Nutricao e o Cancro da Prostata

1. Nutricao e o Cancro da Prostata XV Workshop de Urologia Oncologica J.Edson Pontes KCI/WSU

2. World Cancer Research FundAmerican Institute for Cancer Research • Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective • http://www.dietandcancerreport.org/ • 500+ pages • Major Publication for Nutrition Recommendations Related to Cancer • November 2007 • A Review of thousands of scientific articles • Authors state that these recommendations are intended for cancer survivors as well

3. WCRF/AICR Key Recommendations • If you drink alcohol, limit to: • ≤ 2 drinks/day for men • ≤ 1 drink/day for women • 1 drink = 5 ounces of wine 1.5 ounces of hard liquor 12 ounces of beer • Dietary supplements (vitamin, minerals, other natural supplements) are not generally practical for cancer prevention

4. WCRF/AICR Key Recommendations • Consume “fast foods” sparingly, if at all • Limit salt intake • Avoid moldy grains and legumes (including peanuts) • Eat mostly foods of plant origin • Eat < 18 oz (~24 oz raw) of cooked red meat (beef, pork, lamb) per week • Be wary of portion size

5. Which One is a Healthy Portion Size?

6. WCRF/AICR Key Recommendations • Be as lean as possible – • Keep body mass index (BMI) between 21 and 24 kg/m2 • Calculate BMI: • http://www.cdc.gov/healthyweight/assessing/bmi • Avoid increases in waist circumference • Goal: < 31.5 inches – women • Goal: < 37 inches – men • Exercise Daily • Avoid sugary drinks (Coca-Cola, Lemonade)

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

8. The Science is Difficult MARKET BROCCOLI 3-DAY SPROUTS 3 grams FREEZE-DRIED SPROUT EXTRACT 150 grams 150 mg These preparations contain the same quantity of detoxification enzyme inducer activity, (Glutathione S-transferase and Quinone Reductase)

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

10. Diet-Based Interventions THIS IS NOT “COMPLEMENTARY” OR “ALTERNATIVE” MEDICINE! • General concept: • Altering diet in prostate cancer patients may possibly slow prostate cancer initiation and/or progression • Interventions: • Change in diet • Supplements

11. Typical Well-educated PC Patient

12. Vegetables Pre-clinical evidence: Components of crucifers (isothiocyanates, indole 3-carbinols) and tomatoes (carotenoids): Induce apoptosis of prostate cancer cells Inhibit carcinogenesis Promote expression of cytoprotective enzymes Protect against oxidative DNA damage • Cancer Res, 67: 836, 2007. • Cancer Epidemiol Biomarkers Prev,10:949, 2001. • J Natl Cancer Inst, 93:1872, 2001.

14. Cruciferous Vegetables • Broccoli (baby broccoli sprouts), brussel sprouts, cauliflower, kale • Indole 3-carbinols • in vivo dimeric derivative: 3, 3′-diindolylmethane (DIM) • Conversion of I3C into DIM during cooking • Epidemiological studies (PLCO, HPFS) show protective effect

16. Cruciferous Vegetables • Mechanisms in prostate cancer cells and animal models: • inhibition of cell growth • induction of G1 cell-cycle arrest • Induction of apoptosis by upregulation of BAX, downregulation of Bcl-2 and BCLXL • inactivation of Akt and NF-kB • anti-androgen • DIM down-regulated PSA expression at the transcriptional levels • no androgen receptor (AR) agonist activity

17. LNCaP C42B Sarkar et al.

18. Androgen Receptor and B-DIM LNCaP C42B (AR-immuno-fluorescence) Control B-DIM Sarkar et al.

19. Normal PC3 LNCaP LUCaP 23.1 1 cm SCID-Human Model of Prostate Cancer Bone Metastasis Cher et al.

20. B-DIM and SCID-Human Model of Prostate Cancer Bone Metastasis Sarkar et al.

23. Tomatoes Putative active agent: lycopene Free radical scavenger Induces apoptosis Epidemiological studies inconsistent Emerging consensus: Tomatoes moderately beneficial Lycopene perhaps not Processed tomatoes possibly even better than raw

24. Tomatoes and Prostate CancerMeta-analysis of Published Studies

25. Soy Phase II studies show promise for high soy diets for biochemical recurrence Studies are ongoing • Urology 64: 510, 2004 • Prostate 59: 141, 2004

26. Soy Products Rich in isoflavones (genistein and daidzein) and phytoestrogens Anti-oxidants Inhibit tumor cell proliferation Possible effect on telomerase Estrogenic effects/alterations in androgen receptor Decrease prostate cancer risk in large epidemiological studies

27. Soy Intake and Cancer 17 of 26 animal studies reveal soy or soybean isoflavones reduce tumor development 19 of 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 isoflavonoids (Hsieh, et al. Cancer Res. 58:3833, 1998).

28. 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

29. Soy: Meta-Analysis of Epidemiological Studies 30% Reduction in Prostate Cancer Risk

30. Prostate Cancer Bone Metastasis: Dietary Genistein (Soy), Matrix Metalloproteinases Michael L. Cher, Yiwei Li, Mingxin Che, Sunita Bhagat, Kerrie-Lynn Ellis, Omer Kucuk, Daniel R. Doerge, Judith Abrams, and Fazlul H. Sarkar

31. Genistein Soy isoflavone Cancer prevention (Asian Diet) Pleiotropic anti-tumor effects Phytoestrogen, inhibitor of protein tyrosine kinases, inhibit NF-κB and Akt activation Inhibit cancer cell proliferation and invasion, induce cancer cell apoptosis, inhibit tumor angiogenesis

32. Proteases and the “Vicious Cycle” Winding et al., Clin Cancer Res, 2002. Lee et al., Eur J Cancer, 2001. Weber et al. Int J Oncol, 2002. Expansion of tumor in bone MMP Activity Bone matrix turnover • MMP Inhibition – osteolytic tumors: • Decreased osteoclast recruitment • Decreased bone degradation • Decreased growth of tumor in bone • Nemeth et al., JNCI, 2002.

33. Dietary Genistein and Experimental PC3 Bone Metastasis p0.0001 p=0.0003 control prevention

34. Dietary Genistein and Experimental PC3 Bone Metastasis control Prevention (genistein) MMP-9 (red color)

35. Soy and Bone Metastasis: Summary Dietary genistein disrupts the MMP vicious cycle Decreased gene and protein expression of many MMPs including MMP-9 Pleiotropic effects on various cell cycle pathways Not due to estrogenic effects Not due to direct anti-proliferative effect

36. Fish(Omega-3 fatty acids) Decrease prostate cancer risk in large epidemiological studies Omega-3 polyunsaturated fatty acids alter cyclooxygenase (COX-2) pathways Inhibit tumor growth Induce apoptosis Phase II biomarker studies currently underway

38. Meat and Animal Products • Increase prostate cancer risk in large epidemiological studies • Red meat • Cooked meats contain various mutagens • Heterocyclic amines when meat cooked at high temperature • Polycyclic aromatic hydrocarbons: fat drips on coals which then flame up • Risk may be higher for processed meats • Dietary fat • Increases risk of aggressive cancer and recurrence after treatment • Weight loss > 11 lbs = 40% risk reduction in high-grade cancer

39. Grilling? Reduce Risk • Choose lean cuts (i.e., not ribs or sausage) • Avoid nitrite-cured (hot dogs, bacon, ham) • Flip burgers often • Cook to at least 160°F, but not to well done • Use thin marinades, not thick sauces • Trim fat from red meat and skin from poultry • Avoid flame ups by using tongs, not forks • Remove charred areas • Marinate or cook meats in antioxidants • vinegar, citrus juice, olive oil, cherries, vitamin E, garlic, rosemary, sage, soy powder • Pre-cook in microwave and finish on grill

40. A Brief Word on Pomegranate Juice… • Single trial of 46 patients • Increased PSADT in patients with biochemical recurrence (that’s a good thing) • Limited laboratory studies • No epidemiological studies • Pro-apoptotic, anti-proliferative, and anti-oxidant?

41. SummaryWhat to tell your patients • Studies are ongoing—nothing definitive yet. • Heart healthy = Prostate healthy • There is little downside to making changes in nutritional intake • Vegetable intense diet • Tomatoes • Broccoli • Soy • Fish • Decrease meat, fat, and animal product intake