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

2 World Cancer Research Fund American Institute for Cancer ResearchFood, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective 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 RecommendationsIf 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 RecommendationsConsume “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 RecommendationsBe as lean as possible – Keep body mass index (BMI) between 21 and 24 kg/m2 Calculate 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 ProcessesDNA Repair Carcinogen Metabolism Hormonal Regulation Bioactive Food Components Cell Cycle Differentiation Apoptosis 7

8 The Science is DifficultMARKET 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) 8

9 Types of Bioactive Compounds May Vary with New VarietiesTomato Varieties 9

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

11 Typical Well-educated PC Patient11

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. 12

13 13

14 Cruciferous VegetablesBroccoli (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 14

15 15

16 Cruciferous VegetablesMechanisms 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. 17

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

19 SCID-Human Model of Prostate Cancer Bone Metastasis1 cm Normal PC3 LNCaP LUCaP 23.1 Cher et al.

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

21

22

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

24 Tomatoes and Prostate Cancer Meta-analysis of Published Studies24

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 25

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 26

27 Concerns Soy Intake and Cancer17 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). 13 27

28 Soymilk Intake & Prostate Cancer Risk1.0 0.9 0.8 Relative Risk 0.3* <1 1 >1 Daily Intake (servings) Cancer Causes Control 9: 553, 1998 28

29 Soy: Meta-Analysis of Epidemiological Studies30% Reduction in Prostate Cancer Risk 29

30 Prostate Cancer Bone Metastasis: Dietary Genistein (Soy), Matrix MetalloproteinasesMichael 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”Expansion of tumor in bone Bone matrix turnover MMP Activity MMP Inhibition – osteolytic tumors: Decreased osteoclast recruitment Decreased bone degradation Decreased growth of tumor in bone Nemeth et al., JNCI, 2002. Winding et al., Clin Cancer Res, 2002. Lee et al., Eur J Cancer, 2001. Weber et al. Int J Oncol, 2002.

33 Dietary Genistein and Experimental PC3 Bone Metastasiscontrol prevention

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

35 Soy and Bone Metastasis: SummaryDietary 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 36

37

38 Meat and Animal ProductsIncrease 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 38

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? 40

41 Summary What to tell your patientsStudies 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 41