Can Natural Dietary Supplements Really Impact Prostate Cancer?
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Can Natural Dietary Supplements

Really Impact Prostate Cancer?

Edited from PCRI Insights February 2007, vol. 10, no. 1

By Jacek Pinski, M.D., PhD.

(Medical Oncologist) Assistant Professor of Medicine

USC/Norris Comprehensive Cancer Center, Los Angeles, CA

We now have a body of solid evidence upon which to stand when we claim that natural ingredients can prolong prostate vitality … and prevent PC cells from developing … and may even prompt cancer cell death in men who have the disease.

Consider this: natural dietary supplements are now part of standard treatment and prevention of prostate cancer (PC). Admittedly, it is not an approach traditionally embraced by research scientists, medical practitioners or even patients. Popping vitamin C tablets to treat a common cold is one thing, but conventional wisdom would have it that you do not tackle a threatening disease like cancer with an arsenal of vitamins, herbs and minerals.

Well, conventional wisdom is changing. This article will discuss the results of several studies conducted over the past decade, at highly respected medical research institutions in the United States and Europe, attesting to the efficacy of supplements in preventing PC and affecting PC cell growth. I will also point to equally reputable investigations that indicate that natural supplements can amplify the benefits of more established drug and radiation therapies.

None of this should be terribly shocking. After all, many of the most frequently utilized chemotherapeutic agents are substances originally extracted from plants. Some have been synthesized chemically; but many are plant extracts, pure and simple, administered to patients in very high concentrations. So when we contemplate the irreconcilable differences between “natural supplements” and “serious drugs,” the friction starts to look a lot like the emperor’s new clothes.

As a research oncologist, I do not see tremendous divisionary thinking between practicing physicians and bench top investigators who study the effects of natural products. Supplements, vitamins, herbs — they are all part of the research. My experience is that everyone in the professional community wants precisely the same thing that patients want: curative therapies. If an expensive, synthetic chemotherapeutic agent proves beneficial, then it becomes a valuable new part of the treatment plan. Similarly, if a relatively affordable dietary supplement that is well-tolerated by patients and linked to little or no toxicity proves effective, then it is welcomed onboard. In the fight against PC, it all boils down to one very simple tenet: if it works, use it.

Conversion of a Skeptic

My professional background would not appear to qualify me for easy involvement in the fast-growing movement toward natural treatments for PC. The truth is I spent the first ten years of my career trying to develop new synthetic therapeutics to treat the disease. Although I was trained in Germany, I moved to the United States in 1990 to work at Tulane University. I joined the research team of Nobel laureate Andrew Schally, MD, a remarkable scientist best known for establishing the rationale for Androgen Deprivation Therapy (ADT) in the treatment of PC.

Essentially, Dr. Schally identified the sequencing activity of a specific hormone that ultimately leads to testosterone production in men and estrogen in women. This landmark discovery —- in tandem with the knowledge that PC cells require testosterone in order to survive and proliferate — paved the way for development of several drugs that block testosterone production. First as a research fellow, and later as an assistant professor, I worked with Dr. Schally on creating such hormone and growth factor replicas, drugs that would induce cancer cell apoptosis (cell suicide).

Then in the late 1990s, I moved to Baltimore to do my medical oncology fellowship at Johns Hopkins Oncology Center. While I was there, I did translational research studies with John Isaacs, PhD, another very prominent figure in PC research. Much of this work focused on the molecular mechanism of cancer cell death. The aim was to better understand exactly how PC cells die when they are denied the basic ingredients required for survival and proliferation. We hoped, of course, that such an understanding would result in the development of even better therapeutic agents, drugs that would initiate apoptosis faster and control it more completely.

I think it is fair to say that all this work in ADT and hormone ablation therapy — of which I am proud to have been a part — did not produce altogether stunning results. On the one hand, the drugs we developed do effectively block PC cell proliferation. On the other hand, they cause myriad side effects. Some are relatively minor: hot flashes, night sweats, loss of libido, hair loss, weight gain, fatigue and gastrointestinal toxicity. Others are far more debilitating: osteoporosis, depression, suppressed immunity, anemia, and in some cases cardiac, kidney and liver problems.

Since 2001, I have been a faculty member in the Division of Medical Oncology at the University of Southern California Norris Comprehensive Cancer Center, engaged in clinical research with actual patients as well as laboratory investigations focused on the biology of PC. Over the past few years, I have had the opportunity to design and implement a select number of studies that explore more natural, less toxic therapy options. One of these studies examines the effects of an isoflavin called genistein, essentially a plant estrogen found in soybeans and other soy products.1 It is very much like human estrogen in chemical shape and properties, but it is much weaker than the human form.

In recent years, cell culture evidence has surfaced to suggest that genistein may inhibit PC cell proliferation and induce PC cell death. I designed my project to further substantiate (or contradict) this evidence and to pinpoint the precise mechanism by which this isoflavin results in PC cell growth inhibition. I have been impressed, not so much by the evidence that genistein does induce apoptosis, but by just how effectively and efficiently the substance precipitates cell death.

In the space available here, it would be impossible to discuss all the supplements that may prove protective against PC. I could not hope to acknowledge all the studies that lend credibility to the theory that natural supplements can (a) contribute to the prevention of PC; (b) prevent and reverse symptoms of benign prostatic hyperplasia; (c) enhance the efficacy of more traditional PC therapies; and (d) kill PC cells. So, alternatively, I will focus on those that I consider most important. Together, the results of these studies — done by reputable investigators at renowned institutions in accordance with rigorous scientific research standards — constitute nothing less than a loud and well-reasoned pronouncement that natural dietary supplements can help reduce the incidence of PC and add benefit to standard treatment once the disease occurs.

Evidence from Basic, Translational and Clinical Research

Across the medical research spectrum, natural supplements show impressive power to prolong prostate vitality and battle PC cells. Their benefits are observed in basic test tube research, where laboratory scientists explore compounds thought to be potentially curative. Additional benefits are seen in the results of translational studies that test the compounds on animals. Most important, encouraging results have emerged from multiple clinical trials, which test a supplement in patients in order to establish a maximum tolerated dosage and determine efficacy.

Epigallocatechin – (EGCG) Green tea (without caffeine), apples

EPIGALLOCATECHIN: One of the best-known of these supplements is epigallocatechin (EGCG), more commonly called green tea. Made from the dried leaves of an evergreen shrub native to Asia, it has taken the western world by storm in recent years. Even popular science readers are likely to have come across articles attesting to the theory that EGCG may interfere with cancer-related biochemical reactions.2 In lay language, this means that, while we do not fully understand how or why, green tea seems to make cancer cells sluggish. Under its influence, they appear to stop dividing, and they even self-destruct. In addition, it seems to inhibit the formation of specific carcinogens known as heterocycloic amines. (These are the hazardous chemicals that form when meat is broiled.)

Several translational research studies have looked specifically at how EGCG impacts PC cells in mice. Results from perhaps the most noteworthy of these investigations indicate that EGCG prevents the development of PC cells in a well-respected mouse model.3 Another study shows that once the disease develops in mice, EGCG inhibits PC cells from producing their own growth factor, insulin growth factor (IGF).4 This is important because we have come to realize that PC cells are extremely clever. If we use ADT to block testosterone, they will ingeniously begin producing their own growth factors, such as IGF. So perhaps hormone therapy (to block testosterone) in conjunction with EGCG (to inhibit IGF production) could deliver a debilitating double-punch to PC cells. Finally, there is a clinical study showing that EGCG significantly reduce the incidence of PC in men who are at high risk for developing the disease.5 After a year’s oral administration of green tea, only one man in a group of 32 at high risk for PC developed the disease, compared to nine out of 30 in the placebo control group.

Lycopene – Watermelon, tomato and all tomato-based products, pink grapefruit, apricots, papaya, guava, persimmons

LYCOPENE: In cell culture and animal studies, this carotenoid (found in tomatoes) appears to reduce the stimulatory effect of testosterone and thereby induce PC cells death. In one translational study, for example, researchers supplemented the diet of young rats with lycopene for eight weeks and then looked at their prostate lobes to see if and how the supplement had influenced them.6 Their 2004 findings were among the first to offer evidence that lycopene may reduce local prostate androgen signaling as well as IGF-I expression and basal inflammatory signals in normal prostate tissue. In everyday language: lycopene just might reduce testosterone’s stimulatory effect on PC cells and reduce the effect of the cells’ own growth factor.

There is also evidence that lycopene may reduce the incidence of prostate cancer in humans.7,8 For example, a 2004 retrospective study examined several epidemiological investigations focused on a possible relationship between tomato consumption and subsequent risk for PC.9 One of these studies followed nearly 47,000 men from 1986 through 1992.10 By the end of this period, 773 of these participants had been diagnosed with PC. Statistical analysis indicated that when all dietary sources of tomatoes were combined, consuming more than ten servings per week was associated with a significant 35% reduced risk of PC. In 1998, a longer follow-up period was evaluated.11 By this time, in this same population, 2,481 study participants had been diagnosed with PC. Again, tomato consumption was associated with a reduction in PC risk, this time a 23% reduction. And looking at the issue in an entirely other way, a 2002 study found that men with lower lycopene blood or tissue levels were at higher risk for developing the disease.12

Selenium – Brazil nuts, walnuts, fish (including canned tuna and shellfish), organ meats, beef, turkey, chicken, eggs, whole grains, garlic, onions, broccoli, cabbage and mushrooms

SELENIUM: This mineral, found at highest concentration in some soil, is now among the most popular nutritional supplements in the field of naturopathic cancer prevention. Dietary intake cannot be measured easily because the selenium content in food depends on its concentration in the soil where the food plant grows.

Laboratory cell culture studies have shown that selenium can induce apoptosis of PC cells.13 There is also at least one cell culture study which found that human prostate carcinoma cells pretreated with selenium have increased sensitivity to gamma-irradiation.14 So, again, we see evidence that when used in tandem with traditional treatments (in this case, radiation), natural supplements may amplify the overall therapeutic effect. Translational research data also supports selenium’s efficacy, particularly when administered in conjunction with other natural supplements. In one study, for instance, researchers added vitamin E, selenium and lycopene to the diet of male mice.15 They found that mice treated with this combination had a four-fold reduction in the incidence of prostate cancer as compared to untreated animals.

Several clinical studies have demonstrated that selenium intake may significantly reduce the risk of PC in humans and, together, confirm a need for the more conclusive data that will come from large randomized controlled trials currently underway.16-18 One such investigation looked at 586 men initially enrolled in the 1982 Physicians’ Health Study and subsequently diagnosed with PC.19 The data show an inverse association between baseline blood selenium levels and the ultimate occurrence of advanced PC, suggesting that higher levels of selenium may slow tumor progression even in men who do develop the disease.

Genistein – Soybeans, tofu, soy milk, red clover, curry powder, chili powder, crushed red chili pepper, chickpeas

GENISTEIN: As I mentioned earlier, there certainly is evidence that genistein impacts PC. Cell culture studies as well as translational investigations find that it suppresses PC cell growth.20-22 We have demonstrated that one of the mechanisms by which genistein inhibits the proliferation of PC cells is by transforming some of them into a different, non-proliferative cell type.1

Much like selenium, genistein has been shown to enhance the effects of radiation therapy, both in vitro and in vivo.23 And in human trials, genistein has been shown to powerfully impact PC-cell proliferation. In one study, 76 PC patients between the ages of 50 and 80, with a Gleason score of 6 or below, were given either soy isoflavins or a placebo for 12 weeks.24 Changes in their prostate-specific antigen (PSA) and steroid hormone levels were analyzed both at baseline and after intervention. The data suggest that supplementing early-stage PC patients in this way, even for a short duration, alters markers of proliferation in many subjects, as compared to subjects receiving the placebo.

Another study enrolled 49 patients with a history of PC and rising PSA levels after radical prostatectomy or radiation therapy.25 These subjects were randomly assigned to either receive a dietary supplement high in genistein or a placebo. The researchers found that those receiving the supplement experienced significantly delayed PSA progression. So even when patients relapse subsequent to potentially curative therapy, there is evidence that genistein can arrest continued PC-cell proliferation.

Vitamin E – Wheat germ oil, various vegetable & nut oils (almond, cottonseed, safflower and sunflowers) hazelnuts, mayonnaise, sweet potato, green leafy vegetables

VITAMIN E: Cell culture as well as animal studies indicate that on its own — and particularly when used in combination with other natural supplements — vitamin E (sometimes called Alpha-Tocopherol) may be preventative against PC.26-28 Lab investigators speculate that this protection is due to the vitamin’ s antioxidant activity and suppression of a man’ s testosterone level.29 In addition, there is data from a large clinical trial (of more than 5,000 men) to support the notion that vitamin E gives an added power boost to other supplements, including vitamin C, beta-carotene, selenium and zinc.30 So, vitamin E too seems to act synergistically. Another large clinical trial, involving thousands of men, is presently investigating whether vitamin E in conjunction with selenium can prevent PC.

Vitamin D – Dairy products, eggs, breakfast cereals (which are fortified with vitamin D), fatty fish (including salmon and tuna)

VITAMIN D: The evidence is somewhat similar regarding vitamin D. An article published in the highly-respected British medical journal, Lancet, offers evidence that a lack of vitamin D might actually cause PC.31 There also may be synergistic benefit to augmenting traditional chemotherapy with vitamin D. In one clinical trial, Taxotere® (an FDA-approved drug for use against advanced PC) was combined with an analog of vitamin D — meaning vitamin D at a very high concentration.32 Researchers found that patients who received this combination had better outcomes.

Taken together, the results of the studies mentioned in this article — and many others that were not discussed here — look very promising and suggest that natural supplements may help improve prostate health. Today, there are several dietary supplements commercially-available to men. I myself have developed one and, of course, believe that my Prostate Health Cocktail (PHC) is particularly complete and effective. Of course, more carefully designed clinical trials are needed in order to establish with certainty the role such products can play in prevention and treatment of (benign as well as malignant) prostatic disease. In the meantime, however, I believe that men should be proactive. Starting at age 50, they should all consider taking a supplement of carefully selected ingredients in well-calibrated proportions. As shown above, these natural supplements can be found in a wide variety of readily available foods.

No Longer Medical Heresy

At one time, it was considered medical heresy to suggest that dietary supplements might play a constructive role in the battle against PC. Fortunately, a bold and innovative community of scientific researchers ignored that ethic and moved forward with laboratory investigations, animal studies and real patient trails. Thanks to their efforts, we now have a body of solid evidence upon which to stand when we claim that natural ingredients can prolong prostate vitality … and prevent PC cells from developing … and may even prompt cancer cell death in men who have the disease.

For years, we have watched the limitations of modern chemotherapeutic drugs; and while we have watched, patients have continued to die. Although final figures are not yet available, experts estimate that during 2006, another 234,460 American men were told that they had PC.33 Approximately half of all those new cases were locally advanced or metastatic at the time of diagnosis. Last year, an estimated 27,350 men died from the disease. If we assume that each of them had one mate, two children, five grandchildren and a dozen friends, then it is fair to say that 574,350 people in this country lost their fight against PC in 2006. That is a slightly larger number than the entire population of Washington, DC.

I am not suggesting that natural supplements replace established treatments such as chemotherapy, ADT, or radiation. Each of these respected treatments has proved to be effective, and they all prolong life. Nevertheless, dietary supplements can play an important role in PC prevention. In addition, they may enhance and perhaps even amplify the benefits of standard treatments. So we must look beyond what we already know. I am certain that tremendous therapeutic advances are to be found just beyond the horizon. We should walk toward them.

References

1. Pinski J, Wang Q, Quek ML, Cole A, Cooc J, Danenberg K, Danenberg PV. Genistein-induced neuroendocrine differentiation of prostate cancer cells. The Prostate 66:1136-1143 (2206).

2. Lesch Kelly, Alice and Mestel, Rosie. Still brewing. Health, Los Angeles Times: F1, F6. November 7, 2005.

3. Sartor L, Pezzato E, Dona M, Dell’Aica I, Calabresse F, Morini M, Albini A, Garbisa S. Prostate carcinoma and green tea: (-)epigallocatechin-3-gallate inhibits inflammation-triggered MMP-2 activation and invasion in murine tramp model. International Journal on Cancer: 112, 823-829, 2004.

4. Adhami VM, Siddiqui IA, Ahmad N, Gupta S, Mukhtar H. Oral consumption of green tea polyphenols inhibits insulin-like growth factor-I-induced signaling in an autochthonous mouse model of prostate cancer. Cancer Research 64: December 1, 2004, 8715-8722.

5. American Association for Cancer Research. News. Green Tea Shown to Prevent Prostate Cancer. April 20, 2005. <http://www.aacr.org/Default.aspx?p=1066&d=432>

6. Herzog A, Siler U, Spitzer V, Seifert N, Denelavas A, Hunziker PB, Hunziker W, Goralczyk R, Wertz K. Lycopene reduced gene expression of steroid targets and inflammatory markers in normal rat prostate. The FASEB Journal express article 10.1096/fj. 04-1905fje. Published online November 15, 2004.

7. Giovannucci E. (1991) Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J Natl Canecr Inst. 91: 317-331.

8. Miller EC, Giovannucci E, Erdman JW Jr, Bahnson, R, Schwartz, SJ, Clinton SK.(2002) Tomato products, lycopene, and prostate cancer risk.Urol. Clin. North Am. 29: 83-93.

9. Campbell JK, Canen-Adams K, Lindshield BL, Boileau TWM, Clinton SK, Erdman, Jr., JW. Tomato phyochemicals and prostate cancer risk. American Society of Nutritional Sciences. 0022-3166/04.

10. Giovannucci E, Ascherio A, Rimm EB, Stampfer MJ, Colditz GA, Willett WC. (1995) Intake of carotenoids and retinol in relation to risk of prostate cancer. J. Natl. Cancer Inst. 87: 1767-1776.

11. Giovannucci E, Rimm EB, Liu Y, Stampfer MJ, Willett WC. (2002) A prospective study of tomato products, lycopene, and prostate cancer risk. J. Natly. Cancer Inst. 94: 391-398.

12. Vogt TM, Mayne ST, Graubard BI, Swanson CA, Sowell AL, Schoenber JB, Swanson GM, Greenberg RS, Hoover RN, Hayes RB, Ziegler RG. Serum lycopene, other serum carotenoids, and risk of prostate cancer in US blacks and whites. American Journal of Epidemiology, Johns Hopkins Bloomberg School of Public Health. 2002.

13. Jiang C, Hu H, Malewics B, Wang Z, Lu J. Selenite-induced p53 Ser-15 phosphorylation and caspase-mediated apoptosis in LNCaP human prostate cancer cells. Mol. Cancer Ther. 2004 Jul: 3(7): 877-84.

14. Husbeck B, Peehl DM, Knox SJ. Redox modulation of human prostate carcinoma cells by selenite increases radiation-induced cell killing. National Library of Medicine, Free Radic. Biol Med. 2005 Jan 1; 38(1): 50-7.

15. Venkateswaran V, Fleshner NE, Sugar LM, Klotz LH. Antioxidants block prostate cancer in lady transgenic mice. National Library of Medicine, Cancer Res. 2004 Aug 15; 64(16): 5891-6.

16. Etminan M, Fitzgerald JM, Gleave M, Chambers K. Intake of selenium in the prevention of prostate cancer: a systematic review and meta-analysis. National Library of Medicine, Cancer Causes Control. 2005 Nov; 16(9):1125-31

17. Combs GF, Clark LC, Turnbull BW. Reduction of cancer risk with an oral supplement of selenium. Biomedical and Environmental Sciences 10, 227-234. 1997.

18. Clark LC, Dalkin B, Krongrad A, Combs, Jr.GF, Turnbull BW, Slate EH, Witherington R, Herlong JH, Janosko E, Carpenter D, Borosso C, Falk S, Rounder J. Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. National Library of Medicine, British Journal of Urology.1998 May; 81(5): 730-4.

19. Li H, Stampfer MJ, Giovannucci EL, Morris JS, Willett WC, Gaziano JM, Ma J.A prospective study of plasma selenium levels and prostate cancer risk. National Library of Medicine, J Natl Cancer Inst. 2004 May 5; 96(9): 696-703.

20. Raffoul JJ, Wang Y, Kucuk O, Forman JD, Sarkar FH, Hillman GG. Genistein inhibits radiation-induced activation of NF-kappa B in prostate cancer cells promoting apoptosis and G2/M cell cycle arrest. BMC Canecr.2006 Apr 26; 6: 107.

21. Kazi A, Daniel KG, Smith DM, Kumar NB, Dou QP. Inhibition of the proteasome activity, a novel mechanism associated with the tumor cell apoptosis-inducing ability of genistein. Biochem. Pharmacol. 2003 Sep 15; 66(6): 965-76.

22. PSA Rising Magazine. Genistein from soy reduces prostate cancer growth in mice, cell culture. June 2, 2001. <http://psa-rising.com/medicalpike/nutri/soy-june01.shtml>

23. Hillman GG, Wang Y, Kucuk O, Che M, Doerge DR, Yudelev M, Joiner MC, Marples B, Forman JD, Sarkar FH. Genistein potentiates inhibition of tumor growth by radiation in a prostate cancer orthotopic model. American Association for Cancer Research, Molecular Cancer Therapeutics, 2004; 3: 1271-1279.

24. Kumar NB, Cantor A, Allen K, Riccardi D, Besterman-Dahan K, Seigne J, Helal M, Salup R, Pow-Sang J. The specific role of isoflavones in reducing prostate cancer risk. National Library of Medicine, Prostate. 2004 May 1; 59(2): 141-7.

25. Schroder FH, Roobol MJ, Boeve ER, de Mutsert R, Zuijdgeest-van Leeuwen SD, Kerstein I, Wildhagen MF, van Helvoort A.Randomized, double-blind, placebo-controlled crossover study in men with prostate cancer and rising PSA: effectiveness of a dietary supplement. European Urology, doi: 10.1016/j.eururo.2005.08.005.

26. Malafa MP, Fokum FD, Andoh J, Neitzel LT, Bandyopadhyay S, Zhan R, Iiizumi M, Furuta E, Horvath E, Watabe K. Vitamin E succinate suppesses prostate tumor growth by inducing apoptosis. Int. J. Cancer. 2006 May 15; 118(10): 2441-7.

27. Siler U,Barella L, Spitzer V, Schnorr J, Lein M,Goralczyk R, Wertz K. Lycopene and vitamin E interfere with autocrine/paracrine loops in the Dunning prostate cancer model. National Library of Medicine, FASEB J. 2004 June; 18(9): 1019-21. Epub 2004 April 14.

28. Venkateswaran V, Fleshner NE, Sugar LM, Koltz LH. Antioxidants block prostate cancer in lady transgenic mice. Cancer Res. 2004 Aug 15; 64(16): 5891-6.

29. Hartman TJ, Dorgan JF, Woodson K, Virtamo J, Tangrea JA, Heinonen OP, Taylor PR, Barrett MJ, Albanes D. Effects of long-term alpha-tocopherol supplementation on serum hormones in older men. Prostate. 2001 Jan 1; 46(1): 33-8.

30. Meyer F, Galan P, Douville P, Bairati I, Kegle P, Bertrais S, Estaquio C, Hercberg S. Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.MAX trail.National Library of Medicine, Int J Cancer. 2005 Aug 20; 116 (2): 182-6.

31. Mirkin, Gabe, MD. Vitamin D prevents prostrate cancer. <http://www.drmirkin.com/men/9431.html>

32. Beer, TM. ASCENT: the androgen-independent prostate cancer study of calcitriol enhancing taxotere. National Library of Medicine. BJM Int. 2005 Sep; 96(4): 508-13. 33. CA Cancer J Clin 2006; 56: 106-130.

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