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Food, Facts and Fantasies: Can Your Diet Really Reduce Cancer Risk?

Food, Facts and Fantasies: Can Your Diet Really Reduce Cancer Risk? . J. A. Milner milnerj@mail.nih.gov. Nutrition Science Research Group Division of Cancer Prevention National Cancer Institute Bethesda, MD 20892.

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Food, Facts and Fantasies: Can Your Diet Really Reduce Cancer Risk?

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  1. Food, Facts and Fantasies: Can Your Diet Really Reduce Cancer Risk? J. A. Milner milnerj@mail.nih.gov Nutrition Science Research Group Division of Cancer Prevention National Cancer Institute Bethesda, MD 20892

  2. Unprecedented Opportunities Exist for Expanded Use of Foods and Components to Achieve Genetic Potential, to Increase Productivity and Decrease Risk of Disease

  3. While we have come a long way since this 1940’s United Kingdom Advertisement, we still can not identify who will and will not benefit from dietary intervention strategies

  4. Variety or Category % Positive Vegetables 80% (59/74) Fruits 64% (36/56) Raw vegetables 87% (40/46) Cruciferous Vegetables 69% (38/55) Allium vegetables 77% (27/35) Green vegetables 77% (68/88) Carrots 81% (59/73) Tomatoes 71% (36/51) Citrus Fruit 66% (27/41) Fruits, Vegetables & Cancer Prevention WCRF/AICR Expert Committee Conclusions

  5. Epigenomic Nutritional Genomics and Proteomics CH3-DNA Genomic Post-translational Proteins DNA mRNA Enzymes, structural, Transport,signaling caused by phosphorylation, glycosylation, etc. Bioactive Food Components

  6. Influence of Caffeine on Bone Mass May Depend on Genes 6 < 300 mg Caffeine > 300 mg 0 D Spine Bone Mass Density (%) -6 -12 TT Tt tt TT Tt tt Vitamin D Receptor Genotype Rapuri et al. Am J Clin Nutr 2001 Nov;74(5):694-700

  7. Diet-Gene Interactions in Colon Cancer p21+/+ AIN-76A Diet 100 p21+/- AIN-76A Diet 90 80 p21+/+ Western Diet 70 p21-/- AIN-76A Diet p21+/- Western Diet 60 Percent survival 50 40 p21-/- Western Diet 30 20 10 0 0 4 8 12 16 20 24 28 32 36 Weeks Yang et al, Cancer Res. 61, 565, 2001

  8. Selenium & Skin Cancer Prevention Trial Phase III trial with 1,312 skin cancer subjects Se (200 mg) as Brewers Yeast vs. Placebo, follow-up 6.4 yrs Selenium Placebo RR 97% CI Skin Cancer Squamous cell 218 190 1.14 0.93-1.39 Basal cell 377 350 1.10 0.95-1.28 Cancer (- Skin) Lung 17 31 0.54 0.30-0.98 Prostate 13 35 0.37 0.18-0.71 Colorectal 8 19 0.42 0.18-0.95 Breast 9 3 2.88 0.72-16.5 All Sites (- Skin) 77 119 0.63 0.47-0.85 Clark et al. JAMA 276: 1957, 1996.

  9. Prostate Cancer Prevention Selenium and Vitamin E Cancer Prevention Trail (SELECT) ($175M) 32,000 men, age >55 (> 50 for Black Men) Selenium 200 ug/d Vitamin E 400 mg/d Selenium Vitamin E Placebo 7 + Years Treatment Endpoint Prostate Cancer Incidence

  10. Early Biomarkers Needed • Ideal Qualities: • Readily accessible • Easily & reliably assayed • Differentially expressed • Directly associated with disease progression • Modulable • Predictive

  11. Diet May Influence Genetic & Epigenetic Events Associated with Several Cancer Processes DNA Repair Carcinogen Metabolism Hormonal Regulation Bioactive Food Components CellCycle Differentiation Apoptosis U54 RFA Review Nov

  12. Numerous Dietary Components Can Alter Genetic and Epigenetic Events Essential Nutrients- Ca, Zn, Se, Folate, C, E Non-Essential Phytochemicals-Carotenoids, Flavonoids, Indoles, Isothiocyanates, Allyl Sulfur Zoochemicals-Conjugated linoleic acid, n-3 fatty acids Fungochemicals- Several compounds in mushrooms Bacteriochemical- Those formed from food fermentations and those resulting from intestinal flora

  13. Gene Expression in Human Cultured Colon Cells Curcumin Butyrate Red - increased Green - decreased Black - unchanged . Mariadason et al, Cancer Res . 60, 4561, 2000

  14. How Should We Consume Bioactive Food Components? MARKET STAGE BROCCOLI 3-DAY SPROUTS 3 grams FREEZE-DRIED SPROUT EXTRACT 150 grams 150 mg All preparations contain the same quantity of detoxification enzyme inducer activity, (Glutathione S-transferase and Quinone Reductase)

  15. OLTIPRAZ Isothiocyanates (OLTIPRAZ) S S HS SH keap-1 Cytoplasm nrf2 keap-1 nrf2 nrf2 Nucleus small maf ARE Gene expression “antioxidant responsive element”

  16. Effect of Nrf2 genotype on induction of GST and NQO1 activities by oltipraz in mouse liver (Ramos-Gomez et al.Proc Natl Acad Sci U S A 2001;98:3410) Oltipraz (drug) and isothiocyanates (nutrient) have similar mechanism of action

  17. HO OH O HO R 1 OR 2 OH Tea (Camellia sinensis) Crushed tea leaves Polyphenol oxidase Oxidation, Polymerization Dried Tea Leaves Black Tea Green Tea 30-40% Catechins 3-6% Caffeine ~310 mg polyphenols per 6 ounces 3-10% Catechins 2-6% Theaflavins > 20% Thearubigens 3-6%  Caffeine ~340 mg polyphenols per 6 ounces Yang CS. Personal Communication

  18. Tea and Cancer Prevention Skin Liver Camellia Sinensis Colon Oral Esophagus Prostate Mammary Stomach Lung Yang CS. Personal Communication

  19. Types of Bioactive Compounds May Vary with New Varieties Tomato Varieties

  20. Recent Epidemiologic Studies of Lycopene and Cancer Risk Cancer Type of StudyReference Breast Cohort Dorgan et al. Can Cau Cont 9: 89-97, 1998 Colon Case-control Franceschi et al. Int J Cancer 72:56-61, 1997 Lung Case-control Agudo et al. Eur J Cancer 33:1256-61, 1997 Prostate Cohort Giovannucci et al. J Natl. Cancer Inst. 87:1767-76, 1995

  21. Prospective cohort study with 41,837 women age 55 to 69, examined 127 food items. “The strongest association in the present study was that for garlic consumption, with an approximate 50% lesser risk associated with high consumption.” Steinmetz et al. Amer. J. Epidemiology 139:1, 1994 Recent meta-analysis of Data from 11 trials concluded The random-effects relative risk (RR) estimate for raw and cooked garlic and colorectal cancer was 0.69 and for stomach was 0.53. Fleischauer, et al. Amer JClin Nutr 72, 1047, 2000.

  22. Effects of Microwave Heating of Garlic on Total DMBA-Induced DNA Adducts 1000 30 seconds a 60 seconds a 750 DNA Adducts (nmol Adducts/mol DNA) 500 b b 250 0 Control Peel/ Crushed Microwave/ Peel/ Crushed Song and MilnerJ Nutr 1999;129:657-61

  23. How Much of A Given Food is Needed Indole 3-carbinol changes site of hydroxylation of estradiol (>2 and <16 OH). Causes depression in tumor growth and apoptosis. (Telang, et al. PSEBM 216: 246: 1997).

  24. Top 20 down-regulated genes from 3 microarray analysis from MCF-7 cells (T:with,C: without 100µM indole-3-carbinol) Name T/C (Ave) p value ALOX5AP--arachidonate 5-lipoxygenase-a 0.451 0.016 BMP7--bone morphogenetic protein 7 0.309 0.017 ERCC6--excision repair cross-complemen 0.455 .046 ESR1--estrogen receptor 1 0.415 0.001 EXTL3--exostoses (multiple)-like 3 0.509 0.011 GATA3--GATA-binding protein 3 0.521 0.013 HMG2--high-mobility group (nonhistone 0.479 0.011 Homo sapiens cDNA FLJ14201 fis, clone 0.444 0.015 Homo sapiens clone 23836 mRNA sequence 0.526 0.026 KIAA0165--extra spindle poles, S. cere 0.532 0.003 KRT7--keratin 7 0.505 0.001 LAP18--leukemia-associated phosphoprot 0.528 0.013 NRCAM--neuronal cell adhesion molecule 0.482 0.016 SFRP5--secreted frizzled-related prote 0.498 0.048 TCF3--transcription factor 3 0.528 0.034 UGDH--UDP-glucose dehydrogenase 0.536 0.029 Unknown 0.488 0.008 Unknown 0.481 0.015 Unknown 0.479 0.019 ZXDA--zinc finger, X-linked, duplicate 0.358 0.021 Wang, Kim and MilnerAACR 2002

  25. Indole 3-Carbinol and Tamoxifen Interactions in Attached MCF-7 Cells 100- I3C (mM) 80- 0 50 60- Integrated Density/Area (pixel value/mm2) 100 40- 20- 0- 0 0.5 1 mM Tamoxifen Cover et al. Cancer Research 59:1244, 1999.

  26. Soy Intake and Cancer 17 of 26 animal studies reveal soy or soybean isoflavones reduce tumor tumor development 19 or 21 human epidemiological studies provide evidence of protection against cancer, especially rectal and stomach cancers (1 study reported increase) Concerns Growth enhancement of human mammary tumors transplanted into mice that were fed soy or isoflavonids (Hsieh, et al. Cancer Res. 58:3833, 1998).

  27. Soymilk Intake & Prostate Cancer Risk 1.0 0.9 0.8 Relative Risk 0.3* 0 <1 1 >1 Daily Intake (servings) Cancer Causes Control 9: 553, 1998

  28. More is Not Always Better: Energy Intakes and Expenditures Are Linked to Health!

  29. Caloric Restriction in Yeast causes silencing of genes and extended life span (Guarente and Kenyon Nature 2000; 408:255

  30. Colon Cancer and Exercise

  31. Is it Possiblethat Bioactive Compoundsmight be beneficial in some circumstancesanddetrimental in other?

  32. Some Women Appear Susceptible to Flavonoids Several flavonoids found to cause change in MLL gene on chromosome band 11q23 Associated with increased risk of infant leukemia linked to MLL gene Some cancer patients treated with drugs that modify topoisomerase develop leukemia involving MLL gene. Ross (2000) Proc. Natl Acad. Sci. 97: 4411-4413. Strick et al. (2000) Proc. Natl Acad. Sci. 97:4790-4795

  33. Vitamin E Inhibits Cisplatin-InducedApoptosis in MCF-7 Breast Cancer Cells. 6 - Antioxidant reduces efficacy of cisplatin 4 - % Apoptosis + ** 2 - * 0 - Control E CP CP+E Salganik, et al. Carcinogenesis 21: 909, 2000.

  34. One Size Does Not Fit All!

  35. Just when I knew all of life’s answers, They changed all the questions!!

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