Thursday, October 30, 2014

Curcumin, Genistein, Pomegrenate & Co. - A Dirty Dozen of Supplements & Foods to Keep Your Prostate Cancer Free

Which of the dirty dozen of supplements and foodstuffs in today's SuppVersity review can really help you to make sure, you're not the one out of those nine men who develops prostate cancer?
Supplements that are supposed to protect you from developing prostate cancer and/or agents that may help patients with existing prostate issues are - obviously - in high demand. And as W. Merkle points out in a recent article in the German science journal Urologe using them - even if they may not be as effective as some patients may believe - makes sense: from a psychological perspective, alone (Merkle. 2014).

Taking a pill with selenium, for example, has been shown to alleviate some of the side effects of chemotherapy. General protective effects against prostate cancer, on the other hand, have not been established. In fact, the most recent studies rather suggest that "supplementation did not benefit men with low selenium status but increased the risk of high-grade PCa among men with high selenium status" (Kristal. 2014).
Supplements are nice, but without exercise you are missing 50% of the anti-cancer equation!

Tri- or Multi-Set Training for Body Recomp.?

Alternating Squat & Blood Pressure - Productive?

Pre-Exhaustion Exhausts Your Growth Potential

Full ROM ➯ Full Gains - Form Counts!

Battle the Rope to Get Ripped & Strong

Hula Hooping to Spot Reduce in the Midsection
Luckily, there are other supplements with more promising data. Supplements that will actually complement, a healthy diet and active lifestyle, the two pillars of all (not just prostate) cancer protection. Supplements like...
  • Curcumin - As a SuppVersity reader you've probably already expected to see the curcumin on the list. Its potent anti-inflammatory effects and more specifically its ability to target multiple inflammatory pathways, which include NF-KappaB, COX2, STAT3 and high levels of CRP, Prostaglandins and TNF-alpha make it a particularly valuable anti-tumor agent of which Guo et al. observed in a recent study that it will induce cell cycle arrest and apoptosis of prostate cancer cells by regulation the expression of IkappaBalpha, c-Jun and androgen receptor (Guo. 2013)
  • Genistein - Just like curcumin, genistein acts on NF-KappaB (Adjakly. 2013). In addition it will upregulate a protein called miR-574- 3p that will have cancer cells "kill themselves" (go into apopotosis; Chiyomaru. 2013). In addition scientists have found genistein to support the efficiacy of Cabazitaxel which is used for the treatment of hormone-refractory prostate cancer.
  • Pomegranate - Pomegranate extracts or rather its ingredients, i.e. ellagic acid, caffeic acid, luteolin and punicic acic, have been shown to inhibit the proliferation and induce apoptosis in prostate cancer cells (NCI. 2013).
    Figure 1: If you look at the actual increase in apoptotic cancer cells in response to the pomegranate treatment, it is obvious that some patients (e.g. #53) benefited more than others (Pantuck et al. 2006)
    A clinical trial by Pantuck et al. (2006) was also able to show that the time it takes for the PSA levels, an albeit debatable marker of prostate cancer risk, to double decreased significantly, when the subjects, men with rising PSA after surgery or radiotherapy, were treated with 8 ounces of pomegranate juice daily (Wonderful variety, 570 mg total polyphenol gallic acid equivalents) until disease progression. Unfortunately, a more recent study by Stenner-Liewen et al. (2013) could not confirm these effects. 
  • Brassica vegetables (cruciferous vegetables) - While general vegetable intake is already associated with a -39% reduced risk of developing extraprostatic prostate cancer (cancer, eating tons of cruciferous vegetable, it was the intake of broccoli and cauliflower that made the biggest impact in a 2007 study by Kirsh et al.

    Even if they don't protect you from prostate cancer broccoli & co will inhibit myostatin and could help you to grow more muscle | more.
    As it is usually the case the evidence is yet ambiguous. In a 2002 review of the evidence, Kristal, et al. found that of the six studies they could clearly interpret, only three reported statistically significant reduced risks (P < 0.05), while one reported a borderline significant reduced risk (P = 0.06). Against that background Verhoeven et al. are right, when they say: " Further epidemiological research should separate the anticarcinogenic effect of brassica vegetables from the effect of vegetables in general" (Verhoeven. 1996).

    More recently, Joseph et al. found that the existing differences in the epidemiological data may be due to genetic polymorphisms due to which only men with a certain genetic polymorphisms in glutathione S-transferases M1 and T1 will benefit from eating tons of cruciferous veggies (Joseph. 2004).
  • Green tea - Green tea is good for everything, right? Well unless it's not loaded with toxic molecules (see previous SuppVersity article) this may in fact be right. Convincing evidence from human trials is albeit scarce. What we do have are rodent studies like the ones that were conducted with TRAMP mice, which model closely mirrors the pathogenesis of human prostate cancer.

    In these mice EGCG, one of the main catechins in green tea, decreased the proliferation of prostate cancer cells and reduced the PSA levels. Scientists believe that these effects are mainly mediated by the effects EGCG has on the growth promoting proteins ERK1/2. Unfortunately, the same rodent studies also suggest that it is probably too late for many of you to start drinking green tea, now, because said beneficial effects are only observed in young, not in old TRAMP mice (Donald. 2012).
  • Coffee is for the ladies, too! Studies show significantly reduced risks of breast cancer with 5+ cups of coffee. Tee and cacao help, as well | more
    Coffee - Obviously I am biased, when it comes to coffee. I still hope you believe me when I say that drinking 5+ cups of coffee per day has been associated with significantly reduced risk of prostate cancer in what is probably the most large-scale meta-analysis of the topic today.

    In their meta-analsis of 12 peer-reviewed case-control studies, Lu et al. calculated a 4% risk reduction for Europeans who consumed five or more cups of coffee and Americans who consumed 4 or more regular cups of coffee (equ. to approximately 400-500mg of caffeine). Moreover, the scientist found "a significant inverse association in all categories of prostate cancer except Gleason <7 grade" in both the "fixed-effects model" and the "random-effects model" (Lu. 2014).

    Wilson et al. also report an inverse association between coffee consumption and the incidence of highly malignant prostate cancer (Wilson. 2013). This means that drinking coffee is not only going to reduce your overall risk of developing prostate and other cancers (Geybels. 2013), it will also increase your chance that in the unfortunate case you still develop cancer, it's going to be a benign and treatable form of prostate cancer.
  • Lignans (e.g. from flaxseed) - While many of you will probably know them as "bad anti-androgens", there is little doubt that lignans from flax and other foodstuff inhibit cancer growth. What is particularly interesting about these agents is that they don't work via the "regular" NF-kappaB pathway but inhibit the expression of the vascular endothelial growth favtor (VEGF; cf. Azrad. 2013).
  • Lycopene - It's the bright red carotene and carotenoid pigment and phytochemical that gives tomatoes and other red fruits and vegetables, such as red carrots, watermelons, gac, and papayas, although not in strawberries, red bell peppers, or cherries their color.

    Based on the currently available evidence it appears to help not just with prostate, but also with pancreatic, intestinal and lung cancer (Giovannucci. 1999). In that, it makes a particularly effective adjunct to classic cancer therapy (Tang. 2011).
    Figure 2: Prostate cancer risk w/ high vs. low intakes of the given antioxidants according
    to XRCC1 genotype (Goodman. 2006)
    Unfortunately, the data is ambigious... as usual. Unlike for other agents, it does yet appear as if scientists have already identified a certain gene, i.e. XRCC1, which appears to determine whether you do or do not benefit from the consumption of increased amounts of tomato lycopene (Goodman. 2006).

    In view of the fact that certain genotypes actually increase their prostate cancer risk specifically if they are consuming both, a high amount of lycopene and vitamin E (alpha-tocopherol), the latest Cochrane Review on the protective effects of lycopene against prostate cancer considers the evidence for "preliminary" and "insufficient" (Ilic. 2011).
  • Fish oil / omega-3 - In spite of the fact that the media jumped at the finding of the SELECT trial (learn more) that claimed that selenium would be bad, while a high fish consumption or rather a high amount of omega-3s in the blood would protect you against prostate cancer, a close re-analysis of the data you can read up on at the website of the Life Extension Foundation indicates that this was all media hype.

    With a de facto difference of only 0.18% the difference was... well, you'd say a joke, scientists would say "within the margin of statistical error" and thus by no means significant. If you take an even closer look at the data, it would even seem as if omega-3 fatty acids would increase the risk of prostate cancer.
  • Resveratrol - If you look at the existing evidence you will be surprised to find studies that indicate that resveratrol increases (Klink. 2013) and studies that show that it inhibits prostate cancer growth (Iguchi. 2012; Kai. 2011).

    Again, it took a closer look at the data and another experiment to find out what really was going on: a dose-dependent effect with increased risk with low and decreased risk with high doses of resveratrol (Benitez. 2007). Bad news: With the current low biovailable oral resveratrol preparations you're likely to end up in the "increased risk" resveratrol exposure zone.
  • Selenium - While I have mentioned it in the introduction already, it's certainly worth taking a closer look at what selenium is actually supposed to do.

    In their 2011 review of the literature, Rizky Abdulah et al. didn't just highlight the many different molecular pathways, by which selenium could protect you from developing cancer, they also point out that the type of selenium supplement used could be of critical importance with respect to the success of your efforts to avoid the development of cancer. In that,...
    In rodents selenium acts as corrosion inhibitor in the brain | learn more
    "[...] methylselenol is believed to be the critical metabolite in selenium chemoprevention. Since methylselenol is highly reactive, methylselenol precursors such as Semet and Se-mSC are important both in in vitro and in vivo experiments. Semet and Se-mSC conversion to methylselenol, however, requires enzymatic conversion by the enzyme β-lyase, which is 800 times less prevalent in human tissues than in mouse tissues.
    This may explain why the results of Semet and Se-mSC anticancer studies in humans were not as impressive as in vivo experiments. Although researchers have now turned to other Se compounds such as mSeA, which do not need enzymatic conversion to methylselenol, or selenite, which does not need to be converted to methylselenol for its anticancer properties, more substantial research on selenium compound metabolism in human tissues is necessary." (Abdulah. 2011)
    In other words, as of now, we don't know which form of selenium we actually have to use in human trials to generate similar impressive results as they have been observed in rodents.

    And as if that wasn't already "bad" enough, a meta-analysis of intervention studies by Hurst et al. (2012) indicates that there is a very narrow "band" of serum concentrations, where selenium is actually good for you! When your selenium level passes 170 ng/ml the tumor-protective effect disappears and - worst case scenario - your risk increases. So remember: More does certainly not help more!
  • Silibin (from milk thistle) - You probably think of milk thistle as a "liver supplement". In fact, its main active constituent will yet also reduce the efficacy of osteoclast cytokines and reduce the concentration of RANKL-ligands. Thus it will regulate the NF-κB und AP1 levels in cells and inhibit the proliferation, invasion and migration of metastatic prostate cancer (Ting. 2011; Chen. 2012) 
  • Vitamin D - Believe it or not: There are things vitamin D3 cannot do! One of this things is to protect you prostate cancer. That's the prerogative of active vitamin D aka calciferol. In rodent studies and studies on human cell lines calciferol and multiple analogs of active vitamin D have shown to be promising drugs for prostate cancer protection, though (Tokar. 2005).

    Underestimated Vitamin D Sources: Eggs, Chicken, Pork, Fish & Dairy Contain Ready-Made 25OHD | more
    Since simply popping tons of vitamin D3 is (luckily) without effect on the levels of calciferol (otherwise you would run the risk of being calcified from the currently prevalent abuse of vitamin D3 supplements), using vitamin D3 is less effective, but not useless.

    In 2010, for example, Woo et al. observed that the time it took for the PSA levels of prostate cancer patients to double was significantly reduced, when the subjects received 2,000 IU of vitamin D3 per day (Woo. 2005) - an effect of which previous in vitro studies suggest that it could be due to the local conversion of D3 to active vitamin D in prostate cancer cells (Tokar. 2005).
  • Vitamin E - Needless to say that vitamin E has gotten a bad rep ever since scientists observed an increased risk when they gave the subjects of the SELECT trial vitamin E (learn more). Still, as long as you stay away from "classic" vitamin E and buy one of the still expensive tocotrienol supplements (or eat red palm oil), you can expect an anti-proliferative effect of the vitamins E (Conte. 2004; Srivastava. 2006)
It's never too late to make a change! In September 2005, researchers from the University of California-San Francisco pub- lished a study that shows that intensive lifestyle changes (i.e. changin the way you eat, the amount of exercise you get, etc.) may affect the progression of prostate cancer in a highly beneficial way (Ornish. 2005) - with PSA reductions of -4%, reduced glucose levels (-70%!) improved blood lipids and higher, not lower testosterone levels.
Bottom line: While all of the above supplements and food constituents will help, nothing beats a healthy lifestyle with a balanced whole foods diet, stress control and regular exercise.

Overweight (+20% risk for BMI >25.38, already), gaining 5-10% weight after your 20s (+30%; Putnam. 2000), being self-employed (+170%) and thus probably stressed, having a family history of prostate cancer (father +140%, brother +420%), being a "former drinker" (beer +20%, wine +20%) or a current liquor drinker (+40%) and consuming more than 96g of alcohol per week (+50%), on the other hand, will - for most of the variables unnecessarily - increase your prostate cancer risk (Andersson. 1996) | Comment on FB!
References:
  • Abdulah, Rizky, et al. "Molecular targets of selenium in prostate cancer prevention (Review)." International journal of oncology 39.2 (2011): 301-309. 
  • Andersson, Swen-Olof, et al. "Lifestyle factors and prostate cancer risk: a case-control study in Sweden." Cancer Epidemiology Biomarkers & Prevention 5.7 (1996): 509-513.
  • Azrad, Maria, et al. "Flaxseed-derived enterolactone is inversely associated with tumor cell proliferation in men with localized prostate cancer." Journal of medicinal food 16.4 (2013): 357-360.
  • Benitez, Dixan A., et al. "Mechanisms Involved in Resveratrol‐Induced Apoptosis and Cell Cycle Arrest in Prostate Cancer—Derived Cell Lines." Journal of andrology 28.2 (2007): 282-293. 
  • Chen, Rongxin, et al. "The significance of MMP-9 over MMP-2 in HCC invasiveness and recurrence of hepatocellular carcinoma after curative resection." Annals of surgical oncology 19.3 (2012): 375-384.
  • Chiyomaru, Takeshi, et al. "Genistein up-regulates tumor suppressor microRNA-574-3p in prostate cancer." PloS one 8.3 (2013): e58929. 
  • Conte, Carmela, et al. "γ‐Tocotrienol Metabolism and Antiproliferative Effect in Prostate Cancer Cells." Annals of the New York Academy of Sciences 1031.1 (2004): 391-394.
  • Donald, J. L. "Plasma metabolic profiling reveals age-dependency of systemic effects of green tea polyphenols in mice with and without prostate cancer." Molecular BioSystems 6.10 (2010): 1911-1916.
  • Geybels, Milan S., et al. "Coffee and tea consumption in relation to prostate cancer prognosis." Cancer Causes & Control 24.11 (2013): 1947-1954. 
  • Giovannucci, Edward. "Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature." Journal of the National Cancer Institute 91.4 (1999): 317-331.
  • Guo H, Xu YM, Ye ZQ, Yu JH, Hu XY. "Curcumin induces cell cycle arrest and apoptosis of prostate cancer cells by regulating the expression of IkappaBalpha, c-Jun and androgen receptor." Pharmazie 68.6 (2013):431-4.
  • Hurst, Rachel, et al. "Selenium and prostate cancer: systematic review and meta-analysis." The American journal of clinical nutrition 96.1 (2012): 111-122.
  • Iguchi, Kazuhiro, et al. "Antiandrogenic activity of resveratrol analogs in prostate cancer LNCaP cells." Journal of andrology 33.6 (2012): 1208-1215. 
  • Joseph, Michael A., et al. "Cruciferous vegetables, genetic polymorphisms in glutathione S-transferases M1 and T1, and prostate cancer risk." Nutrition and cancer 50.2 (2004): 206-213.
  • Kai, Li, and Anait S. Levenson. "Combination of resveratrol and antiandrogen flutamide has synergistic effect on androgen receptor inhibition in prostate cancer cells." Anticancer research 31.10 (2011): 3323-3330.
  • Kirsh, Victoria A., et al. "Prospective study of fruit and vegetable intake and risk of prostate cancer." Journal of the National Cancer Institute 99.15 (2007): 1200-1209.
  • Klink, Joseph C., et al. "Resveratrol worsens survival in SCID mice with prostate cancer xenografts in a cell‐line specific manner, through paradoxical effects on oncogenic pathways." The Prostate 73.7 (2013): 754-762.
  • Kristal, Alan R., et al. "Baseline selenium status and effects of selenium and vitamin E supplementation on prostate cancer risk." Journal of the National Cancer Institute 106.3 (2014): djt456.
  • Lu, Yu, et al. "Coffee consumption and prostate cancer risk: an updated meta-analysis." Cancer Causes & Control 25.5 (2014): 591-604. 
  • Merkle, W. "Prostatakarzinomprophylaxe durch Nahrungsergänzungsmittel." Der Urologe (2014): 1-7.
  • NCI (2013) Pomegranate: prostate cancer, nutrition and dietary supplements (PDQ). NCI, Bethesda. http://www.cancer.gov
  • Ornish, Dean, et al. "Intensive lifestyle changes may affect the progression of prostate cancer." The Journal of urology 174.3 (2005): 1065-1070.
  • Pantuck, Allan J., et al. "Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer." Clinical Cancer Research 12.13 (2006): 4018-4026.
  • Putnam, Shannon D., et al. "Lifestyle and anthropometric risk factors for prostate cancer in a cohort of Iowa men." Annals of epidemiology 10.6 (2000): 361-369.
  • Stenner-Liewen, Frank, et al. "Daily Pomegranate Intake Has No Impact on PSA Levels in Patients with Advanced Prostate Cancer-Results of a Phase IIb Randomized Controlled Trial." Journal of Cancer 4.7 (2013): 597. 
  • Srivastava, Janmejai K., and Sanjay Gupta. "Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells." Biochemical and biophysical research communications 346.2 (2006): 447-453.
  • Tang, Yaxiong, et al. "Lycopene enhances docetaxel's effect in castration-resistant prostate cancer associated with insulin-like growth factor I receptor levels." Neoplasia 13.2 (2011): 108-119. 
  • Ting, Harold, Gagan Deep, and Rajesh Agarwal. "Molecular mechanisms of silibinin-mediated cancer chemoprevention with major emphasis on prostate cancer." The AAPS journal 15.3 (2013): 707-716. 
  • Tokar, Erik J., and Mukta M. Webber. "Chemoprevention of prostate cancer by cholecalciferol (vitamin D3): 25-hydroxylase (CYP27A1) in human prostate epithelial cells." Clinical & experimental metastasis 22.3 (2005): 265-273.
  • Verhoeven, Dorette T., et al. "Epidemiological studies on brassica vegetables and cancer risk." Cancer Epidemiology Biomarkers & Prevention 5.9 (1996): 733-748.
  • Wilson, Kathryn M., et al. "Coffee and risk of prostate cancer incidence and mortality in the Cancer of the Prostate in Sweden Study." Cancer Causes & Control 24.8 (2013): 1575-1581.
  • Woo, Tony Choon Seng, et al. "Pilot study: potential role of vitamin D (cholecalciferol) in patients with PSA relapse after definitive therapy." Nutrition and cancer 51.1 (2005): 32-36.