Nutrigenomics and Cancer: The importance of a Healthy Diet

Introduction

Plants have played a significant role in maintaining human health and improving the quality of human life for thousands of years, and have served humans well as valuable components of foods, seasonings, beverages, cosmetics, dyes, and medicines.

In traditional foods and herbs, a wide variety of active phytochemicals, including the flavonoids, terpenoids, lignans, sulfides, polyphenolics, carotenoids, coumarins, saponins, plant sterols, curcumins, and phthalides; which have been recently researched and found to possess important actions in health promotion and cancer prevention.  A more detailed study of these compounds has lead to the science of nutrigenomics.

Nutrigenomics and Cancer

Until recently, nutrition research concentrated on nutrient deficiencies and impairment of health. The advent of genomics; an understanding of scientific information about the composition and functions of genomes, has created unprecedented opportunities for increasing our understanding of how nutrients modulate gene and protein expression and ultimately influence cellular and organismal metabolism.  The diverse tissue and organ-specific effects of bioactive dietary components include gene-expression patterns (transcription); organization of the chromatin (epigenome); protein-expression patterns, including posttranslational modifications (proteome); as well as metabolite profiles (metabolome).  (Afman L, Muller M. Nutrigenomics: from molecular nutrition to prevention of disease. J Am Diet Assoc. 2006 Apr;106(4):569-76.)

Nutrigenomics is the application of genomics tools to the study of diet-gene interactions in order to identify dietetic components having beneficial or detrimental health effects. Nutrition becomes indeed one of the environmental factors influencing gene expression. We can consider nutrigenomics as a multidisciplinary science that applies the genomic techniques besides the biochemical and epidemiological aspects, with the aim to understand the etiologic aspects of chronic diseases such as cancer, cardiovascular diseases (CVD), type 2 diabetes mellitus, obesity, metabolic syndrome, etc. Nutrigenomics is linked to nutrigenetics, which studies the genetic basis of the different individual response to the same nutritional stimulus. This phenomenon arises from gene polymorphism. As a consequence genes are important in determining a function, but nutrition is able to modify the degree of gene expression.  (Miggiano GA, De Sanctis R. Nutritional genomics: toward a personalized diet, Clin Ter. 2006 Jul-Aug;157(4):355-61) Nutrigenomics, the junction between health, diet, and genomics, can be seen as the combination of molecular nutrition and genomics. There is now good evidence that nutrition has significant influences on the expression of genes, and, likewise, genetic variation can have a significant effect on food intake, metabolic response to food, individual nutrient requirements, food safety, and the efficacy of disease-protective dietary factors.
(Ferguson LR., Nutrigenomics: integrating genomic approaches into nutrition research., Mol Diagn Ther. 2006;10(2):101-8)

A significant number of human studies in various areas are increasing the evidence for interactions between single nucleotide polymorphisms (SNPs) in various genes and the metabolic response to diet, including the risk of obesity. Many of the same genetic polymorphisms and dietary patterns that influence obesity or cardiovascular disease also affect cancer, since overweight individuals are at increased risk of cancer development. The control of food intake is profoundly affected by polymorphisms either in genes encoding taste receptors or in genes encoding a number of peripheral signaling peptides such as insulin, leptin, ghrelin, cholecystokinin, and corresponding receptors. Total dietary intake, and the satiety value of various foods, will profoundly influence the effects of these genes.
(Ferguson LR. Nutrigenomics: integrating genomic approaches into nutrition research. Mol Diagn Ther. 2006;10(2):101-8.)

Human diets of plant origin contain many hundreds of compounds which cannot be considered as nutrients, but appear to play a role in the maintenance of health. Nutrigenomic also examines the affects of specific dietary chemicals, often called phytonutrients, and/or nutraceuticals. In some cases where the disease process is at least partially understood, elements of protection can be related to a single compound or structurally related group of compounds in the diet. Some of the bioactive components of food, spices, and beverages, which are of special interest include the following groups: polyphenols, phytoestrogens, saponins, terpenoids, isothiocynates, phytosterols, phytates and omega-3 fatty acids. 
(Orzechowski A, Ostaszewski P, Jank M, Berwid SJ. Bioactive substances of plant origin in food--impact on genomics. Reprod Nutr Dev. 2002 Sep-Oct;42(5):461-77. Review. Erratum in: Reprod Nutr Dev. 2002 Nov-Dec;42(6):625)  Catechins, for example, belong to the flavonoid family, which are polyphenolic compounds available in foods of plant origin, and there is much research into their beneficial affects as well as multi-mechanisms.  Several epidemiological studies have reported that consumption of flavonoids, and especially catechins might function as chemopreventive agents against cancer.
(Mariappan D, Winkler J, Parthiban V, Doss MX, Hescheler J, Sachinidis A.
Dietary small molecules and large-scale gene expression studies: an experimental approach for understanding their beneficial effects on the development of malignant and non-malignant proliferative diseases. Curr Med Chem. 2006;13(13):1481-9)

Nutrigenomic and the Applications in dietary programs

Nutrigenomics is giving us an increased understanding of how nutrition, as well as botanical medicine, influences metabolic pathways and homeostatic control; how this regulation is disturbed in the early phases of diet-related cancers, and the extent to which specific genotypes contribute to cancer. The food we consume can either turn on cancer-related genes or turn them off.  Certain phytonutrients, found in large amounts in particular foods, can also maintain genes that inhibit cancer, and other diseases, that often go array as we age.  Nutrigenomics will lead to evidence-based dietary intervention strategies for restoring health and fitness and for preventing diet-related disease. The integration of many sources of information relating to ones diet approach and in particular the ones arising from genomic, proteomic and metabolic analyses will be useful to define the "nutritional phenotype."

It is well observed that alteration of cell cycle regulatory gene expression is frequently found in tumor tissues and/or cancer cell lines, and studies have suggested that the herbal-based or plant-originated cell cycle regulators represent a new set of potential targets for anticancer programs, both dietary and supplemental with nutraceutical-based formulations. The recent upsurge of interest in this area of research and advances made therein indicate that the impact of a number of diseases affecting humans and animals can be lessened, by 50% or more, if not prevented, by simple dietary and supplemental intake with putative therapeutic properties.
(Orzechowski A, Ostaszewski P, Jank M, Berwid SJ., Bioactive substances of plant origin in food--impact on genomics., Reprod Nutr Dev. 2002 Sep-Oct;42(5):461-77. Reprod Nutr Dev. 2002 Nov-Dec;42(6):625)

In my practice I outline a diet rich in a diversity of important plant compounds, as well as put people on a supplemental program that includes concentrated forms of these compounds.  One such formula I have created, Botanical Treasures, contains an array of well-researched plant-based compounds including concentrated extract forms of Turmeric (Curcuma l.), 95% curcuminoids, 75% curcumin, Green tea (Camellia s.), 95% polyphenols, 60% catechins, Grape seed/skin (Vitis v.), OPC’s, 95%, in the seed and total polyphenols, 30%, in the skin, Japanese Knotweed (Polygonum c.), 20% resveratrol, Ginger, (Zingiber off.) 5% gingerols, Rosemary ((Rosemarinus off.) 6% carnosic acid, 1% rosemarinic acid, 1.5% ursolic aicd, etc.  All of these compounds have demonstrated broad-spectrum, multi-targeting, anti-cancer effects, as well as diseases preventive, and health promoting benefits. The other important aspect of these compound-rich foods, spices and herbs, is that have been regularly many cultures throughout the world.  Also I have my patients all consuming a health-enriched smoothie that included organic fruit and vegetable concentrates to assure therapeutic levels of the diversity of nutraceutical, as well as vitamin and minerals present in them.

As a person matures their taste for bitter fruits and vegetables increases - the taste-buds for bitter actually outlast taste-buds for sweets.  Dr. Adam Drewnowski, an expert on taste and food preferences, obesity and cancer prevention said last year that the food industry has spent decades ridding foods of natural chemicals that taste bitter. Yet many bitter foods are healthful. The solution, Drewnowski says, is not food processing but good cooking. Olive-eating people around the Mediterranean appreciate bitter as a true flavor and dress it out with salt and pepper, lemon, vinegar and olive oil. Or the cook takes a bitter ingredient -- rhubarb or citrus rind, say -- and adds just enough sugar to leave a tangy edge.  The USDA has patented an enzyme process that "removes the bitter white portion of grapefruit peel, eliminating hand-peeling and allowing more precise portion control." The pre-peeled fruit, they say, "is ideal for school lunch programs and restaurants."  Not so many years ago, school children who needed nutrients would eat the bitter white lining of citrus peel. We still don't know all of what's in it.

Seed-breeding too has usually had contempt for bitter plants. USDA phytochemical specialist Dr. Jim Duke writes: "All of these bitter herbs contain many important nutraceuticals which primitive and modern agriculture tends to select against as seeds of more palatable variants are saved, more bitter ones discarded; or modern agriculture selectively breeds to diminish the bitter nutraceuticals. I suspect that a half cup a day each of ... five bitter herbs would lower the incidence of many diseases of modern man."

The Mediterranean diet includes locally grown wild vegetables, as well other common vegetables, such as cabbage, leafy and root vegetables, bitter greens including arugula, radicchio, endive, mushrooms, tomatoes and other fruiting vegetables, grapes and berries, fish, a moderate intake of hard cheeses, grains, and plenty of olive oil.

People between the ages of 70-90 eating a Mediterranean diet consistently lower rates of all cancers by 50%, but in particular, stomach cancer, colorectal cancer, breast and prostate cancer and cancer of the esophagus, pancreas and liver than men in the wealthier industrial North East.  There is also a reduction in heart disease by 50% as well.

Knoops KT, de Groot LC, Kromhout D, Perrin AE, Moreiras-Varela O, Menotti A, van Staveren WA. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA. 2004 Sep 22;292(12):1433-9.

Older men in the USA who eat more than two servings a day of any dark green and deep yellow vegetable have a lower rate of heart disease, according to the US Department of Agriculture. They have up to a 70 percent lower risk of cancer than men who eat less than one serving a day.

Dauchet L, Amouyel P, Hercberg S, Dallongeville J. Fruit and vegetable consumption and risk of coronary heart disease: a meta-analysis of cohort studies. J Nutr. 2006 Oct;136(10):2588-93.

Once one gains a good understanding of the general concepts of eating well for cancer prevention and treatment the next step will be personalizing the diet.  A really personalized diet will be a diet considering the nutritional status, the nutritional needs based on age, body composition, work and physical activities, the type of cancer, the state of the blood and organ systems, but also considering the genotype and energetic-type as well.  Energetic-typing can be applied to the person as well as the food.  For example a person with a cold constitution may benefit from foods of a warming nature, particularly the addition of aromatic spices, such as ginger, cardamom, cinnamon, and pepper). A person during the summer with sign of excess heat may benefit from fresh water-melon or cucumber juice.  Diet, as you will learn, is foundational to cancer prevention and treatment.

Diet, genes, and cancer connection

Anyone that would take the time to review all of the epidemiological research regarding diet and cancer, would easily ascertain it is even more important than smoking, as a cause of cancer, and that fruits and vegetables, as well as, whole-grains, nuts, omega-3 fatty acid rich foods, such as cold water fish, and many commonly used herbs, spices, and teas, protect us against getting cancer, as well as reduce the aggressiveness, and spread of cancer, if you all ready have cancer. We are now discovering that diet is key for the prevention of cancer-causing mutations and genetic polymorphisms, and that just because you have a predisposition to getting cancer you don’t have to if your diet is healthy throughout your life.  Even the BRCA breast cancer associated gene is affected by diet.  A diet rich in fruits and vegetables, protects a woman from the BRCA gene becoming activated. (Nkondjock A, Ghadirian P. Diet quality and BRCA-associated breast cancer risk. Breast Cancer Res Treat. 2006 Oct 25) Also, that smoking, drinking alcohol, and eating a poor diet each of these alone cause an increase in cancer but the combination is deadly increasing the risk 3-4 fold.
(Asakage T, Yokoyama A, Haneda T, Yamazaki M, Muto M, Yokoyama T, Kato H, Igaki H, Tsujinaka T, Kumagai Y, Yokoyama M, Omori T, Watanabe H. Genetic polymorphisms of alcohol and aldehyde dehydrogenases and drinking, smoking, and diet in Japanese men with oral and pharyngeal squamous cell carcinoma. Carcinogenesis. 2006 Oct 27)

Components of a modern-Western-style diet such as high consumption of red meat and foods that increase glycemic load are associated with a p53 disease pathway (Slattery ML, Curtin K, Ma K, Edwards S, Schaffer D, Anderson K, Samowitz W. Diet activity, and lifestyle associations with p53 mutations in colon tumors. Cancer Epidemiol Biomarkers Prev. 2002 Jun;11(6):541-8)
Through modification of one’s diet and with the use of dietary adjuncts in the form of concentrated botanical/phyto-chemical compounds as gene-behavior-mediators (GBM) and adaptogens, the expression of genes involved in advent of cancer can be reprogrammed. The phenolic antioxidant resveratrol found in berries and grapes inhibits the formation of prostate tumors by acting on the regulatory genes such as p53 while activating a cascade of genes involved in cell cycle and apoptosis including p300, Apaf-1, cdk inhibitor p21, p57 (KIP2), p53 induced Pig 7, Pig 8, Pig 10, cyclin D, DNA fragmentation factor 45. The group of genes significantly altered by selenium includes cyclin D1, cdk5, cdk4, cdk2, cdc25A and GADD 153. Vitamin D shows impact on p21(Waf1/Cip1) p27 cyclin B and cyclin A1. Genomic expression profile with vitamin D indicated differential expression of gene targets such as c-JUN, JUNB, JUND, FREAC-1/FoxF1, ZNF-44/KOX7, plectin, filamin, and keratin-13, involved in antiproliferative, differentiation pathways. Curcumin mediated NrF2 pathway significantly altered p21(Waf1/Cip1) levels. Aromatase inhibitors, such as Grape seed extract and Chrysin, affect the expression of cyclin D1. Green Tea polyphenol EGCG has a significant effect on TGF-beta expression, while several other earlier studies have shown its effect on cell cycle regulatory proteins.  (Narayanan BA. Chemopreventive agents alters global gene expression pattern: predicting their mode of action and targets. Curr Cancer Drug Targets. 2006 Dec;6(8):711-27) The comprehensive diet and the supplement foundation program within the Triphastic System addresses cell cycle regulatory pathways modifying genes in cancer.

Fruit and vegetables and the vitamin/mineral connection

Epidemiological research overwhelming points to a protective affect against cancer from fruits and vegetables.  In the past researchers focused on the connection between certain vitamins and minerals and their cancer inhibiting affects.  Gladys Block, a professor at Berkeley, reviewed about 200 studies on fruit and vegetable intake and cancer and found general agreement: fruits and vegetables have a big effect in  protecting against cancer.  By now there are close to 500 studies in all from all around the world, and they’re amazingly consistent, demonstrating a significant protective effect of fruits and vegetables.  The difference between incidence among people in the top quarter of fruit and vegetable intake and incidence in the bottom quarter is more than double, so cancer rates double for people in the bottom quarter compared with the top.  For oral cancer, 9 of 9 studies find a similar effect; cancer of the larynx, 4 of 4 studies; cancer of the esophagus, 15 of 16 studies; stomach cancer, 17 of 19 studies. There is more argument when we consider the effects of hormones on cancer.  For breast cancer, 8 of 14 studies show that fruits and vegetables have a  protective effect.  That’s not a very big proportion, so epidemiologists tend to be more skeptical. But for ovarian and endometrial cancer, 3 of 4 studies confirm a protective effect; for prostate cancer, 4 of 14 studies.   We know that the majority of lung cancer is due to smoking but why does the rate fall by half if you eat your fruits and vegetables?  It has been known for years that there is a big interaction between diet and smoking.  A smoker who eats a good diet incurs half the risk of one eating a poor diet.  Why?  I think the difference is due to the vitamin C and folic acid, and phytonutrients such as phenols, like ellagic acid, carotenoids, and isothiocynates, in fruits and vegetables.   Smoking depletes vitamin C.  A smoker has to eat half more vitamin C than a nonsmoker just to keep the blood  level the same.  Someone with low levels of vitamin C and phytonutrients, retains oxidants in the body, and the effect of excess oxidants is free radical damage, genetic mutations, abnormal cell behavior and then cancer.   A similar thing happens with stomach cancer, one cause of which is a bacterial infection.  Heliobacter pylori lives between the protective lining of the stomach and the stomach cells, where it causes a chronic inflammation.  The  phagocytic cells that attack this bacteria, create a chronic inflammatory state, that increases the release of oxidants.  So Helio-bacter induced chronic inflammation, after twenty years  causes ulcers and stomach cancer. Chronic inflammation and oxidative stress are sure ways of getting cancer.  How can diet  help?  Again, phenolic compounds, carotenoids, vitamins C, folic acid, isothiocynates, etc. which you get in fruits and  vegetables, act as an antidote to inflammation and all of the oxidants the phagocytes are pouring out.

A USDA group in San  Francisco showed that men with low vitamin C  levels are oxidizing their sperm DNA, as well as the  rest of the cells in their bodies.  About 25% of U.S.  males are very low in vitamin C and they are  harming their sperm.  Male smokers are  harming their sperm DNA more than nonsmokers.  Researchers have shown there are more chromosome abnormalities in the sperm of smokers.   All of this suggests that male smokers are harming the next generation. (Rubes J, Lowe X, Moore D 2nd, Perreault S, Slott V, Evenson D, Selevan SG, Wyrobek AJ., Smoking cigarettes is associated with increased sperm disomy in teenage men, Fertil Steril. 1998 Oct;70(4):715-23. Fraga CG, Motchnik PA, Wyrobek AJ, Rempel DM, Ames BN., Smoking and low antioxidant levels increase oxidative damage to sperm DNA, Mutat Res. 1996 Apr 13;351(2):199-203) People have investigated the  effects of smoking on offspring by studying the  mothers.  They reasoned that since the woman is carrying the baby, damage would come from her.   Because a woman’s eggs were made when she was a fetus inside her mother, we should actually look at whether the grandmother was smoking.  An interesting observation made by the famous British geneticist J.B.S. Haldane showed seventy-five years ago that most mutations come  through the male line, so it is the diet of the father  that is more relevant. (Dronamraju KR.J.B.S. Haldane's (1892-1964) biological speculations. Hum Gene Ther. 1993 Jun;4(3):303-6)

Sperm replace themselves all the time and thus are subject to environmental effects.  We reviewed the literature and found more neonatal deaths, more malformations, and more childhood cancer in the offspring of male smokers.  There have been three studies out of England showing that fathers who smoke have more children with cancer,  and there is a large study from China showing that  the rate of acute lymphocytic leukemia, brain  tumors, and lymphomas is up three or four times in  children of male smokers.  So I am starting to believe this, and it is certainly plausible.     Although several factors are needed for cancer, the child of a smoker already has one strike against him or her.  No one even asks about diet.  If, as I think, oxidative stress and the amount of redox coupling agents, such as polyphenols and vitamin C, you consume are important factors, smokers who eat a good diet may have no extra risk, and smokers who eat a bad diet—and most smokers eat worse-than-average diets—might have much  more of a risk.

The vitamins and minerals that we require in our diet are called micronutrients, as distinct from macronutrients, such as starch and protein.  You need forty micronutrients to keep your biochemistry in harmony.  Considerable evidence is accumulating that deficiencies in many of the vitamins and  minerals lead to DNA damage.  Jim MacGregor, at the Food and Drug Administration (FDA), works on  broken chromosomes measured as micronuclei,  pieces of broken chromosomes.  These are found in  red blood cells, which do not normally have any  DNA.  If there is a chromosome break, a little piece of DNA gets left behind when the nucleus is  extruded to make a red blood cell, and you can stain  it to identify the DNA fragment.  Normally, one in 2,000 red blood cells in a mouse stains for a broken  chromosome, but if you irradiate the mice, you get  more.  McGregor stumbled on the fact that folic acid deficiency does the same thing as radiation.  Folia is Latin for “leaves,” and folic acid comes from leafy  greens, such as spinach.  MacGregor found a patient who had huge levels of chromosome breaks, and very low folic acid levels.  After the man was given folic acid, his chromosome breaks went down to the  normal range, and when he discontinued this  treatment, the breaks started going up again. (MacGregor JT, Wehr CM, Hiatt RA, Peters B, Tucker JD, Langlois RG, Jacob RA, Jensen RH, Yager JW, Shigenaga MK, Frei B, Eynon BP, Ames BN., 'Spontaneous' genetic damage in man: evaluation of interindividual variability, relationship among markers of damage, and influence of nutritional status. Mutat Res. 1997 Jun 9;377(1):125-35)

Folic acid, B12, B-6: important for proper methylation, gene stability and cancer inhibition

Folic acid deficiency breaks your  chromosomes in the same way that radiation does.   Many people have a vitamin B12 deficiency, which damages DNA in the same way and has the same  effect.   Folic acid and B12 protect against chromosome damage.  (Fenech MF, Dreosti IE, Rinaldi JR. Folate, vitamin B12, homocysteine status and chromosome damage rate in lymphocytes of older men. Carcinogenesis. 1997 Jul;18(7):1329-36)
Vitamins are converted into co-enzymes, which work  with enzymes to do various things.  Folic acid is involved in moving carbon units, called methyl groups, around.  The body adds a methyl group to homocysteine to make the amino acid methionine, which is present in proteins.   Methyl groups are needed to make neurotransmitters and lipids, liver detoxification, and for all sorts of other things.  Every one of these is crucial in human  metabolism.  Deficiencies in vitamin B12, or folic acid, or vitamin B6, cause high levels of  homocysteine which damages the endothelial cells  that line blood vessels, and that causes heart  disease.  (Sadeghian S, Fallahi F, Salarifar M, Davoodi G, Mahmoodian M, Fallah N, Darvish S, Karimi A; Tehran Heart Center. Homocysteine, vitamin B12 and folate levels in premature coronary artery disease., BMC Cardiovasc Disord. 2006 Sep 26;6:38.) I check homocysteine levels in all my patients.  When you like at the strong correlation between diet, aging and cancer, and then look at the importantance of folic acid, B12 and B-6 for the prevention of cell damage you can not stop and think that everyone at a certain age should be supplementing these vitamins.  There is another pool of folate, methylene  tetrahydrafolate, which methylates uracil to make  thymine.  Thymine is in DNA and uracil is in RNA.   If you don’t get enough folate, uracil is misincorporated in DNA.  Every time the repair enzymes remove it, a transient nick is formed, and if  one nick appears across from another, the  chromosome falls apart.  If people ingest folic acid, uracil is lowered and chromosome breaks are reduced.

Radiation induces DNA damage and is a known cause of cancer.  Radiation gives clusters of electrons, and sometimes it hits two DNA  bases at once, near each other.  That’s why radiation  is particularly dangerous.  The radiation biologists  think that the important part is when two of these  opposing lesions are near each other; in the course  of attempting to repair them, transient nicks are  formed and the chromosome falls apart.

(Agrawal A, Choudhary D, Upreti M, Rath PC, Kale RK., Radiation induced oxidative stress: I. Studies in Ehrlich solid tumor in mice. Mol Cell Biochem. 2001 Jul;223(1-2):71-80.
Agrawal A, Chandra D, Kale RK., Radiation induced oxidative stress: II studies in liver as a distant organ of tumor bearing mice. Mol Cell Biochem. 2001 Aug;224(1-2):9-17)

Little or no red meat is best for cancer inhibition

Limit your intake of red meat.  Unless you are extremely blood deficient meat, and red meat in particular has many drawbacks with regards to gene behavior and cancer.  Moderate intake of wild, or organic meat really isn’t a problem, but high intake more than 3 times a week of commercial meat, in problematic. Dietary epidemiological studies indicate correlations between the consumption of red meat and/or processed meat and cancer of the colon, rectum, stomach, pancreas, bladder, endometrium and ovaries, prostate, breast and lung, heart disease, rheumatoid arthritis, type 2 diabetes and Alzheimer's disease. The correlation of all these major diseases with dietary red meat indicates the presence of factors in red meat that damage biological components. Heme compounds in red meat and their oxidative byproducts resulting from reactive processes. Raw red meat contains high levels of oxymyoglobin and deoxymyoglobin and oxyhemoglobin and deoxyhemoglobin and cytochromes in muscle and other tissues. Cooked and processed meat contain hemichromes and hemochromes. After being eaten heme proteins are hydrolyzed to amino acids and peptides and the heme group which is coordinated with strong ligands. The iron of heme coordinates to the sulfur, nitrogen or oxygen of amino acids and peptides and other biological components. The coordinated heme groups are absorbed and transported by the blood to every organ and tissue. Free and coordinated heme preferentially catalyze oxidative reactions. Heme catalyzed oxidations can damage lipids, proteins, DNA and other nucleic acids and various components of biological systems. Heme catalysis with hydroperoxide intermediates can initiate further oxidations some of which would result in oxidative chain reactions. Biochemical and tissue free radical damage caused by heme catalyzed oxidations is similar to that resulting from ionizing radiation. Oxidative biochemical damage is widespread in diseases. It is apparent that decreasing the amount of dietary red meat will limit the level of oxidative catalysts in the tissues of the body. Increasing consumption of vegetables and fruits elevates the levels of antioxidative components, for example, selenium, vitamin E, vitamin C, lycopene, phenols, sterols, cysteine-glutathione and various phytochemicals.

(Tappel A. Heme of consumed red meat can act as a catalyst of oxidative damage and could initiate colon, breast and prostate cancers, heart disease and other diseases.
Med Hypotheses. 2006 Oct 1)

Vitamin E

Although supplemental vitamin E still needs for research to determine its effects on cancer, dietary intake of vitamin E clearly demonstrates a protection from cancer and heart disease, even in smokers. In a recent study a diet rich in vitamin E protected middle-aged male smokers from dieing from certain cancers and coronary heart disease, says.
(Wright ME, Lawson KA, Weinstein SJ, Pietinen P, Taylor PR, Virtamo J, Albanes D. Higher baseline serum concentrations of vitamin E are associated with lower total and cause-specific mortality in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Am J Clin Nutr. 2006 Nov;84(5):1200-7)

Fatty acids as Nutrigenomic cancer suppressing agents

Fish, and omega-3 fatty acids from fish inhibit cancer and are important nutritional compounds in treatment protocols.  Mechanisms accounting for the fish oil’s anti-tumor effects are reduced levels of PGE(2) and inducible NO synthase as well as an increased lipid peroxidation, or translation inhibition with subsequent cell cycle arrest. Further, omega-3 eicosapentaenoic acid is capable of down-regulating the production and effect of a number of mediators of cachexia, such as IL-1, IL-6, TNF-alpha and proteolysis-inducing factor.

(Stehr SN, Heller AR. Omega-3 fatty acid effects on biochemical indices following cancer surgery. Clin Chim Acta. 2006 May 16)

Olive oil: cancer inhibiting/gene normalizing

Olive oil is an integral ingredient of the "Mediterranean diet" and accumulating evidence suggests that it may have a potential role in lowering the risk of several types of cancers. A number of epidemiological studies have linked consumption of olive oil with a reduced risk of cancer and researchers are increasingly investigating this association further in laboratory studies.  The mechanisms by which the cancer-preventing effects of olive oil as having novel anti-cancer actions may relate to the ability of its monounsaturated fatty acid (MUFA) oleic acid (OA; 18:1n-9) to specifically regulate cancer-related oncogenes. Supporting our hypothesis, exogenous supplementation of cultured breast cancer cells with physiological concentrations of OA was found to suppress the overexpression of HER2 (Her-2/neu, erbB-2), a well-characterized oncogene playing a key role in the etiology, progression and response to chemotherapy and endocrine therapy in approximately 20% of breast carcinomas. OA treatment was also found to synergistically enhance the efficacy of trastuzumab (herceptin) a humanized monoclonal antibody binding with high affinity to the ectodomain (ECD) of the Her2-coded p185(HER2) oncoprotein. Moreover, OA exposure significantly diminished the proteolytic cleavage of the ECD of HER2 and, consequently, its activation status, a crucial molecular event that determines both the aggressive behavior and the response to trastuzumab of Her2-overexpressing breast carcinomas. Recent findings further reveal that OA exposure may suppresses HER2 at the transcriptional level by up-regulating the expression of the Ets protein PEA3 -a DNA-binding protein that specifically blocks HER2 promoter activity- in breast, ovarian and stomach cancer cell lines. This anti-HER2 property of OA offers a previously unrecognized molecular mechanism by which olive oil may regulate the malignant behavior of cancer cells. From a clinical perspective, it could provide an effective means of influencing the outcome of Her-2/neu-overexpressing human carcinomas with poor prognosis. Indeed, OA-induced transcriptional repression of HER2 oncogene may represent a novel genomic explanation linking olive oil and cancer as it seems to equally operate in various types of Her-2/neu-related carcinomas.
(Colomer R, Menendez JA. Mediterranean diet, olive oil and cancer. Clin Transl Oncol. 2006 Jan;8(1):15-21)

In another study OA treatment in Her-2/neu-overexpressing cancer cells was found to induce up-regulation of the Ets protein polyomavirus enhancer activator 3 (PEA3), a transcriptional repressor of Her-2/neu promoter. Also, an intact PEA3 DNA-binding-site at endogenous Her-2/neu gene promoter was essential for OA-induced repression of this gene. Moreover, OA treatment failed to decrease Her-2/neu protein levels in MCF-7/Her2-18 transfectants, which stably express full-length human Her-2/neu cDNA controlled by a SV40 viral promoter. OA-induced transcriptional repression of Her-2/neu through the action of PEA3 protein at the promoter level.

(Menendez JA, Papadimitropoulou A, Vellon L, Lupu R. A genomic explanation connecting "Mediterranean diet", olive oil and cancer: Oleic acid, the main monounsaturated Fatty acid of olive oil, induces formation of inhibitory "PEA3 transcription factor-PEA3 DNA binding site" complexes at the Her-2/neu (erbB-2) oncogene promoter in breast, ovarian and stomach cancer cells. Eur J Cancer. 2006 Oct;42(15):2425-2432. Epub 2006 Jan 6)

Olive oil also contains squalene, a triterpene compound, that has demonstrated cancer-inhibiting actions. Olive oil contains 0.2-0.7% squalene.
(Smith TJ, Squalene: potential chemopreventive agent. Expert Opin Investig Drugs, 2000 Aug;9(8):1841-8)

The mechanisms involved for the chemopreventive activity of squalene may include inhibition of Ras farnesylation, modulation of carcinogen activation and anti-oxidative activities.
(Rao CV; Newmark HL; Reddy BS, Chemopreventive effect of squalene on colon cancer. Carcinogenesis 1998 Feb;19(2):287-90)

Appreciable quantities of simple phenols (hydroxytyrosol and tyrosol) are also in olive oils, with significant differences between extravirgin (41.87 +/- 6.17) and refined virgin olive oils (4.72 +/- 215; P<0.01). The major linked phenols were secoiridoids and lignans. Although extra virgin contained higher concentrations of secoiridoids (27.72 +/- 6.84) than refined olive oils (9.30 +/- 3.81) this difference was not significant. On the other hand, the concentration of lignans was significantly higher (P<0.001) in extra virgin (41.53 +/- 3.93) compared to refined virgin olive oils (7.29 +/- 2.56). All classes of phenolics were shown to be potent antioxidants. In future epidemiologic studies, both the nature and source of olive oil consumed should be differentiated in ascertaining cancer risk.
(Owen RW; Mier W; Giacosa A; Hull WE; Spiegelhalder B; Bartsch H Phenolic compounds and squalene in olive oils: the concentration and antioxidant potential of total phenols, simple phenols, secoiridoids,  lignansand squalene. Food Chem Toxicol 2000 Aug;38(8):647-59)

But while a recent report from the US suggests that one of the oil's fats - oleic acid - could be responsible for protecting against breast cancer, the latest research, by a team at the, suggests that the phenols in olive oil, could protect against colon cancer.  The in vitro study found that incubation of one cancer cell line with increasing concentrations of olive oil phenols for 24 hours protected the cells from DNA damage.  The effect of olive oil phenols on another cell line after 48 hours of exposure suggested that they may exert an anti-promoter effect in the carcinogenesis pathway.  The researchers say that the olive oil phenols also led to a significant reduction in the invasiveness of a colon cancer cell line in vitro.

(Gill, Chris, Olive oil compounds fight colon cancer, International Journal of Cancer, Oct., 2006, vol 117, issue 1, pp1-7, University of Ulster in Northern Ireland)

Gamma-linolenic acid (GLA) inhibits Cancer

Gamma-linolenic acid (GLA), the essential omega-6 fat that is found in evening primrose, black currant seed, borage oil, and Pine seed oil, can inhibit the action of the cancer gene Her-2/neu. This gene is responsible for almost 30 percent of all breast cancers.  When cancer cells, that over-express the Her-2/neu gene, are treated with GLA, it not only helps suppress the cancer-causing gene, but also causes up to a 40-fold increase in response to the drug Herceptin (trastuzumab), which is used as part of breast cancer treatment. GLA also selectively affects cancer cells without damaging normal cells.  This is especially good news because patients who possess the Her-2/neu gene also typically have an aggressive form of the disease and a poor prognosis.  GLA is one of two essential fatty acids, which are necessary for the normal functioning and growth of cells, nerves, muscles and organs.

(Menendez JA, Vellon L, Colomer R, Lupu R. Effect of gamma-linolenic acid on the transcriptional activity of the Her-2/neu (erbB-2) oncogene. Journal of the National Cancer Institute November 2, 2005; 97(21): 1611-1615)

HER2 and the targeted effects of the omega-3 fatty acids in breast cancer

Data derived from epidemiological and experimental studies suggest that alphalinolenic acid (ALA; 18:3n-3), the main omega-3 polyunsaturated fatty acid (PUFA) present in the Western diet, may have protective effects in breast cancer risk and metastatic progression. A recent pilot clinical trial assessing the effects of ALA-rich dietary flaxseed on tumor biological markers in postmenopausal patients with primary breast cancer demonstrated significant reductions in tumor growth and in HER2 (erbB-2) oncogene expression. Hypothesis. The molecular mechanism by which ALA inhibits breast cancer cell growth and metastasis formation may involve a direct regulation of HER2, a well-characterized oncogene playing a key role in the etiology, progression and response to some chemo- and endocrine therapies in approximately 20% of breast carcinomas. In a recent study ALA exposure was found to dramatically repress the activity of a HER2 neu. Moreover, the nature of the cytotoxic interaction between ALA and trastuzumab (Herceptin(R)) revealed a significant synergism.  Omega-3 fatty acids suppress overexpression of HER2 oncogene at the transcriptional level, which, in turn, interacts synergistically with anti-HER2 trastuzumab- based immunotherapy.

(Menendez JA, Vazquez-Martin A, Ropero S, Colomer R, Lupu R. HER2 (erbB-2)-targeted effects of the omega-3 polyunsaturated. Fatty acid alpha-linolenic acid (ALA; 18:3n-3) in breast cancer cells: the <<fat features>> of the <<Mediterranean diet>> as an <<anti-HER2 cocktail>>. Clin Transl Oncol. 2006 Nov;8(11):812-20.)

Flavonoid intake decreases colon cancer risk

Dietary flavonoids can inhibit cancer development by protecting tissues against free oxygen radicals and inhibiting cell proliferation. Because of their several biological activities, flavonoids may have an important role in explaining the protective effects of vegetables, fruit, and, possibly, tea against cancer.
(Lin J, Zhang SM, Wu K, Willett WC, Fuchs CS, Giovannucci E. Flavonoid intake and colorectal cancer risk in men and women. Am J Epidemiol. 2006 Oct 1;164(7):644-51. Epub 2006 Aug 21)
The potential relation between flavonoids and colorectal cancer risk was investigated using data from a multicenter Italian case-control study, including 1,953 cases of colorectal cancers (1,225 colon cancers and 728 rectal cancers) and 4,154 hospital controls admitted for acute nonneoplastic diseases. We have applied recently published data on the composition of foods and beverages, in terms of six principal classes of flavonoids, on dietary information collected through a validated food-frequency questionnaire. Odds ratios (OR) were estimated by multiple logistic regression models, including terms for sex, age, study center, family history of colorectal cancer, education, alcohol consumption, body mass index, physical activity, and energy intake. A reduced risk of colorectal cancer was found for increasing intake of isoflavones (OR, 0.76, for the highest versus the lowest quintile, P(trend) = 0.001), anthocyanidins (OR, 0.67, P(trend) < 0.001), flavones (OR, 0.78, P(trend) = 0.004), and flavonols (OR, 0.64, P(trend) < 0.001).
(Rossi M, Negri E, Talamini R, Bosetti C, Parpinel M, Gnagnarella P, Franceschi S, Dal Maso L, Montella M, Giacosa A, La Vecchia C. Flavonoids and colorectal cancer in Italy. Cancer Epidemiol Biomarkers Prev. 2006 Aug;15(8):1555-8)

One recent study investigated the chemoprotective activity of anthocyanin-rich extracts (AREs) from bilberry (Vaccinium myrtillus L.), chokeberry (Aronia meloncarpa E.), and grape (Vitis vinifera) by assessing multiple biomarkers of colon cancer in male rats treated with a colon carcinogen, azoxymethane. Fischer 344 male rats were fed the AIN-93 diet (control) or AIN-93 diet supplemented with AREs for 14 wk. Biomarkers that were evaluated included the number and multiplicity of colonic aberrant crypt foci (ACF), colonic cell proliferation, urinary levels of oxidative DNA damage, and expression of cyclooxygenase (COX) genes. To assess the bioavailability, levels of anthocyanins in serum, urine, and feces were evaluated. Total ACF were reduced (P<0.05) in bilberry, chokeberry, and grape diet groups compared with the control group. The number of large ACF was also reduced (P<0.05) in bilberry and chokeberry ARE-fed rats. Colonic cellular proliferation was decreased in rats fed bilberry ARE and chokeberry ARE diets. Rats fed bilberry and grape ARE diets had lower COX-2 mRNA expression of gene. High levels of fecal anthocyanins and increased fecal mass and fecal moisture occurred in ARE-fed rats. There was also a significant reduction (P<0.05) in fecal bile acids in ARE-fed rats.

(Lala G, Malik M, Zhao C, He J, Kwon Y, Giusti MM, Magnuson BA. Anthocyanin-rich extracts inhibit multiple biomarkers of colon cancer in rats. Nutr Cancer. 2006;54(1):84-93)