Photobiol 2005; 81: 25-31)