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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 only for 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 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 breast prostate Lungs Uterus Frequency in % (Ø) 16 29w 24m 7w, 14m 3 or 6 w Alcohol abuse X X - - - age > 40 years > 50 years > 50 - > 50 years Anamnestic X X - X - Diabetes mellitus - - - - X Inflammatory Inflammation - Prostatitis - - Unbalanced diet, heavy on meat, low in fiber X - X - - Nutrition X - X - - Genetics Familial approx. 5% approx. 5-10 X approx. 5-10% Sex - X X - X Infections - - - - Sexually transmitted HPV immunosuppression - - - - X Childlessness - - - - X Medications - hormone - - estrogens, early menarche, - - - - X Nicotine abuse X X - XX X polyps, cysts intestinal polyps - - - ovarian cysts race - - Black - - pollution load - - - e.g. Asbestos - Shift work X X X X - Sexual partner - - - - X radiation exposure - X - X X Overweight X X X - X Factor urinary bladder Malignant head pancreas Non Leukemia Frequency in % (Ø) 4w, 8m 1w, 3m 3 3 3 3 Alcohol abuse - - X - - - Anamnestic - X - - - - Diabetes mellitus - - - X - - Inflammatory 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 HTLV Medications cyclophosphamide, phenacetin Arsenic - - - cytostatics, mouth hygiene - - X - - - Nicotine abuse X - X X - X race - fairness - - - - pollution load e.g. - X - - X shift work X - - X X X radiation exposure - UV light X - - X Radiation exposure X Factor Ovaries Testicles Liver stomach kidney Frequency in % (Ø) 5w 2m <1 4 4 Alcohol abuse - - X X X age X - - - - Anamnestic - X - - - Cystic - - - - X Iron storage disease - - X - - Inflammatory - - - stomach lining - Unbalanced diet, heavy on meat, low in fiber - - - - X birth weight - X - - - Genetics X X - X X Sex - X - - - undescended testicles - X - - - Infections - - hepatitis, Helicobacter - Childlessness X - - - - Cirrhosis of the liver - - X - - Medications - - - - painkillers Nicotine abuse - - - X X Estrogen levels ↑ - X - - - reflux esophagitis - - - X - pollution load - - X X X Overweight - - - - X Factor pharynx 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 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, General information and screening for organ disorders and tissue breakdown Immune screening (initial, tumor phase I) Differential blood count with granulocytes, Primarily measures the quality of the Immune system advanced (tumour phase II) lymphocyte differentiation, Indication of tumor-associated changes in immune competence and help in therapy decisions, therapy monitoring Inflammation screening hsCRP, TNFα, histamine, IP-10 Indications of acute or chronic inflammation Detox Screening GSH (intracellular) Indications of the quality of the detoxification function Screening of oxidative-nitrosative stress MDA-LDL, nitrotyrosine, Indications of exposure to radicals and antioxidant capacity Acid-base screening Daily urine pH profile with test strips Indications of acidosis Intestinal function screening Intestinal flora determination, zonulin Indications of the function of the intestine Neuro-endocrine screening Daily cortisol profile (saliva), Indications of the function of the Mitochondrial screening ATP Indications of the function of Nutrition of the tumor TKTL1 Indication of Micronutrient diagnostics e.g.Zinc and iron (low levels Indications of undersupply Bleeding diagnostics hemoglobin-haptoglobin in stool Indications of microbleeds What can make sense for graded oncologically oriented laboratory diagnostics in practice measure Use TPA (tissue polypeptide antigen) Non-specific tumor marker, mutation of the gene p53 capacity for apoptosis unspecific p53 autoantibody Non-specific tumor marker positive in 10-30% of tumors Apo10 antigen Non-specific tumor marker (healthy cells are Apo10-negative), Cyp1B1 enzyme Non-specific tumor marker Chemosensitivity test Tumor tissue is treated with medication in order to find the most suitable substance for the CEA (carcinoembrional antigen) Highly specific, especially for colon-Ca (80%) and less PSA (prostate specific antigen) In suspected prostate Ca TG (thyroglobulin), In suspected thyroid Ca AFP (α1-fetoprotein) In suspected liver Ca, teratoma AFP and HCG (human In suspected germ cell tumors (testicles, ovary) CA 72-4 In case of suspected stomach-Ca, breast-Ca Monoclonal immunoglobulins In suspected multiple fibroids CA 19-9, CA 195, TPA In suspected pancreas-.Ca CA 15-3, CA 549, MCA (Mucin-like 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 In suspected bone metastasis11 SCC (squamous cell carcinoma antigen) In V.a.Cervical Ca Bence Jones proteins and 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 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, 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, 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 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. 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, Do you live - or have you lived - within a 5 km radius of a Are you overweight? Important micronutrient groups for general cancer prevention micronutrient Special features (general effects) Antioxidants have an antioxidant effect (protect cells from damage caused by radicals), polyphenols (e.g. isoflavonoids) have an antioxidant and anti-inflammatory effect, zinc Balances the immune system, activates lymphocytes, controls apoptosis, selenium activates DNA repair enzymes, induces tumor cell apoptosis, 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 fatty acids (e.g.γ-linolenic acid, 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 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 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 α-lipoic acid Antioxidant, detoxifying (chelating agent) Secondary plant substances Antioxidant, anti-inflammatory, antiproliferative, selenium (inorganic) reduces resistance and angiogenesis iron Iron deficiency is common in cancer patients and must be optimally treated zinc Immune balancing, possibly inhibits tumor cell apoptosis 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), 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 antioxidants Prostate, breast, uterus, ovaries, intestines, lungs, pancreas, glioblastoma, melanoma polyphenols 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, 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) 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 Vit C, Vit E and β-carotene (with paclitaxel, carboplatin), antioxidants (general), omega-3 fatty acids Enhancement of Genistein (in Re-neg breast cancer), Vit D, γ-linolenic acid, coenzyme Q10,Vit B2 and Vit B3 Increase in the number of glutathione Improvement of the Antioxidants (such as Vit C, Vit E, glutathione) improvement of 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: 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. 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. 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 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: 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. Selected studies on selenium in oncology Enzymes There are basically three main groups of enzymes to be distinguished in therapeutic use in cancer: 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 ii) Cancer risk for individual tumor types Prostate Gynecological tumors / breast carcinoma lungs gastrointestinal tract (incl. liver and pancreas) Urology Hematology Individual tumor types A) Prostate B) Gynecological tumors C) Gastrointestinal tract and pancreas D) Hematology E) SKIN Source: Dr. Udo Böhm, Handbuch Krebs, 2014
carcinoma
cancer
cancer
(cervix, endometrium)
years
malignancies
diseases
of the intestine
(more than 1 liter
milk per day)
Polyposis
(mainly
BRCA-1,
BRCA-2)
%
(e.g.HNPCC syndrome)
replacement
therapy,
calcium
antagonist
tamoxifen,
aromatase inhibitors
late menopause
(especially with
night work)
alternating
(e.g.through
diagnostic or
therapeutic
medicine, profession)
melanoma
(skin)
neck
tumors
Hodgkin
lymphoma
malignancies
diseases
Barr
immunosuppressants
lacking
aromatic
amines
(especially with
night work)
(eg.through
diagnostic or
therapeutic
medicine, profession)
(living within
5 km to
nuclear power plant)
malignancies
kidney disease
diseases
low
moulds
pylori
(mother or man)
larynx
lacking
uric acid, protein electrophoresis,
LDH, GOT, GPT, y-GT, AP, SP,
TSH, K, Na, calcium, Fe, HDL, LDL,
triglycerides, urinary status
monocytes, lymphocytes (cellular),
immunoglobulins
IgA, IgG, IgM, IgE (humoral),
TH1/TH2 balance
defense, says little about
tumor-specific defense (since
tumor cells are mostly camouflaged, at least initially
)
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
IL-1, IL-6, NFkB
Detox advanced
Paracetamol, caffeine metabolite test
GSH/GSSG
Oxidative-nitrosative stress advanced
Antioxidant capacity (TAS),
hydroperoxides, antioxidants,
lactate pyruvate, methylmalonic acid,
8-OH-deoxyguanosine
Acid-base advanced
Sander titration
Intestinal function advanced
(serum marker for intestinal permeability)
antitrypsin
(inflammatory marker in stool)
Neuro-endocrine function advanced
noradrenaline, serotonin
tryptophan, tyrosine, dopamine, DHEA
neurotransmitter metabolism
Mitochondria advanced
L-carnitine, coenzyme Q10
mitochondria
energy production in the tumor
indicate tumor activity),
copper and ferritin (high levels
indicate tumor activity),
selenium, Vit B12, Vit B2, glutathione,
homocysteine , folic acid
and imbalance as well as
tumor activity
erythrocytes in urine
Tumor associated proliferation antigen
Independent of the primary tumor and generally applicable
(prognostic factor for various tumors)
(healthy cells are p53 autoantibody negative)
which indicates disturbances in apoptosis of tumor cells
(from the cytochrome p450 family)
(according to Dr. Dan Burke, healthy cells are Cyp1B1 negative)
tumor in question
tumor associated antigen
specific for pancreatic-Ca (60%), mamma-Ca (55%) and
bile-duct and bronchial-Ca (50%) or similar tumors
Tissue specific antigen
hCT (human calcitonin)
chorionic gonadotropin)
and Bence Jones proteins
Carcinoma Associated Antigen)
(ostasis, bone AP)
beta-2 microglobulin
cancers: breast cancer, colon cancer, ovarian cancer, uterine cancer,
stomach cancer?
pancreas, gastric mucosa, reflux oesophagitis)?
Eppstein-Barr, HTLV, AIDS, hepatitis, mold, Helicobacter pylori)
calcium antagonists, contraceptives, estrogens, tamoxifen, phenacetin, painkillers,
cyclophosphamide, arsenic, cytostatics, immunosuppressants or so-called aromatase inhibitors?
asbestos, mercury, aromatic amines)?
diagnostic or therapeutic medicine)?
nuclear power plant?
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.
(e.g. Vit. C, Vit E, glutathione)
support detoxification, reduce the overall risk of cancer
carotenoids
(e.g. β-carotene, lycopene)
support detoxification, reduce the overall risk of cancer
Zinc deficiency increases cancer incidence
reduces overall cancer risk
by B12, but: deficiency increases cancer incidence
omega-3 fatty acids)
standard substance
(most effective as
natural Vit E
with all tocopherols)
In late therapy, possibly tumor cell protection factor (protection from therapeutic
radicals) and possibly Multi-drug resistance (when levels ↑)
(polyphenols, carotenoids)
Cave high-dose phytoestrogens in Re+ breast cancer
(KI under hormone therapy)
standard substance
caveat: distance to Vit C
(administration after basic therapy and in case of deficiency)
other B vitamins unproblematic
certain types of cancer
(e.g. Vit.C, glutathione)
(e.g. resveratrol, isoflavonoids),
carotenoids (e.g. lycopene)
B-CLL, myeloma
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,
γ-linolenic acid and oleic acid (enhance cytotoxic effect of docetaxel,
paclitaxel)
Vit E (enhance cytotoxic effect of cisplatin)
and prolongation of
survival time
tamoxifen effect
therapy cycles
operation success
(e.g.Improvement of
wound healing, reduction
of infection risk and
organ failure)
Selenium
Zinc
L-arginine, L-glutamine
Omega-3 fatty acids
Probiotics
radiation success
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.
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)
(Bhat K, Pezzuto JM; Cancer Chemopreventive Activity of Resveratrol, Annals of the New York Academy of Sciences 2006; 957; 210-229)
(Harikumar KB et al.; Resveratrol: a multitargeted agent for age-associated chronic diseases; Cell Cycle 2008; 7; 1020 -1035)
(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)
(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)
(Tsan MF et al.; Anti-leukemia effect of resveratrol.Leuk.Lymphoma 2002;43, 983-987)
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)
(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)
(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 )
(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)
(Roccaro AM et al.; Resveratrol Exerts Antiproliferative Activity and Induces Apoptosis in Waldenstrom's Macroglobulinemia; Clin. Cancer Res 2008; 14: 1849-1858)
(Bishayee A; Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials; Cancer Prev Res (Phila Pa) 2009; 2: 409-418)
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)
(Aggarwal BB et al.; Role of Resveratrol in prevention and therapy of cancer: preclinical and clinical studies; Anti-cancer Res 2004; 24; 2783-2840 )
(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)
(Goswami SK, Das DK; Resveratrol and chemoprevention; Cancer Lett 2009; 284: 1-6)
(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)
(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)
(Mahyar-Roemer M et al.; Role of Bax in resveratrol-induced apoptosis of colorectal carcinoma cells; BMC Cancer 2002; 2; 27-36)
(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)
(Opipari AW et al.; Resveratrol-induced autophagy in the ovary Cancer Cells; Cancer Research 2004; 64, 696-703)
(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)
(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
(Review; Vidavalur R et al.; Significance of wine and resveratrol in cardiovascular disease: French paradox revisited;Exp Clin Cardiol.2006;11:217-225)
(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)
(Lipinski B; Rationale for the treatment of cancer with sodium selenite; Med Hypotheses 2005; 64; 806-810)
(Wallenberg M et al.; Selenium cytotoxicity in cancer; Basic & Clinical Pharmacology & Taxocology 2014; 1-10)
(Björnstedt M, Fernandes AP; Selenium in the prevention of human cancers. EPMA J 2010;1: 389-95)
(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)
(Combs GF Jr; Chemopreventive mechanism of selenium; Med Klin 199; 94 Suppl 3; 18-24)
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-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)
(Review; Boyer J et al.; Apple phytochemicals and their health benefits; Nutr J 2004; 3; 5)
(Randomized, double-blind, placebo-controlled; 13017 participants; SU.VI.MAX; 2004; Serge Hercberg et al.; Arch Intern Med .2004;164;2335-2342)
(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)
(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)
(36265 participants over 8 years; Knekt P et al.; Vitamin E and cancer prevention; The Amer J of Clin Nutr 1991; 53; 283S-286S)
(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)
(Ignatowicz E et al.; Resveratrol, a natural chemopreventive agent against degenerative diseases; Pol J; Pharmacol 2001; 53; 557-569)
(Jang MS et al.; Cancer chemopreventive activity of reseveratrol, a natural product derived from grapes; Science; 1997; 275 ; 218-220)
(Baur JA, Sinclair DA; Therapeutic potential of resveratrol: the in vivo evidence; Nature Reviews Drug
Discovery 2006; 5, 493 -506)
(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)
(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)
(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)
(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)
( 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)
(Seo YR et al.; selenomethionine regulation of p53 by a ref1-dependent redox mechanism; Proc Natl Acad Sci USA 2002;99;14548-14553)
(Rayman MP; Selenium in cancer prevention: a review of the evidence and mechanism of action; Proc Nutr Soc 2005; 64; 527-542)
(Ujiie S et al.; Serum Selenium contents and the risk of cancer; Gan To Kagaku Ryoho 1998;25;1891-1897)
(Combs GF Jr; Chemopreventive mechanism of selenium; Med Klin 199; 94 Suppl 3; 18-24)
(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)
(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)
(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)
(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)
(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))
(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)
(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)
(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)
(Corcoran NM et al.; Inorganic selenium retards progression of experimental hormone refractory prostate cancer;J Urol 2004;171:907-910)
(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)
(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)
(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)
(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)
(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)
(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)
(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)
(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)
(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 )
(Van Die MD et al.; Soy and soy isoflavones in prostate cancer : a systematic review and meta-analysis of randomized controlled trials.)
(Adlerkreutz H et al.; Plasma concentrations of phyto-oestrogens in Japanese men; Lancet 1993; 342; 1209-1210)
(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)
(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)
(Case-control study; 1563 participants; Ziegler RG et al.; Migration patterns and breast cancer risk in Asian-American women; JNCI 1993 ;85;1819-1827)
(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)
(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)
(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)
(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)
(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)
(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)
(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)
(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.)
(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)
(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)
(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)
(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)
(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)
(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)
(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)
(Randomized case-control study; Ingram D. et al.; case-control study of phyto-oestrogens and breast cancer; Lancet. 1997;350;990-994)
(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)
(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)
(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)
(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)
(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)
(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)
(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)
(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.)
(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)
(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)
(Lopez-Saez Jb et al .; Selenium in breast cancer; Oncology 2003; 64; 227-231)
(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)
(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)
(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)
(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)
(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)
(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)
(Cohort study, 500 participants; Hartman TJ et al.; Selenium concentration and lung cancer in male smokers; Cancer causes Control 2002 ;123;923-928)
(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)
(Review; Fritz H et al.; Selenium and lung cancer: a systemic review and meta analysis; PLoS One 2011; 6; #26259)
(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)
(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)
(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)
(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)
(Eberhardt MV et al. ; Antioxidant activity of fresh apples; Nature 2000;405:903-904)
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)
(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)
(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)
(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)
(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)
(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)
(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)
(517 participants; Amarai AF et al; Pancreatic cancer risk and levels of trace elements; Gut 2011)
(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)
(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)
(Shukla VK et al.; Micronutrients, anbtioxidants, and carcinoma of the gallbladder; J Surg Oncol 2003; 84; 31-35)
(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)
(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)
(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)
(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)
(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)
( 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)
(Gorham ED et al.; Vitamin D and prevention of colorectal cancer; J Steroid Biochem Mol Biol 2005; 97; 179-194)
(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)
(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 )
(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)
(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)
(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)
(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.)
(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)
(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)
(Jones DP; Glutathione distribution in natural products: absorption and tissue distribution; Methods in Enzymology 1995; 25; 3 -13)
(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)
(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)
(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)
(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)
(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)
(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)
(Altwein JE; Primary prevention of bladder cancer; What's new? Urologe A 2007; 46; 616-621)
(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)
(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)
(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)
(249 participants over 10 years; Thompson JR et al.; The Lancet 2001; 358; 9297)
(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)
(Jiang XR et al.; The anti-leucaemic effects and the mechanism of sodium selenite; Leuk Res 1992; 16; 347-352)
(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)
(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)
(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)
(Randomized, double-blind; 29,133 smokers; Heinonen OP et al .;ATCB study;J Natl Cancer Inst 1998;90;440-446)
(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)
(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)
(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)
(Kallifatidis G, Herr I et al.; Sulforaphane targets pancreatic tumor-initiating cells by NF-kB-induced antiapoptotic signaling. GUT 2008 , in press)
(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)
(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)
(558 Participants; Palmieri C et al.; Serum 25-hydroxyvitamin D levels in early and advanced breast cancer; J Clin Pathol 2006; 59; 1334-1336)
( 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 )
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)
(Opipari AW et al.; Resveratrol-induced autophagocytosis in ovarian cancer cells ; Cancer Research 2004; 64, 696-703)
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)
(Jiang C et al.; Selenium induced inhibition of angiogenesis in mammary cancer at chemopreventive levels of intake; Mol Carcinog 1999; 26; 213-225)
(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)
(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)
(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)
(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)
(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)
(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)
(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)
(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)
(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)
(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)
(Ding XZ et al.; Resveratrol inhibits proliferation and induces apoptosis in human pancreatic cancer cells; Pancreas 2002; 25: e71-76)
(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)
(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)
(Kallifatidis G et al.; Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB-induced antiapoptotic signalling.
(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)
(Mahyar-Roemer M et al.; Role of Bax in resveratrol-induced apoptosis of colorectal carcinoma cells; BMC Cancer 2002; 2; 27-36)
(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)
(Donadelli M etal.; Intracellular zinc increase inhibits p53(-/-) pancreatic adenocarcinoma cell growth by ROS/AIF-mediated apoptosis (Biochim Biophys Acta. 2008)
(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)
(Tsujioka T et al; The mechanisms of vitamin K2-induced apoptosis of myeloma cells; Haematologica 2006; 91: 613-619)
(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)
(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)
(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)
(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)
(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)
(Tsan MF et al.; Anti-leukemia effect of resveratrol.Leuk.Lymphoma 2002;43, 983-987)
(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)
(Roccaro AM et al.; Resveratrol Exerts Antiproliferative Activity and Induces Apoptosis in Waldenstrom's Macroglobulinemia; Clin. Cancer Res 2008; 14: 1849-1858)
(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)
(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)
(Malafa MP et al.; Inhibition of angiogenesis and promotion of melanoma dormancy by vitamin E succinate; Ann Surg Oncol 2002;9:1023-1032)
(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)
(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)
(101 participants; Reinhold U et al.; Serum selenium levels in patients with malignant melanoma; Acta Derm Venereol 1989; 69: 132-136)
(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)
(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)