Factor

Colorectal
Carcinoma

Breast
Cancer

Prostate
Cancer

Lungs

Womb
(cervix, endometrium)

Frequency in % (Ø)

16

29 w

24m

7w, 14m

3 or 6w

Alcohol abuse

X

X

-

-

-

Age

> 40 years

> 50 years

> 50
years

-

> 50 years

Anamnestic
Malignant tumors

X

X

-

X

-

Diabetes mellitus

-

-

-

-

X

Inflammatory
diseases

Inflammation
of the intestine

-

Prostatitis

-

-

Diet unbalanced, heavy on meat, low in fiber

X

-

X

-

-

Nutrition
(more than 1 liter
milk per day)

X

-

X

-

-

Genetics

Familial
Polyposis

approx. 5%
(especially
BRCA-1,
BRCA-2)

approx. 5-10
%

X

approx. 5-10%
(e.g.b HNPCC syndrome)

Gender

-

X

X

-

X

Infections

-

-

-

-

Sexually transmitted HPV

Immunosuppression

-

-

-

-

X

Childlessness

-

-

-

-

X

Medicines

-

hormone
replacement
therapy,
calcium
antagonists

-

-

Estrogens,
Tamoxifen,
Aromatase inhibitors

Early menarche,
Late menopause

-

-

-

-

X

Nicotinine abuse

X

X

-

XX

X

Polyps, cysts

Intestinal polyps

-

-

-

Ovarian cysts

Race

-

-

Black

-

-

pollutant pollution

-

-

-

e.g.b Asbestos

-

Shift work
(especially with
night work)

X

X

X

X

-

Sexual partner
changing

-

-

-

-

X

Radiation exposure
(e.g.b 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
Malignant tumors

-

X

-

-

-

-

Diabetes mellitus

-

-

-

X

-

-

Inflammatory
diseases

Inflammation of the bladder

-

-

Inflammation of the pancreas

-

-

Diet unbalanced, heavy on meat, low in fiber

X

-

-

-

-

-

Genetics

-

X

-

X

-

-

Skin nevi

-

X

-

-

-

-

Immunosuppression

-

X

-

-

-

-

Infections

-

-

Eppstein Barr

-

Eppstein
Barr

HTLV

Medicines

Cyclophosphamide, Phenazetin

Arsenic

-

-

-

Cytostatics,
Immunosuppressants

Oral hygiene
lacking

-

-

X

-

-

-

Nicotinine abuse

X

-

X

X

-

X

Race

-

Fair skinnedness

-

-

-

-

pollutant pollution

e.g.b
aromatic
amines

-

X

-

-

X

Shift work
(especially with
night work)

X

-

-

X

X

X

Radiation exposure
(e.g.b

Note

This blog post provides information about micronutrients and would like to encourage people to deal with health issues independently. 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 about dosages, forms of application or any inaccuracies in the content. Each application is the user's own responsibility.

Cancer as a multifactorial disease of the entire body

Cancer is not just a disease of one organ, but can be viewed as a disease of the whole body . The entire metabolism is involved in its prevention, establishment and progression. Its development represents a complex, multi-stage process that can take place over many years and depends on many factors (see figure below). In the development of malignant tumors, endogenous and exogenous causes interact with incorrect control or excessive demands on the metabolism to varying degrees. 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, which can develop into malignancies. So-called proto-oncogenes, which promote malignant transformations and suppressor genes (e.g. control genes, repair genes), which inhibit the transformation, are also associated with the development of cancer.

Genetic factors are, according to the current state of knowledge, on average only for approx. 5.5% of Cancers are responsible, but can occur more frequently in individual tumors, for example in 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 poor diet or abuse of everyday drugs (such as nicotine and alcohol). Recognized risk factors for the development of prostate cancer include - in addition to genetics - obesity, a diet with a high proportion of “unfavorable” fats, alcohol, lack of exercise and low sexual activity.

In addition, if the damaged cells themselves want to multiply and later develop into cancer, they must have special properties that enable them to survive in a “hostile environment”. These include the ability

• To remain invisible to the immune system (including repair mechanisms and apoptosis) for as long as possible
• to build up your own blood supply or to form new vessels (angiogenesis)
• to survive in a hypoxic environment
• to migrate from a cell network and form metastases

In order to really “defeat” cancer or even just push it back, we have to deal intensively with the above-mentioned causes of cancer development and with the factors that promote or inhibit cancer growth.

In order to prevent the development of cancer, the body has various effective aids that cascade in the event of danger and complement each other. 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 overwhelmed or fail.

Important for the success of the repair measures are, among others:

• A well-functioning metabolism (including energy production in the mitochondria)
• a good detoxification performance
• a fine coordination of the cellular (especially T-lymphocytes) and humoral (especially antibodies) components of the immune system
• the influence of inflammation and latent acidosis as well as
• reducing the occurrence of free radicals

The 3 phases of cancer

Today, cancer development is divided into three phases

1. Cancer initiation
2. Cancer promotion
3. Cancer progression

In each of these phases, the above-mentioned factors such as oxidative stress, changes in energy balance, infections or chronic inflammation are also involved, which is why considerations on influencing these functional circuits must be incorporated into future concepts.

During Cancer initiation one or more healthy cells change, which - if they are not repaired or destroyed - serve as “cancer stem cells” and, under favorable conditions, transform into active cancer cells over time and become can multiply uncontrollably. The cause is damage to the mitochondrial or nuclear DNA due to unfavorable genetics or - more often - due to one or more other factors (e.g. carcinogens, infections, oxidative stress). Chemical carcinogens such as polycyclic aromatic hydrocarbons, for example, are metabolized to reactive species and tumor-promoting substances promote the expression of genes whose products promote inflammation. This primarily includes 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 and cell proliferation and the apoptosis of a cell) and other transcription factors are closely linked to inflammatory and immune responses as well as to 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 in preventing cancer initiation. The genetic damage in the cell is passed on to daughter cells.

If “pro-carcinogenic” factors are present (e.g. inflammation, growth factors, hormones) and the repair mechanisms and the initiation of programmed cell death to dispose of cancer cells do not work, 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 play a role that are involved in the regulation of cell proliferation and programmed cell death. 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 stimulates NFkB activity.

After a usually longer period of time (usually between 2 and 30 years), the third phase of cancer development occurs, the phase of cancer progression, in which the tumor grows. It can lead to - in this case undesirable - new vessel formation (angiogenesis) and ultimatelych come to metastasis. The increased angiogenesis ensures the tumor's energy supply and facilitates its spread. Other important promoters of tumor promotion and tumor progression are accelerated cell growth and a 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 as well as the transcription factor p53, the cell cycle inhibitor p21 induced by p53 and various tumor-promoting substances such as protein kinases and cyclins.

Development of cancer

Metabolic cycles and cancer

Cancer itself, the effects associated with the disease and the therapeutic efforts change us in general, as well as our bodies and our metabolism in particular. Metabolic dysfunctions, in turn, further increase 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. In particular, the burden of exogenous pollutants is increasing significantly, and it is particularly problematic that we do not even recognize many of these pollutants and that even small individual amounts can accumulate to create a large overall level of harmfulness. Most pollutants have a carcinogenic effect and must therefore be detoxified as quickly as possible before they can cause damage. This happens via a multi-stage detoxification program primarily 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 functions function optimally.

b) Oxidative stress and cancer

Radicals are formed in different types and quantities through a variety of exogenous and endogenous processes, depending on individual lifestyle, genetics and metabolic situation. They usually have a negative effect on metabolism and are recognized, among other things, as causing damage to mitochondrial DNA and cell DNA or 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 levels. Therefore, in addition to avoiding the formation of harmful radicals from endogenous and exogenous sources, it is important to remove unavoidable radicals.< as quickly as possible t5>

An exception to this rule exists, for example, during oncological chemotherapy and radiation therapy, because tumor cells are supposed to be killed in part through the formation of radicals. Unfortunately, as an unpleasant side effect, the still healthy cells are damaged. University and complementary oncology should therefore work together to find ways that, on the one hand, do not hinder 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 individual patients.

c) Inflammation and cancer

Inflammation is now recognized as an important player in the development of cancer and many other diseases, although according to today's scientific standards, acute inflammation tends to have a protective effect and chronic inflammation promotes the development of cancer. It is assumed that approx. 15-20% of all cancers are caused by inflammationbe caused (see study examples). A balance must therefore be found between promoting useful inflammation and minimizing damaging inflammatory processes and, in particular, undesirable chronic inflammation must be avoided or ended using measures that are as gentle as possible.

d) Immune system and cancer

In the medical literature you can often find 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 a strong body's guard against cancer risks. Its initial task is to chronic inflammation (e.g. chronic hepatitis) or biological pollutants (e.g. oncogenic viruses such as EBV, HHV-8 , HTLV or HPV) to be eliminated in advance of any resulting changes in body cells and to prevent mutations. For this to happen, the immune system must function optimally and perceive these dangers as completely as possible. This is hardly possible, for example, with an immune system that is suppressed (even therapeutically). Next, the immune system must destroy degenerated body cells that can no longer be repaired. This is more difficult because damaged cells are also the body's own cells and their antigens are initially not recognized by the immune system. However, since damaged cells trigger inflammation and certain tumor-specific antigens can arise through genetic reprogramming or oncogenic viruses, they are often presented to the immune system for destruction.

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 ultimately, the immune system must be able to protect the body weakened by cancer therapy, for example from the uncontrolled proliferation of remaining cancer cells or from new infections, which is why any disease- and therapy-related immunosuppression occurs 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, the immune system often already has tolerance to tumor antigens at the level of CD4 and CD8 T cells. Tumors also produce cytokines such as TGF-β or IL-10, which reduce inflammation and create tolerance to T cells, or they produce increased levels of IDO (indoleamine 2,3-dioxygenate), which leads to tryptophan deficiency (which in turn impairs the function of the T cells impaired) and FASL (ligand of member 6 of the TNF receptor superfamily), which causes apoptosis of T cells.

University oncology is therefore trying to mobilize the immune system against larger tumors that are already visible, but this has so far only been unsuccessful because the immune system is apparently unable to attack or even destroy larger tumors. However, the oncologists hope that at least micrometastases or tumor residues remaining after basic therapy can be eliminated by an optimally functioning immune system. For this purpose, passive immunizations with monoclonal antibodies or activation of the complement system, NK cells or macrophages against components of tumor cells are being tested. Antibodies are also used to increase T cells against tumor antigens and NK cells and to reduce VEGF (vascular endothelial growth factor), which promotes the formation of new blood vessels. To the late non-specificTo activate the immune system in tumors that have already been detected, the use of cytokines such as TNF-α, IL-2 or IFN-α is being tested.

However, it is probably not sufficient to strengthen the immune system of the already ill person in late therapy (i.e. at the point at which university measures usually begin to take effect) with possibly additional stressful medications. Instead, the immune system should be modulated long beforehand in prevention and early therapy with gentle activities and, for example, the humoral and cellular immune system should be strengthened using 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 now been confirmed several times, cancer cells can also obtain their energy through the fermentation of sugar (aerobic glycolysis) in the cell cytosol. In this case, you largely forgo 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 occur 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, among other things, through the amounts formed is controlled at TKTL1. The additional glycolysis via the pentose phosphate pathway enables the tumor cell to achieve higher energy yield.

During fermentation, the cancer cell requires 20 to 30 times the amount of sugar compared to the oxygen combustion in the mitochondria to generate sufficient amounts of energy. In contrast to normal cells, which usually only use fermentation when there is a lack of oxygen, cancer cells actually use fermentation in the presence of oxygen. Due to the increased lactate formation when glycolysis is primarily used, the tissue surrounding the tumor becomes hyperacidic, 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 can result.

An attempt should therefore be made to inhibit energy production by 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, the inhibition of fermentation should be combined with an 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. To this end, in addition to the generally valid risk factors, it appears necessary to know as many recognized risk factors as possible that are specific to individual tumor types and, if present, early therapy appears to make sense. These specific factors can be found, for example, in the various oncological guidelines or from the German Cancer Aid (Blue Guide, Your Cancer Risk). The most well-known of these factors are listed in the following tables.

Cancer risk factors and types of cancer that these factors preferentially trigger

If, after knowing the basic data, we want to decide on “early cancer therapy” at a time when the tumor is still too small to be generally visible, tumor markers, ultrasound examinations or whole-body CTs come at a very early stage Tumor stage often provides no reliable results. However, the laboratories in particular offer a large number of additional diagnostic parameters, which are listed below. Tables are listed.

What could make sense for a graduated or...ncologically oriented laboratory diagnostics in practice

Approaches for useful reserve diagnostics in practice (including common tumor markers)

Sample questionnaire for a “cancer check”

The one below Of course, the questionnaire does not replace a medical diagnosis, but rather serves to raise awareness of your own cancer risk by asking about some relevant cancer risk factors. Even if all questions are answered in the negative, this of course does not mean that there is no risk of cancer.

If you answered “yes” to one or more of these questions, it is likely that you have an increased risk of cancer. In this case, be sure to discuss with your therapist what further steps, if any, should be taken.

Important micronutrient groups for general cancer prevention

Guide micronutrients for Primary prevention of cancer and their special features

Lead substances in early cancer therapy and late cancer therapy

Lead substances in cancer therapy and a proven influence on certain types of cancer

Synergistic effects of micronutrients on basic university therapy

The benefits of the above-mentioned micronutrients can be explained by their biochemical effects and by 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 are useful here include vitamin C, vitamin E, vitamin A, glutathione, α-lipoic acid, coenzyme Q10 and secondary plant substances (polyphenols, carotenoids) as well as cofactors of enzymatic antioxidants such as selenium, manganese, zinc or iron.

• Anti-inflammatory and immunomodulating substances:
  Omega-3 fatty acids and vitamin D as well as zinc, selenium and secondary plant substances have proven to be particularly useful in this function. Vitamin D, for example, in addition to anti-inflammatory tasks, takes on important functions for a balanced immune system (acts as a regulator in the immune system, activates macrophages and the formation of the body's own antibodiesiotics) and for calcium metabolism.
• In addition to these substances, other substances described in the table above 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 development and are suitable as chemopreventive substances against cancer initiation, but also against cancer promotion and cancer progression, are widely used, which is why they can also be used as a complement to the basic treatment of the disease.

Resveratrol initially acts primarily preventively 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 influences cancer initiation (Phase I). Through its antioxidant effects and the promotion of the formation of antioxidant enzymes (e.g. catalase, superoxide dismutase and hemoxygenase-1), it protects DNA from oxidative damage. 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 resistance to therapy because they inactivate chemotherapy drugs such as tamoxifen or docetaxel. The reaction of resveratrol with Cyp 1B1 also produces the resveratrol metabolite and tyrosine kinase inhibitor piceatannol, which activates the apoptosis of tumor cells. 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 HIF-1α protein in cancer cells. In cancer, it reduces the activities of the hypoxia-induced VEGF promoter and the release of VEGF as well as the activity of various protein kinases, which also leads to a significant decrease in the accumulation of the HIF-1α protein and the activation of VEGF transcription.

Resveratrol also significantly inhibits the invasiveness of cancer cells. In its function in detoxification processes, it inhibits phase 1 enzymes, which can activate procarcinogens, and promotes the formation of phase II enzymes, which contribute to the 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 has an effect in secondary prevention or early therapy on various factors involved in tumor promotion and tumor progression and thereby inhibits tumor cell number, tumor growth and tumor spread. Here too, it is initially involved in the downregulation of inflammatory processes in several ways. It inhibitst Synthesis and release of pro-inflammatory and cancer-promoting 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 the 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 by altering biomarker expression.

Resveratrol promotes pro-apoptotic factors and induces the programmed cell death (see figure), which is essential for protection against cancer, 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

The Apoptosis is the better known form of programmed cell death and can be initiated both extrinsically and intrinsically.

• The extrinsic pathway begins with the binding of a ligand (e.g. TNF or other 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, tumor suppressors such as p53 are activated by DNA damage. P53 stimulates substances of the pro-apoptotic Bcl-2 family (Bax, Bad), which release cytochrome C from mitochondria and thereby trigger the caspase cascade and the final apoptosis.

Apoptosis can be suppressed by anti-apoptotic substances of the Bcl-2 family (Bcl-2, Bcl-xL) as well as by protein kinase B and IAP (inhibitor of the apoptosis protein). The initiation 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 CD95-independent activation of Caspases (e.g. caspase-9, caspase-3).

Resveratrol additionally 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 COX-2 mRNA and TPA-induced protein kinase-C and casein kinase 2. It suppresses 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 the mRNA for survivin 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 via inactivation of the cell death protease caspase-9 and facilitate aberrant mitotic progression.

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 Epigallocatechin-3-gallate (EGCG) in green tea , which blocks an important enzyme in the proliferation of cancer cells. The lesser-known secondary plant substances include protease inhibitors, which are mainly found in soybeans, legumes and various grains. They are also said to have good anticancer effects, which is also reflected in the fact that synthetic protease inhibitors such as bortezomib are now used in university oncology. What is particularly interesting is the idea that resveratrol has a positive synergistic effect with other secondary plant substances (e.g. quercetin) and that there is no significant cytotoxicity towards healthy cells in any of the processes influenced by resveratrol.

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 linked by a p53-independent induction of p21 and p21-mediated cell cycle inhibition with a depletion of survivin. Simultaneous analysis of cell cycle, survivin expression, and apoptosis demonstrated that resveratrol-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 followed by 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 apoptosis induced by dead receptor ligation or cancer drugs. This combined sensitizer (resveratrol) and inducer (e.g. TRAIL) strategy may be a new approach to improving the effectiveness 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 have antioxidant and antimutagenic effects and thus as an anti-initiation agent. Resveratrol selectively suppresses transcriptional activation of cytochrome P-450 1A1 and inhibits the formation of carcinogen-induced preneoplastic lesions in 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 COX-2 mRNA- and TPA-induced activation of protein kinase C and 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 linked to inflammatory and immune responses and to oncogenesis in some models of cancer development. Resveratrol suppresses the induction of this transcription factor. The mechanism also involves a reduction in phosphorylation and degradation of IκBα. At the cellular level, resveratrol induces apoptosis, cell cycle Vdelay or block the G1→S transition phase in a number 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-γ), 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 disease, cardiovascular disease and lung disease. Efforts are also underway to improve its effect 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 nervous system, liver, cardiovascular system and cancer chemoprevention. It blocks the different phases of cancer development (tumor initiation, promotion and progression). One of the possible mechanisms for its biological activities includes the downregulation of inflammatory responses by inhibiting the synthesis and release of pro-inflammatory mediators, the alteration of eicosanoid synthesis, the inhibition of activated immune cells by inducible nitric oxide synthase (iNOS) and by cyclooxygenase-2 ( COX-2) via its inhibitory effect on nuclear factor B (NF-B) or activator protein-1 (AP-1). Recent data provide interesting insights into the effect of resveratrol on lifespan in 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 reviews its potent anti-inflammatory activity and the plausibility of these mechanisms and provides an update on the bioavailability and pharmacokinetics of resveratrol as well as its 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, cell cycle S-phase 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 cultures. 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 the growth of human colon cancer cells by 70%. The cells
  accumulated in the S/G2 phase transition of the cell cycle. Resveratrol significantly reduces the activity of ornitine decarboxylase (key enzyme in polyamine biosynthesis, which is 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 highly 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 through depolarization of mitochondrial membranes and through activation of caspase-9, independent of CD-95 signaling. There is no significant cytotoxicity towards 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 colon cancer carcinogenesis in rats. It significantly reduces the cell number and changes the expression of bax and p21.
  (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 or apoptosis in Waldenström's macroglobulinemia (WM) cells. 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. The anti-cancer property of resveratrol is supported by its ability to inhibit the proliferation of a variety of human tumor cells in vitro and in animal studies. This review presents data from preclinical in vivo studies and interventional studies on cancer and associated mechanisms of action. The bioavailability, pharmacokinetics and potential toxicity of resveratrol as well as its usefulness in cancer are also 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 a concentration- and time-dependent manner in pancreatic carcinoma cell lines (PANC-1 and AsPC-1) 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-carcinogenic 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 as well as 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 suppressing angiogenesis. Resveratrol also enhances the apoptotic effects of cytokines, chemotherapy drugs and radiation. It blocks carcinogen activation by inhibiting the expression and activity of CYP1A1 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-carcinogenic effects of resveratrol appear to be closely linked to its ability to interact with multiple molecular parameters involved in carcinogenesis while minimizing toxicity in healthy tissues. Resveratrol should therefore 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)
• Various studies have demonstrated the modulatory effects of Resveratrol on a variety of cell signaling and gene expression pathways. This article summarizes the effects of resveratrol in the context of 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 investigated using a two-stage model in rats. Resveratrol 50-300 mg/kg body weight dose-dependently reduces the incidence, number, volume and variety of visible hepatocyte nodules. It leads to a decrease in cell proliferation and an increase in apoptotic cells in the liver. It also induces the expression of the pro-apoptotic protein Bax, reduces the expression of the anti-apoptotic Bcl-2 and simultaneously increases the Bax/Bcl-2 ratio. Due to its favorable toxicity profile, resveratrol can potentially 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 the induction of apoptosis and reduction of cell growth in human leukemia cells (MOLT-4). The combination of ellagic acid with resveratrol has a more than additive synergistic effect. 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 resveraterole in the induction of caspase-3 activity. The anticarcinogenic potential of foods containing 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 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)
• Interfering with multistep carcinogenesis through modulation of intracellular signaling pathways may provide a molecular basis for chemoprevention with phytochemicals. Resveratrol has been extensively studied for its chemopreventive activity related to its ability to intervene in multistage carcinogenesis. Numerous intracellular signaling cascades converge on the activation of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), which act independently or coordinately to regulate the 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. Resveratrol significantly downregulates survivin and the cell cycle in a dose- and time-dependent manner, induces apoptosis and improves the effect of chemotherapy drugs in multidrug-resistant non-small cell lung carcinoma cells.
  (Zhao W et al.; Resveratrol down-regulates survival 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 death of ovarian carcinoma cells (more via autophagy than via apoptosis), associated, among other things, with caspase activation. It therefore 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 autophagocytosis in ovarian 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 containing constitutively active Stat3 demonstrate irreversible cell cycle arrest of v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), human breast (MDAMB-231), pancreas (Panc-1 ) and prostate carcinoma (DU145) cell lines in the G0-G1 or S phase of human breast cancer (MDA-MB-468) and pancreatic cancer (Colo-357) cells, and a loss of viability 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 contain constitutively active Stat3, including human prostate cancer DU145 cells and v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), resveratrol suppresses Stat3-regulated cyclin D1 as well as Bcl-xL and Mcl - 1 genes, suggesting that the anti-tumor cell activity of resveratrol is due in part to die 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 use in 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 examined the effect of resveratrol on the accumulation of hypoxia-induced HIF-1α protein and the expression of vascular endothelial growth factor (VEGF) in tongue squamous cell carcinoma and hepatoma cells. Resveratrol significantly inhibits both basal levels and accumulation of hypoxia-induced HIF-1α protein in cancer cells, but not HIF-1α mRNA levels. Pretreatment of cells with resveratrol significantly reduced the activities of the hypoxia-induced VEGF promoter and the secretion of VEGF at both the mRNA and protein levels. The mechanism of inhibition of the accumulation of hypoxia-induced HIF-1α by resveratrol appears to involve a shortened half-life of the HIF-1α protein, which is caused by increased degradation of proteins by the 26S proteasome system. In addition, resveratrol inhibits the hypoxia-mediated activation of extracellular signal-regulated kinase 1/2 and Akt, resulting in a significant decrease in the accumulation of hypoxia-induced HIF-1α protein and the activation of VEGF transcription. Resveratrol also significantly inhibits the hypoxia-stimulated invasiveness of cancer cells. These data indicate that HIF-1α/VEGF may represent a promising target for resveratrol in the development of effective chemoprevention and therapy against 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. Cancer Ther 2005; 4: 1465 – 1474)
• 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 positive effects. It has been shown that these positive effects can be attributed to polyphenols in red wine, especially resveratrol in grape skins. These effects include reductions in cardiovascular morbidity and mortality, lung cancer and prostate cancer by approximately 30% to 50%, 57% and 50%. Polyphenols possess antioxidant, superoxide scavenging, ischemia preconditioning, and angiogenic properties. Some of these properties of polyphenols may explain their protective effects on the cardiovascular system as well as other organs of the body. Therefore, the United States Department of Health and Human Services recommended moderate alcohol consumption in its 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). There are several different mechanisms of action of the substance:

• The antioxidant effect, for which there is sufficient evidence for use in the supportive oncological therapy exists. 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 quality of life
• The cytotoxic effect on cancer cells especially with high-dose parenteral administration. As with radiation and some chemotherapy drugs, it is mediated via anti-proliferative, but especially via pro-oxidative effects the formation of H2O2. When oral vitamin C was administered, a cytotoxic effect was only found in early therapy, where it can also reduce the levels 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 when taken orally, the amounts of vitamin C absorbed 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 already visible tumors. However, there is sufficient evidence that parenteral vitamin C in pharmacological dosages in late therapy achieves sufficient effective levels from approx. 25-30 mmol/l and, above all, in combination with other active ingredients, taking into account possible interactions with chemotherapeutic agents and radiation It is useful in first-line chemotherapy for a wide variety of tumor types - without fear of systemic toxicity or damage to healthy cells.
• In addition, vitamin C has an anti-inflammatory effect, activates collagen formation, increases the cytotoxic potency of chemotherapy drugs, 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 the 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 them

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 surveillance and destruction by the immune system. 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 the development of resistance.
  (Wallenberg M et al.; Selenium cytotoxoicity 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 induce cell death selectively 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 the risk of cancer as well as progression and metastasis in all types of cancer (and especially in prostate, liver, gastrointestinal and lung cancer), especially in people with low selenium status (among other things, there is a reduction in 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)
• Seleniumsupplementation increases antioxidant protection through increased expression of selenium-dependent GSHPeroxidase and thioredoxin reductase. Selenium protects against cancer: it influences 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 that can be distinguished for 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 cosubstrates for their activities, such as B vitamins, iron, zinc, selenium, manganese, magnesium or polyphenols, which belong to the narrowest circle of micronutrients.

The proteases belong to the hydrolases. In complementary oncology, the substances bromelain and papain as well as trypsin and chymotrypsin are usually used in combination in enteric-coated preparations.

The proteases have, for example, anti-inflammatory effects, improve phagocytosis, stimulate the body's own defenses, reduce immune and cytokine complexes as well as adhesion molecules and TGFβ, reabsorb edema and hematomas and contribute to the unmasking of tumor cells. They are used primarily 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 for malignant effusions.

Study examples and articles on the use of micronutrients in tumor diseases

PREVENTION

i) General cancer risk

• 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 hinders apoptosis and can promote cancer development, interferons can promote DNA repair and stabilize p53. This makes them anti-oncogenic. (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
    intestinal diseases (Crohn's disease, ulcerative colitis), viral infections, bacterial infections (e.g. due to Helicobacter pylori), parasitosis, asbestos exposure, alcohol and nicotine abuse or obesity. 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 Heidelberg; March 10, 2006)
  • Inflammation contributes to the development of approximately 15% of all cancers. Inflammation and the NFkB protein induced by
    inflammation contribute to uncontrolled cancer cell growth and
    Macrophages produce substances that stimulate tumor growth, including TNFalpha, which stimulates 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. Ingredients in 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 high antioxidant capacity, suppress the proliferation of cancer cells, reduce lipid oxidation and cholesterol. They contain various secondary plant substances including quercetin, catechin or phloridzin. The phytochemical content varies greatly between different apples and there are also differences in the 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 overall mortality (relative risk, 0.63, 95% CI) in men. Note: The results were not available in women: 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 cancer 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 old; 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 (especially with the combination of beta-carotene, vitamin E and selenium) reduces the risk of cancer in the population of Linxian (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 the cancer risk by 1.5 times for various types of cancer, the correlation being strongest for gastrointestinal tumors and for cancers that are independent of nicotine abuse as well as for non-smokers with low selenium levels .
    (36265 participants over 8 years old; 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 activation of the Ah receptor. Resveratrol also impacts several factors involved in tumor promotion and progression. Because tumor-promoting agents alter the expression of genes whose products are associated with inflammation, chemoprevention of cardiovascular disease, and cancer, common mechanisms may exist. This primarily includes 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 as well as to the regulation of cell proliferation and apoptosis. It is therefore important for tumor development and many other diseases such as atherosclerosis. Although the mechanisms by which resveratrol interferes with the activation of NF-κB are not clear, it appears that inhibition of its degradation, which is necessary for its cellular activation, represents the most important target. Based on the amount and variety of data available on the biological activity of resveratrol, it must be considered 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 in three important stages of cancer development. It has antioxidant, antimutagenic effects and induces phase II drug-metabolizing enzymes (anti-initiation activity). It mediates anti-inflammatory effects and inhibits cyclooxygenase and hydroperoxidase functions (anti-promotion activity) and induces differentiation of human promyelocytic leukemia cells (anti-progression 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 suitable as a potential chemopreventive agent for use in humans.
    (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 did not significantly affect the incidence of basal cell carcinoma and squamous cell carcinoma compared to placebo (RR 1.10 and RR 1.14, respectively; 95% CI). The patients receiving selenium had a nonsignificant reduction in all-cause mortality (RR 0.83; 95% CI) as well as a significant reduction in all-cancer mortality (RR 0.50; 95% CI) and total cancer 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. An increase in vitamin D levels of 25 nmol/l 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 14 years. 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 connection 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 against cancer. There is no increasing risk reduction with doses above 1300 mg. Dairy products (e.g. 3 cups of low-fat or fat-free 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 cancer as well as 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)
  • The 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 further reduce the risk. Calcium intake is inversely associated with the risk of gastrointestinal cancer in men and women (RR 0.84; 95 CI in men and RR 0.77; 95% CI in women) and particularly colon cancer.
    ( National Institutes of Health-AARP-Diet and Health Study; Approximately 500,000 participants over 7 years; 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 progression and metastasis in all types of cancer (and especially in prostate, liver, gastrointestinal and lung cancer), especially in people with low selenium status (there is a reduction, among other things of 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 Selenium levels 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)
  • Seleniumsupplementation increases antioxidant protection through increased expression of selenium-dependent GSHPeroxidase and thioredoxin reductase. Selenium protects against cancer: it influences 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 the cancerbincidence (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 people with the highest selenium levels. In people with low selenium and low vitamin E levels, it was increased 11.4 times. 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) reduce all-cause mortality (HR 0.83), cancer mortality (HR 0.69) and cardiovascular mortality (HR 0.94). Very high selenium levels (> 150 ng/ml), on the other hand, increase mortality slightly.
    (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 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 achieving selenium levels; J Natl Cancer Inst 2013; 105; 1394-1401)
  • There is a 63% lower risk of prostate Ca with 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 (see original study evaluation from 1996 in JAMA 1996; 276; 1957-1963))
  • Selenium 200 mcg has a significant influence on the overall prostate Ca incidence (RR 0.51; 95% CI), especially with PSA < 4 ng/ml and low selenium levels < 123.2 ng/ml )
    (Randomized, 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 Ca.
    (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 additionally controlling for family history of prostate cancer, BMI, calcium and saturated fat intake, vasectomy, and geographic region, an OR of 0.35 (95% CI) was found.
    (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 selenium levels up to 170 ng/ml.
    (Hurst R et al.; Selenium and prostate cancer: systematic review and meta-analysis ; Am J Clin Nutr July 2012vol. 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 prostate cancer: a prospective cohort study; Cancer Epidemiol Biomerkers Prevent 2003; 12; 866-871)
• Vitamin E
  • Vitamin E (+alpha-tocopheryl-succinate) and Selenium (methylselenic acid) alone each lead to a moderate inhibition of survival and growth of human prostate cancer cells. A combination results in a dramatic increase in the inhibition of prostate cancer cell growth. There is an induction of apoptosis, an increase in Bax, Bak and Bi proteins and a decrease in the Bcl-2 protein.
    (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 by 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 former smokers who consume at least 100 IU Vitamin E have a reduced risk of metastatic or fatal prostate cancer. (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 cancer (regionally invasive or metastatic) decreased significantly depending on the dosage 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 cancer (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 risk reduction is 35% (RR 0.65), the risk of advanced prostate cancer. is reduced by 63% (RR 0.37). The connection with menaquinone from dairy products is more pronounced than with meat vitamin K2. Vitamin K1 (phylloquinone, especially 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 phyto-estrogen levels may inhibit the growth of prostate cancer in Japanese men and explain the low mortality from prostate cancer in Japan.
    (Adlerkreutz H et al.; Plasma concentrations of phyto-estrogens 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 especially the risk of metastatic carcinoma (RR 0.56; 95% CI). Each intake of 0.5 g of fish oil is associated with a 24% risk reduction for metastatic prostate ca
    (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 an 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 maintain Western lifestyles have at least a 60% higher risk of breast cancer than Eastern-born controls, regardless of whether ancestors were born in the West or East. Among emigrants born in the East, those from urban areas have a 30% higher risk than emigrants from rural areas. (An up to 6-fold increased risk of breast cancer due to migration is 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 around 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 of life and 4.4% of cases to a weight gain of at least 2 kg after the menopause. Women who have lost at least 11 kg after menopause have a 57% lower 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 juice) significantly increases the risk of breast cancer by twice as 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: In general, no relationship was found between postmenopausal total breast cancer and micronutrient intake. Dietary beta-carotene reduces Risiko for 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 the 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) correlate inversely 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 general 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 not taking 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: 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 highest and lowest 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 excessively increased risk of breast cancer due to increased alcohol consumption is reduced by adequate intake of folic acid (RR for 600 mcg folic acid per day compared to 150 - 299 mcg was 0.55, 95% CI).
    (Prospective cohort study over 16 years; 88,818 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 of glutathione) or NAC are significantly associated with a reduced risk of breast cancer in a dose-dependent manner (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 the inverse Relation between intake of omega 3 fatty acids and the risk of breast cancer. Omega 3 fatty acids reduce the risk by 14%. For every 0.1 g increase in O3-FA intake, the risk decreased by 5%.
    (Meta-analysis from 26 publications with 883,585 participants; Zheng JS et al.; Intake of fish and marine n-3-polkyunsaturated Fatty acids and risk of breast cancer: meta-analysis 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 compared to an intake of < 5 mg. The risk decreases by approximately 16% for every 10 mg of isoflavone intake - in pre- and postmenopausal cancer. (In 11 studies with Western populations and low soy intake of 0.8-0.15 mg of isoflavones per day, no correlation was found 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 with the highest intake), especially 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)
  • The level of soy intake in youth is inversely associated with breast cancer risk in both pre- and postmenopausal Chinese women (OR 0.51; 95% CI for the highest compared to 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)
  • The excretion of isoflavonoids and lignans is significantly lower in women with breast cancer compared to controls. As the excretion of isoflavonoids and lignans increases, the risk of breast cancer decreases (OR 0.62 and 0.40 and 0.28, respectively; 95% CI at the highest versus lowest intake for isoflavonoids, lignans or isoflavonoids and lignans)
    (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 reduction in the risk 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% versus 37.5% in controls). The menstrual cycle lengthened 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 when 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; 95% CI each).
    (Kim MK et al.; Dietary intake of soy protein and tofu in association with breast cancer risk based on a case control study; Nutr Cancer 2008; 60: 568-576)
  • In postmenopausal American women, the risk of breast cancer decreases with the intake of flavonoids, 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, overall mortality decreases with high intake of flavonoids compared to low intake, most strongly for flavones (OR=0.63; 95% CI), anthocynidins (OR=0 .64) and isoflavones (OR=0.52). Similar results can be 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 clearly correlates inversely 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 as great as 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 without 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 stronger 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 Inst. 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 cancer and colorectal cancer.
    (15,646 women in the WHI 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 Calciumintake significantly inversely correlates 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
  • There is a significant inverse association in China 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 case control study in China. Cancer Sci. 2013; 104(2):250-8.)
• Selenium
  • Women with breast cancer have lower Seleniumconcentrations than in healthy people (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 the 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 on premenopausal breast cancer when supplemented for > 10 years. Multivitamins as well as Vitamin C, E and Beta-carotene have a significant positive effect on postmenopausal breast cancer when supplemented for > 10 years.
    (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 versus 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 was a significant reduction in the incidence of lung cancer by 45% (95% CI)
    (Randomized; multicenter, double-blind, placebo-controlled: 1312 Participants over 8 years old; 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 linked to increased lungencancer risk.
    (Cohort study, 500 participants; Hartman TJ et al.; Selenium concentration and cancer lung in male smokers; Cancer causes Control 2002; 123; 923-928)
  • Low Selenium levels are linked to 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 people with the highest selenium levels. In people with low selenium and low vitamin E levels, it was increased 11.4-fold. 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 drank moderately once a day. '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 (such as ashwagandha)
  • The risk of lung cancer decreases with increasing intake of phytoestrogens (more significant for isoflavones than for phytosterols) 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 connection between the intake of flavanones and proanthocyanidins. Smokers and former smokers with very high intakes of flavanones and proanthocyanidins had a significantly lower incidence of lung cancer than in smokers and former smokers with very low intakes. Women who consumed higher amounts of isoflavones were less likely to develop cancer.
    (34,708 participants over 18 years old; 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 (including liver and pancreas)

• Apples
  • The odds ratio of the incidence of cancer of the oral cavity and pharynx is 0.79 for the intake of > 1 apple/day compared to < 1 apple/day and 0.75 for the esophagus and 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 stomach cancer is inversely correlated with the 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 leads to a 31% significant reduction in the risk of pancreatic cancer (OR 0.69; 95% CI). Beta-carotene (OR 0.57; 95% CI) and Total carotenoids (OR 0.58; 95% CI) only significantly reduce the risk 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)
• Vitamin A and C
  • Patients who take supplements containing Vitamin A have a reduced risk of stomach cancer (RR = 0.4; 95% CI). There is an inverse relationship between Vitamin C intake and stomach cancer (RR 0.7; 95% CI for the highest versus lowest intake)
    (Netherlands Cohort Study; 120,852 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 old; 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 was a significant reduction in the incidence of colon carcinoma by 58% (95% CI).
    (Randomized; multicenter, 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 selenium status have an increased risk of colon 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 pancreatic carcinoma (OR 0.45; 95% CI), high cholesterol increases it significantly.
    (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 colon cancer risk. 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 , a high intake of calcium and vitamin E was associated with a reduced risk, with vitamin having the best effect (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 Folate levels in cell cultures increase the risk of DNA damage to colonocytes (and the increase in proteins such as Nit2 and COMT) and thus the risk of colon cancer.
  • High folic acid intake from food significantly reduces the risk of pancreatic carcinoma (multivariable rate ratio 0.25; 95% CI).
    (81,922 participants over 6.8 years; 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 cancer and colorectal cancer.
    (15,646 women in the WHI 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; 1,905 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
  • The 25(OH)D levels (= vitamin D) are inversely related to the risk of colorectal cancer (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 (above 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.
    (Review 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 colon cancer is reduced by half at values ​​of 25-hydroxy vitamin D of over 33 ng/ml compared to values ​​of under 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 highly dependent on the calcium intake (RR 0.59 with high calcium intake versus RR 1.00 with low intake) and the vitamin D3 -Intake (RR 0.76 versus RR 1.00 at low intake). For calcium and vitamin D3 together, the risk reduction was 45% (RR 0.55).
    (Cohort study over 9 years; 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 influences the pathogenesis of pancreatic carcinoma (RR 0.59 at the highest compared to 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 uses 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 phranyx cancer 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 level 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. On 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 was determined using carotenoids as protective substances: alpha-carotene 0.22, lutein 0.42, lycopene 0.94 and beta-cryptoxanthin 0.90. With regard to the joint 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)
  • Fat sea fish (such as mackerel, herring, sardines, salmon) with lots of omega-3 fatty acids and vitamin D at least once a week significantly reduces the risk of kidney cancer (OR 0.56). the control group. With a corresponding diet lasting more than 10 years, the risk falls even further (OR 0.26).
    (Cohort study with 61,433 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 the risk of renal cell carcinoma (risk 0.26 for regular consumption of fatty 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 seleniumconcentration 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)
  • The selenium concentration is inversely linked to the risk of bladder cancer 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 risk of bladder cancer.
    (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 selenium levels 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? Urologist A 2007; 46; 616-621)
  • A high seleniumstatus significantly reduces the risk of bladder cancer 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 of the p53 gene against bladder cancer.
    (1,875 participants; Wallace K et al.; Selenium and risk 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 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) from the mother is inversely associated with acute lymphoblastic leukemia (ALL) in children (ALL can occur in utero arise).
    (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 (hematological 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 lymphomas (hematological neoplasms) and the intake of polyunsaturated fatty acids, linoleic acid and vitamin D (OR each 0.6; 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 replication, transcription and translation of DNA.
    (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 and thus drive 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 fish intake 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 the diet and Fat type have a significant influence on cancer cell growth: In contrast to a high-fat Western diet, a fat-modified diet leads to a significant inhibition of prostate cancer. 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, i.edouble 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 expansion (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 receptor. 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 Ca influences 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 approx. 10% of these cells) vulnerable and slows down metastasis of the pancreas (in Germany Approximately 12,650 cases of pancreas 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: The 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 the 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 influences cell cycle regulation and possibly delays 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 the phosphorylation of the cell division cycle 25C (CDC25C) tyrosine phosphatase via activation of the checkpoint kinases Chk1 and Chk2, which in turn were activated via the ATM (ataxia telangiectasia mutant)/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 increased resveratrol-related activation of ATM/ATR-Chk1/2 as well as 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 the 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 cancer cells and provides a rationale for the potential effectiveness of ATM/ATRA agonists in the prevention and intervention of cancer.
    (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 death of ovarian carcinoma cells (more via autophagy than via apoptosis), associated, among other things, with caspase activation. It therefore 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 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 people with low selenium intake) before 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 therefore 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% for colorectal cancer, but remains the only most effective treatment method. Antioxidants (such as Vit E) induce apoptosis in CRC cells via activation of p21 WAF1/CIP1, a potent cell cycle inhibitor (incorporating C/EBPbeta, a member of the CCAAT enhancer-binding protein family of transcription factors) – independent of p53 . Antioxidants significantly increase tumor growth inhibition through cytostatic therapy with 5 FU (and doxorubicin). The combination of chemotherapyRape and antioxidants provide 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 lower number of advanced ductular lesions in rat pancreatic carcinomas. 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 series.
    (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
    (Randomized, placebo-controlled; 3365 participants; Ma Jl et al.; Fifteen year effects of Helicbacter pylori, garlic, and vitamin treatments ongastric cancer incidence and mortality; J Natl Cancer Inst 2012; 104; 488-492)
• Vitamin D
  • Vitamin D decreased in patients with Kolonka. significantly increased mortality for all causes of death (HR 0.52 for highest versus lowest levels). The reduction in colonca mortality 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: When supplemented 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 prevents cell proliferation in human colon carcinoma cells and activation of the 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 the growth of human colon cancer cells by 70%. The cells accumulated in the S/G2 phase transition of the cell cycle. Resveratrol significantly reduces the activity of ornitine decarboxylase (key enzyme in polyamine biosynthesis, which is 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 the carcinogenesis of colon cancer in rats. It significantly reduces the cell number and changes die Expression of bax and p21.
    (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 a concentration- and time-dependent manner in pancreatic carcinoma cell lines (PANC-1 and AsPC-1) 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 alcoholic beverages)
  • There is a dose-response relationship between alcohol and rectal cancer. Drinking more than 41 drinks per week conferred a relative risk of rectal cancer of 2.2 (95% CI) compared with non-drinkers. More than 14 drinks of beer and spirits - but not wine - per week yielded an RR of 3.5 for rectal cancer compared to non-drinkers, while those who drank the same amount of alcohol but more than 30% of it Wine had an RR of 1.8 for rectal cancer. No association was found between alcohol and colon carcinoma when examining the effects of the total amount of alcohol from beer, wine and spirits as well as 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.
    (Randomized, 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 stomach cancer, but the type of alcohol seems to influence the 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 tumor-initiating cells by NF-kappaB-induced antiapoptotic signaling. 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 investigated using a two-stage model in rats. Resveratrol 50-300 mg/kg body weight dose-dependently reduces the incidence, number, volume and variety of visible hepatocyte nodules. It leads to a decrease in cell proliferation and an increase in apoptotic cells in the liver. It also induces the expression of the pro-apoptotic protein Bax, reduces the expression of the anti-apoptotic Bcl-2 and simultaneously increases the Bax/Bcl-2 ratio. Due to its favorable toxicity profile, Resveratrol could potentially 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 the G1 to the 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 (particularly 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, especially those who are not suitable 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 depend on the season. The season of diagnosis is also a strong prognostic factor for Hodgkin's disease (hematological neoplasia), with approximately 20% fewer fatal cases in autumn compared to winter (RR 0.783; 95% CI). Survival time is increased by more than 60% in Herbst patients under 30 years of age (RR 0.364; 95% CI). The increased vitamin D levels have a beneficial influence 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 lymphoblastic leukemia ALL and malignant lymphoma (hematological neoplasms), there are reduced levels of magnesium in the hair compared to controls (significant only in T-cell ALL) as well as significantly reduced levels of Zinc. The serum zinc levels are also reduced.
    (58 participants; Sahin G et al.; High prevalence 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 lymphoma (hematological neoplasm) taking anthracyclicsn-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 as well as overall survival (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)
  • Apoptosis in human leukemia cells is induced in a dose- and time-dependent manner by grape seed extract (OPC) (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 survivin downregulation and apoptosis as well as 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 cultures. 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 through depolarization of mitochondrial membranes and through activation of caspase-9, independent of CD-95 signaling . There is no significant cytotoxicity towards 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 the malignant lymphoma disease Waldenström'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)
  • The aim of this study was to investigate interactions of ellagic acid and quercetin with resveratrol (polyphenols) in the induction of apoptosis and the reduction of cell growth in the human leukemia cells (MOLT-4). The combination of ellagic acid with resveratrol has a more than additive synergistic effect. 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 the induction of caspase-3 activity. The anticarcinogenic potential of foods containing 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 apop in vitrotosis of melanoma cells.
    (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 melanomas.
    (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 levels in the normal range of at least 30 ng/ml.
    (764 participants; Gambichler T et al.; Serum 25-hydroxyvitamin D serum levels in a large German cohort of patients with melanoma; Br J Dermatol 2013; 168; 625-628)
  • Polymorphisms of the vitamin D receptor gene 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 influence 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 encompasses a wide electromagnetic spectrum including ultraviolet radiation, which is potentially harmful to normal cells, and ionizing radiation, which is therapeutically useful in destroying cancer cells. UV radiation is responsible for a majority of skin cancers as well as precancerous lesions such as actinic keratosis. Chemoprevention of UV damage via nontoxic substances, particularly plant antioxidants, is an approach to prevent photodamage including photocarcinogenesis. In this article, 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 against cancer cells. Based on literature data, resveratrol may be useful in preventing UVB-mediated damage, including skin cancer, and improving the effect of radiotherapy 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)
  • Nonmelanoma skin cancer is the most commonly diagnosed malignancy in the United States. The main cause is multiple contact with ultraviolet (UV) radiation (especially the UV-B componentnente, 290-320 nm) of the Sun. Chemoprevention using naturally occurring substances is considered a new dimension in the management of neoplasms (including skin cancer). We demonstrated that resveratrol mediates protection against acute UV-B-mediated cutaneous damage in SKH-1 hairless mice. Understanding this mechanism is important. We have previously shown that Resveratrol has chemopreventive effects against a number 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 alternating days. Topical pretreatment with resveratrol resulted in a significant inhibition of UV-B exposure-mediated increases in cell proliferation (Ki-67 immunostaining), epidermal cyclooxygenase-2 and ornithine decarboxylase, established markers of tumor promotion, protein and messenger RNA -Survivin levels and survivin phosphorylation in the skin of mice. Resveratrol pretreatment also resulted in a reversal of the UV-B-mediated decrease in Smac/DIABLO and the increase in the UV-B-mediated induction of apoptosis in the mouse skin 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 its 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, Cancer Handbook, 2014

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X

-

-

Overweight

-

-

X

-

Measure

Parameters

Benefit

General laboratory screening

BKS, blood count, creatinine, BZ,
uric acid, protein electrophoresis,
LDH, GOT, GPT, y-GT, AP, SP,
TSH, K, Na, calcium, Fe, HDL, LDL,
triglycerides, urine status

General information and screening for organ disorders and tissue decay

Immunoscreening (initial, tumor phase I)

Differential blood count with granulocytes,
monocytes, lymphocytes (cellular),
immunoglobulins
IgA, IgG, IgM, IgE (humoral),
TH1/TH2 balance

Primarily measures quality of the
defense, says little about
tumor-specific defense (since
tumor cells are mostly camouflaged, at least initially
)

Immune system advanced (Tumorphase 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 with therapy decisions and therapy monitoring

Inflammation screening

hsCRP, TNFα, histamine, IP-10
IL-1, IL-6, NFkB

Indications of acute or chronic inflammation

Detoxification screening
Detoxification advanced

GSH (intracellular)
Paracetamol, caffeine metabolite test
GSH/GSSG

Indications of the quality of the detoxification function

Screening 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

Urine pH daily profile with test strips
Titration according to Sander

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 intestinal function

Neuro-endocrine screening
Neuro-endocrine function advanced

Cortisol daily profile (saliva),
norepinephrine, serotonin
tryptophan, tyrosine, dopamine, DHEA

Indications of the function of the
neurotransmitter metabolism

Mitochondria screening
Mitochondria advanced

ATP
L-carnitine, coenzyme Q10

Indications of the function of the
mitochondria

Nutrition of the tumor

TKTL1

Indication of the
energy production in the tumor

Micronutrient diagnostics

e.g.b 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

Hemorrhage diagnostics

Hemoglobin-haptoglobin in stool
Erythrocytes in urine

Indications of microbleeds

Measure

Benefit

TPA (tissue polypeptide antigen)
Tumor-associated proliferation antigen

Non-specific tumor marker,
Independent of primary tumor and generally applicable

Mutation of the gene p53

Apoptotic ability non-specific
(prognostic factor for various tumors)

p53 autoantibodies

Nonspecific 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 disorders of the 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 substance that is optimally suitable for the
tumor in question

CEA (carcinoembrional antigen)
tumor-associated antigen

Highly specific especially for colon Ca (80%) and less
specific for pancreas Ca (60%), mamma Ca (55%) and
biliary tract and bronchial Ca (50%) O.a Tumors

PSA (prostate-specific antigen)
Tissue-specific antigen

At V.a Prostate Ca

TG (thyroglobulin),
hCT (human calcitonin)

At V.a Thyroid Ca

AFP (α1-fetoprotein)

At V.a Liver Ca, teratoma

AFP and HCG (human
chorionic gonadotropin)

At V.a Germ cell tumors (testicles, ovaries)

CA 72-4

At V.a Stomach Ca, mammary Ca

Monoclonal immunoglobulins
and Bence Jones proteins

At V.a multiple myoma

CA 19-9, CA 195, TPA

At V.a Pancreas-Ca

CA 15-3, CA 549, MCA (Mucin-like
Carcinoma Associated Antigen)

At V.a Mamma Ca

CA 24, CA 50

At V.a Intestinal Ca, pancreatic Ca

CA 125

At V.a Stomach Ca

NSE (neuron-specific enolase)

At V.a Bronchial Ca, neuroblastoma

CYFRA 21-1 (cytokeratin fragment)

At V.a Bronchial Ca

Skeletal alkaline phosphatase
(ostasis, bone AP)

At V.a Bone metastasis 11

SCC (squamous cell carcinoma antigen)

At V.a Cervical Ca

Bence Jones proteins and
beta-2 microglobulin

At V.a Plasmacytoma

5-S-cysteinyldopa

At V.a malignant melanoma

Neopterin, ß2-microglobulin

At V.a Leukemia, lymphoma

BTA (bladder tumor antigen)

At V.a Bubble Ca

M2-PK

At V.a Renal cell carcinoma, colon and rectal carcinoma

5-HIES (5-hydroxyindoleacetic acid)

At V.a Carcinoid (especially in the gastrointestinal tract)

Protein S100

Prognostic factor in malignant melanoma

HER2-new oncogene

Prognostic factor in mammary Ca

Mutations of the gene BRCA 1+2

Indication of breast cancer risk

YES

Has one or more related members of your family had one of the following
cancers: breast cancer, colon cancer, ovarian cancer, uterine cancer,
stomach cancer?

Were there times in your life when you consumed alcohol for a long time?

Have you ever had cancer in the past?

Do you have diabetes mellitus?

Have you ever had an inflammatory disease (e.g.b of intestine, prostate, bladder,
pancreas, gastric mucosa, reflux esophagitis)?

Have you had or do you have intestinal polyps?

Have you had or do you have ovarian cysts (only valid for women)?

Are you childless (only valid for women)?

Did you or your mother have elevated estrogen levels (only valid for men)?

Did or do you have birthmarks?

Have you had or do you have cold thyroid nodules?

Have you had or do you have iron storage disease?

Do you have cystic kidney disease?

Did you have a low birth weight?

Have you had or do you have an undescended testicle?

Would you say that your oral hygiene is inadequate?

Is your diet rather unbalanced, heavy on meat, low in fiber?

Do you drink more than 1 liter of milk per day?

Have you had or do you have any noticeable infectious diseases (e.g.b 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 (only valid for women)?

Are you taking or taking medications over a longer period of time such as
calcium antagonists, contraceptives, estrogens, tamoxifen, phenazetin, painkillers,
cyclophosphamide, arsenic, cytostatics, immunosuppressants or so-called. Aromatase inhibitor?

Did your menarche occur early (only valid for women)?

If you were already in menopause, did it come on late (only valid for women)?

Do you smoke or have you smoked regularly over a long period of time?

Were or are you exposed to pollutants over a longer period of time (e.g.b
Asbestos, mercury, aromatic amines)?

Shift work (especially with night work)

Do you frequently change sexual partners?

Are you or have you been exposed to increased radiation exposure (e.g.b through UV light, occupation,
diagnostic or therapeutic medicine)?

Do you live - or have you lived - within a 5 km radius of a
nuclear power plant?

Are you overweight?

Micronutrient

Special features (general effects)

Antioxidants
(e.g.b Vit C, Vit E, glutathione)

have an antioxidant effect (protect cells from damage caused by radicals),
support detoxification, reduce overall cancer risk

Polyphenols (e.g.b Isoflavonoids)
Carotenoids
(e.g.b β–carotene, lycopene)

have an antioxidant and anti-inflammatory effect,
support detoxification, reduce overall cancer risk

Zinc

Balances 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 the risk of cancer (especially in women > 65 years of age)

Vit B12

Cave: different statements regarding. Cancer protection or cancer promotion
through B12, but: deficiency increases cancer incidence

Fatty acids (e.g.b γ-linolenic acid,
omega-3 fatty acids)

Reduce overall cancer risk

Vitamin D

Reduces overall cancer risk

Vitamin K2

Reduces overall cancer risk

Micronutrient

Special features

Vitamin C
Standard substance

Antioxidant, cytotoxic, anti-inflammatory, antiangiogenic, cofactor of detoxification phase I, promotes collagen formation

Cave: distance from inorganic selenium and, in late therapy, distance from radical-forming cytostatics and radiation

Vitamin E
(most effective as
natural Vit E
with all tocopherols)

Antioxidant, anti-inflammatory, has independent anticancer activity and inhibits - probably only in high pharmacological doses - growth and mitosis of cancer cells

Glutathione

Antioxidant, detoxifying, strengthens repair and apoptosis mechanisms, reduces cancer cell and tumor growth, improves tolerability of basic therapy without damaging healthy cells.
Possibly in late therapy. Tumor cell protection factor (protection against therapeutic
radicals) and possibly. Multi-drug resistance (if level ↑)

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
Cave: Distance to Vit C

Iron

Iron deficiency is common in cancer patients and must be treated optimally

Zinc

Immune balancing, may inhibit. Tumor cell apoptosis
(administration after basic therapy and in case of deficiency)

B vitamins

If applicable B12 administration only after basic therapy and in cases of deficiency as well as in combination with Vit C (B12 in high doses may be increased. 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

Micronutrient

Study results on the effect of individual micronutrients against
certain types of cancer

Antioxidants
(e.g.b Vit C, glutathione)

Prostate, breast, uterus, ovaries, intestines, lungs, pancreas, glioblastoma, melanoma

Polyphenols
(e.g.b Resveratrol, isoflavonoids),
carotenoids (e.g.b Lycopene)

Mamma, ovaries, prostate, gastrointestinal, leukemia, pancreas, liver

Selenium

Melanoma, thyroid, non-Hodgkin lymphoma, bladder, gastrointestinal, esophagus, leukemias, prostate, liver, lung, breast

Zinc

Acute lymphocytic leukemia (ALL), malignant lymphoma, pancreas, bladder

Calcium

Intestine

Magnesium

Acute lymphocytic leukemia (ALL), malignant lymphoma

Omega-3 fatty acids

Prostate, pancreas

Vitamin D

Mamma, intestine, M. Hodgkin, melanoma, thyroid, bladder, pancreas,
B-CLL, myeloma

Vitamin A

Bubble

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 (increase cytotoxic effect of docetaxel,
paclitaxel)
Vit E (increase cytotoxic effect of cisplatin)

Apoptosis

Selenium, α-tocopherol, resveratrol

Angiogenesis inhibition

Selenium, α-tocopherol, resveratrol, coenzyme Q10 (with tamoxifen)

Proliferation inhibition

Antioxidants, genistein, quercetin, vitamin D

Inhibition of inflammation

Omega-3 fatty acids

Increase the response rate
and extend the
survival time

Vit C, Vit E and β-carotene (with paclitaxel, carboplatin), antioxidants (general), omega-3 fatty acids

Increase in the
tamoxifen effect

Genistein (for re-neg breast cancer), Vit D, γ-linolenic acid, coenzyme Q10, Vit B2 and Vit B3

Increase the number of
therapy cycles

Glutathione

Improvement of
surgical success
(e.g.b Improving
wound healing, reducing
the risk of infection and
organ failure)

Antioxidants (such as Vit C, Vit E, glutathione)
Selenium
Zinc
L-arginine, L-glutamine
Omega-3 fatty acids
Probiotics

Improvement of
irradiation success

Resveratrol, proteases, selenium