Board Meetings and Iced Tea

Jacob Schor ND FABNO

September 16, 2008

I’ve spent a good bit of my free time this summer doing what I call “Board Meetings.”  Not your typical board meetings, but rather the sort where the focus is on the eight-foot board that has to meet the four-foot board on top of the two by six inch board.  I’ve been building a deck in our back yard that will cover most of the backyard that isn’t taken up by the vegetable garden.

For our readers who do not live in Denver, this is not the part of Colorado that you see in calendars or beer commercials; there are no cold mountain streams running through Denver.  It gets hot here and this summer was a record setter.  We beat the old record set in the late 1800’s of consecutive days over 100 degrees by several days.

During thse hot summer ‘board meeting’ days, I’ve developed a deep appreciation for cold beverages.  What I’ve settled on is a mixture of green tea and pomegranate juice on ice.

Even if you live under a rock and never read the news, the knowledge that green tea is good for people shouldn’t come as a surprise.  The chemical, epigallocatechin gallate, found in green tea is hot stuff in the nutritional world.  A current PubMed search yields 1150 peer reviewed medical journal articles just on green tea and cancer.

I’ve written about green tea action in cancer ad nauseam in the past so no need to elaborate.  The only contraindication for green tea is that pregnant women should avoid drinking excess amounts as it may increase risk of spina bifida in their babies.

And pomegranate another thing that you’ve heard enough about it already as well.

The think is, some of us don’t like the taste of green tea.  It’s easy enough to talk about how good it is for you but when you get right down to it, the stuff tastes like, well green tea.

Hard to believe but some people have told me that they feel the same way about pomegranate juice.  “It’s way too strong,” is the refrain I hear most often.

So dilute it with green tea.  My preferred ratio is about 4 parts green tea to one part juice.  But to each their own.

Now for the science part. It seems that this mixture is particularly useful for guys.  Several papers have looked at both green tea and pomegranate juice as protective against prostate cancer.  Adhami and Mukhtar from the University of Wisconsin have been researching this for years.  A paper they wrote back in 2003, said that green tea is protective against prostate cancer.   Then they wrote about pomegranate juice as having a similar effect in 2006.   Now we’re seeing papers where they write about both pomegranate and green tea together, first in 2006 and then again in 2007.

Of course Pantuck’s 2006 UCLA prostate cancer study is still the landmark example of pomegranate juice inhibiting advanced prostate cancer growth.   It’s worth repeating the numbers.  “Mean PSA doubling time significantly increased with treatment from a mean of 15 months at baseline to 54 months post treatment.” PSA doubling time in months is the standard measure used to gauge growth rate in advanced prostate cancer. In the fellows who were drinking fake pomegranate juice, their PSA scores doubled on average in 15 months.  Drinking daily pomegranate juice slowed the cancer growth so that it took an average of 54 months for the experimental group’s PSAs to double.

The studies on green tea and prostate cancer so far have not been this impressive.  A paper earlier this year from Lee et al in Hong Kong described their work with mice into which they implanted prostate cancer tumor.  Green tea extracts slowed the growth, lowered PSA, inhibited angiogenesis and triggered apoptosis.

All good things, but they were looking at mice not men.

In another mouse experiment, again University of Wisconsin, Mukhtar and 8 collaborators tested green tea extracts alone or in combination with a prescription cox-2 inhibiting drug called, celecoxib.  Their data showed that the effect of the tea extract and the drug were additive and possibly synergistic, that is more than the sum you would get from adding the individual effects together.

Mentioning this cox-2 inhibitor study reminds me of the Stanford study from several years back in which a cox-2 inhibitor, in that case Naproxan vastly increased the anti prostate cancer effect of vitamin D by some outrageous amount.  David Feldman did the original work and inhibitory effect increased from 25% to 70% when the two actions were combined.  See our article from 2005:

http://denvernaturopathic.com/news/DandAleve.html

Feldman has had several papers describing the mechanisms underlying this action  published since then. One in AntiCancer Research was published in Summer 2006 and another in December 2007.   

Of course mentioning vitamin D requires mention of the fact that majority of people in Denver are deficient in vitamin D.  This hardly needs mentioning for our regular readers but I metion it because I’m still entertained to discover that the first name of the primary researcher, listed on the paper, the eminent S.A. Linnebur, is Sunny.

Feldman has also reported an increased effect results from combining genistein, a chemical found in soy beans, with vitamin D.   It would be tempting to claim that I add soy milk to my iced green tea and pomegranate drink.  Honestly though, I haven’t tried it yet.

Drinking green tea is nice and is certainly reasonable for prevention but with actual cancer we do add concentrated green tea extracts in capsules.  One capsule will supply more epigallocatechin gallate than most people can drink in a day.  These chemicals in these supplements are actually better absorbed than they are when drunk as tea. We suggest that people take these green tea supplements at least 30 minutes prior to eating breakfast.  Doing this increases the amount of green tea that is absorbed by almost three times.  Now I suppose someone will want me to find the reference to these last few facts.  I’ve got them somewhere but am feeling lazy about finding them at the moment. 

You see if I’m researching these things, I’m not working on the deck.  I still have grand hopes of finishing the deck before ski season starts.

Links:

 

Green tea article (circa 2004):

http://denvernaturopathic.com/news/greentea.html

 

green tea and dioxin:

http://denvernaturopathic.com/news/greenteadioxin.html

 

Green tea bioavailability: home brewed versus extracts

http://denvernaturopathic.com/news/EGCGbioavailabiliy.html

 

Green tea contraindicated in pregnancy

ttp://denvernaturopathic.com/news/greenteafolate.html

Pomegranate Juice:

http://denvernaturopathic.com/news/pomegranate.html

 

Pomegranate Juice and Prostate Cancer http://denvernaturopathic.com/news/PomandPC.html

 

Pomegranate People: two very different people are behind the sudden interest in pomegranate and cancer.  Article appeared in Naturopathy Digest

http://www.naturopathydigest.com/archives/2006/apr/schor.php

 

References:

Nutr Cancer. 2003;47(1):13-23.Links

    Tea beverage in chemoprevention of prostate cancer: a mini-review.

    Saleem M, Adhami VM, Siddiqui IA, Mukhtar H.

    Department of Dermatology, University of Wisconsin, 1300 Medical Science Center, Madison, WI 53706, USA.

    Because prostate cancer has a long latency period and is typically diagnosed in elderly men, it represents an ideal candidate disease for chemoprevention. Therefore, even a modest delay achieved through intervention could have a significant impact on the outcome of this disease. Epidemiological and laboratory studies have provided convincing evidence that diet, genetic factors, and lifestyle are major causes of prostate cancer. Although surgery, radiotherapy, and hormone therapy are the most widely accepted curative options for a selected group of patients suffering from prostate cancer, the side effects of these treatments are many. In recent years, many dietary agents have been being described that show a wide range of chemopreventive effects in cell culture and selected animal model systems of prostate carcinogenesis. One such agent is the beverage tea, which, next to water, is the most popularly consumed beverage in the world. The epidemiological studies and recent data, amassed from various laboratories around the world, provide evidence that tea polyphenols such as epigallocatechin-3-gallate, epigallocatechin, and epicatechin-3-gallate may have the potential to lower the risk of prostate cancer in the human population. Recently, it has been shown that green tea polyphenols, when given to TRAMP, a transgenic mouse model that mimics progressive forms of human prostate cancer, exert remarkable preventive effects against prostate cancer development. Chemoprevention of prostate cancer by tea polyphenols appears to occur through the modulation of various molecular targets. This article attempts to address the issue of the possible use of tea, especially green tea, for the chemoprevention of prostate cancer.

 

Cell Cycle. 2006 Feb;5(4):371-3. Epub 2006 Feb 15.Click here to read Links

    Prostate cancer prevention through pomegranate fruit.

    Malik A, Mukhtar H.

    Department of Dermatology, University of Wisconsin, Madison 53706, USA.

    Prostate cancer (CaP) is the second leading cause of cancer-related deaths among U.S. males with a similar trend in many Western countries. CaP is an ideal candidate disease for chemoprevention because it is typically diagnosed in men over 50 years of age, and thus even a modest delay in disease progression achieved through pharmacological or nutritional intervention could significantly impact the quality of life of these patients. In this regard we and others have proposed the use of dietary antioxidants as candidate CaP chemopreventive agents. The fruit pomegranate derived from the tree Punica granatum has been shown to possess strong antioxidant and anti-inflammatory properties. In a recent study, we showed that pomegranate fruit extract (PFE), through modulations in the cyclin kinase inhibitor-cyclin-dependent kinase machinery, resulted in inhibition of cell growth followed by apoptosis of highly aggressive human prostate carcinoma PC3 cells. These events were associated with alterations in the levels of Bax and Bcl-2 shifting the Bax:Bcl-2 ratio in favor of apoptosis. Further, we showed that oral administration of a human acceptable dose of PFE to athymic nude mice implanted with CWR22Rnu1 cells resulted in significant inhibition of tumor growth with concomitant reduction in secretion of prostate-specific antigen (PSA) in the serum. The outcome of this study could have a direct practical implication and translational relevance to CaP patients, because it suggests that pomegranate consumption may retard CaP progression, which may prolong the survival and quality of life of the patients.

 

Free Radic Res. 2006 Oct;40(10):1095-104.Click here to read Links

    Polyphenols from green tea and pomegranate for prevention of prostate cancer.

    Adhami VM, Mukhtar H.

    Department of Dermatology, University of Wisconsin-Madison, Madison, WI 53706, USA.

    Prostate cancer (PCa) is the most common non-cutaneous cancer diagnosed in North America with similar trends in many Western countries. Geographic, epidemiological and laboratory studies suggest a role for dietary constituents in the etiology as well as prevention of PCa. The rising incidence of PCa in several countries appears to be coincidental with adoption of western lifestyle. Increase in the incidence of PCa has also been found in Asian populations migrating to the west. These facts give numerous leads to explore testable PCa prevention strategies. There is growing evidence in support of use of dietary ingredients in prevention and treatment of PCa. While substantial data exists in favor of use of polyphenols from tea as PCa chemopreventive agent, interest in anti-cancer properties of polyphenols from pomegranate has recently emerged. This review summarizes current literature on the effects of polyphenols from green tea and pomegranate against PCa.

 

Mol Biotechnol. 2007 Sep;37(1):52-7.Links

    Anti-oxidants from green tea and pomegranate for chemoprevention of prostate cancer.

    Adhami VM, Mukhtar H.

    Department of Dermatology, University of Wisconsin, 1300 University Avenue, Medical Sciences Center, Room B-25, Madison, Wisconsin 53706, USA.

    Among males, prostate cancer has become the second leading cause of cancer-related deaths in North America, with similar trends in many Western and developing countries. One way to control prostate cancer is through chemoprevention, which refers to the administration of synthetic or naturally occurring agents to block, reverse, or delay the process of carcinogenesis. For a variety of reasons, the most important of which is human acceptance, for chemopreventive intervention, naturally occurring diet-based agents are preferred. Prostate cancer is an ideal candidate disease for chemopreventive intervention, because it grows very slowly, likely for decades, before symptoms arise and a diagnosis is finally established, it has a long latency period, and it is typically diagnosed in men >50 years of age. Most chemopreventive agents are antioxidant in nature. We have been defining the usefulness of dietary anti-oxidants for chemoprevention of prostate and other cancers. It is increasingly appreciated that some of these dietary anti-oxidants are nature's gift molecules endowed with cancer preventive and therapeutic properties. This review will focus on prostate cancer chemopreventive effects of polyphenolic anti-oxidants derived from green tea and pomegranate. It is a challenge to custom-tailor these gift molecules as cocktails in concentrations that can easily be consumed by humans for delaying prostate and other cancers.

 

Clin Cancer Res. 2006 Jul 1;12(13):4018-26.Click here to read Links

    Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer.

    Pantuck AJ, Leppert JT, Zomorodian N, Aronson W, Hong J, Barnard RJ, Seeram N, Liker H, Wang H, Elashoff R, Heber D, Aviram M, Ignarro L, Belldegrun A.

    Department of Urology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-1738, USA. apantuck@mednet.ucla.edu

    PURPOSE: Phytochemicals in plants may have cancer preventive benefits through antioxidation and via gene-nutrient interactions. We sought to determine the effects of pomegranate juice (a major source of antioxidants) consumption on prostate-specific antigen (PSA) progression in men with a rising PSA following primary therapy. EXPERIMENTAL DESIGN: A phase II, Simon two-stage clinical trial for men with rising PSA after surgery or radiotherapy was conducted. Eligible patients had a detectable PSA > 0.2 and < 5 ng/mL and Gleason score < or = 7. Patients were treated with 8 ounces of pomegranate juice daily (Wonderful variety, 570 mg total polyphenol gallic acid equivalents) until disease progression. Clinical end points included safety and effect on serum PSA, serum-induced proliferation and apoptosis of LNCaP cells, serum lipid peroxidation, and serum nitric oxide levels. RESULTS: The study was fully accrued after efficacy criteria were met. There were no serious adverse events reported and the treatment was well tolerated. Mean PSA doubling time significantly increased with treatment from a mean of 15 months at baseline to 54 months posttreatment (P < 0.001). In vitro assays comparing pretreatment and posttreatment patient serum on the growth of LNCaP showed a 12% decrease in cell proliferation and a 17% increase in apoptosis (P = 0.0048 and 0.0004, respectively), a 23% increase in serum nitric oxide (P = 0.0085), and significant (P < 0.02) reductions in oxidative state and sensitivity to oxidation of serum lipids after versus before pomegranate juice consumption. CONCLUSIONS: We report the first clinical trial of pomegranate juice in patients with prostate cancer. The statistically significant prolongation of PSA doubling time, coupled with corresponding laboratory effects on prostate cancer in vitro cell proliferation and apoptosis as well as oxidative stress, warrant further testing in a placebo-controlled study.

 

Nutr Cancer. 2008;60(4):483-91.Links

    Effect of a prodrug of the green tea polyphenol (-)-epigallocatechin-3-gallate on the growth of androgen-independent prostate cancer in vivo.

    Lee SC, Chan WK, Lee TW, Lam WH, Wang X, Chan TH, Wong YC.

    Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, HKSAR, China.

    Epigallocatechin-3-gallate (EGCG) is the major and most potent polyphenol compound of green tea that has been shown to have anticancer effects against various types of cancers. In this study, in addition to the EGCG compound, a synthetic derivative, the peracetate of EGCG (EGCG-P), was used to investigate the inhibitory effects on growth of androgen-independent prostate cancer in vivo. The advantage of EGCG-P is that it may act as a prodrug, leading to higher bioavailability than EGCG itself. The aim of our study was to compare the differences between EGCG and EGCG-P on their inhibitory effect on androgen-independent prostate cancer, CWR22R, xenograft model in nude mice. The mice were administrated daily with solvent dimethyl sulfoxide, EGCG, and EGCG-P separately through intraperitoneal injection for 20 days. Tumor volume and body weight of nude mice were recorded daily. Serum prostate-specific antigen (PSA) levels were also measured before and after the treatment. The effects of both EGCG and EGCG-P on tumor cell proliferation were assessed by immunohistochemical (IHC) method using antibodies against Ki-67 and proliferating cell nuclear antigen. The apoptotic effect was evaluated by IHC against B-cell non-Hodgkin lymphoma-2 and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay by in situ apoptosis detection kit. Moreover, the potential suppression of angiogenesis by EGCG and EGCG-P on prostate cancer was examined by IHC against CD31. Our results revealed that treatment of EGCG and EGCG-P compounds suppressed the growth of CWR22R xenografts without causing any detectable side effects in nude mice. The suppression of growth of the tumor was correlated with the decrease of serum PSA level together with the reduction in tumor angiogenesis and an increase in apoptosis on prostate cancer cells. The results showed that treatment of EGCG and EGCG-P inhibited tumor growth and angiogenesis while promoting apoptosis of the prostate cancer cells in vivo. Our results suggest that EGCG-P may be a more stable and useful compound for increasing the therapeutic anticancer effects in androgen-independent prostate cancer.

 

Clin Cancer Res. 2007 Mar 1;13(5):1611-9.Click here to read Links

    Combined inhibitory effects of green tea polyphenols and selective cyclooxygenase-2 inhibitors on the growth of human prostate cancer cells both in vitro and in vivo.

    Adhami VM, Malik A, Zaman N, Sarfaraz S, Siddiqui IA, Syed DN, Afaq F, Pasha FS, Saleem M, Mukhtar H.

    Department of Dermatology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.

    PURPOSE: Cyclooxygenase-2 (COX-2) inhibitors hold promise for cancer chemoprevention; however, recent toxicity concerns suggest that new strategies are needed. One approach to overcome this limitation is to use lower doses of COX-2 inhibitors in combination with other established agents with complementary mechanisms. In this study, the effect of (-)epigallocatechin-3-gallate (EGCG), a promising chemopreventive agent from green tea, was tested alone and in combination with specific COX-2 inhibitors on the growth of human prostate cancer cells both in vitro and in vivo. EXPERIMENTAL DESIGN: Human prostate cancer cells LNCaP, PC-3, and CWR22Rnu1 were treated with EGCG and NS398 alone and in combination, and their effect on growth and apoptosis was evaluated. In vivo, athymic nude mice implanted with androgen-sensitive CWR22Rnu1 cells were given green tea polyphenols (0.1% in drinking water) and celecoxib (5 mg/kg, i.p., daily, 5 days per week), alone and in combination, and their effect on tumor growth was evaluated. RESULTS: Combination of EGCG (10-40 micromol/L) and NS-398 (10 micromol/L) resulted in enhanced (a) cell growth inhibition; (b) apoptosis induction; (c) expression of Bax, pro-caspase-6, and pro-caspase-9, and poly(ADP)ribose polymerase cleavage; (d) inhibition of peroxisome proliferator activated receptor gamma; and (e) inhibition of nuclear factor-kappaB compared with the additive effects of the two agents alone, suggesting a possible synergism. In vivo, combination treatment with green tea polyphenols and celecoxib resulted in enhanced (a) tumor growth inhibition, (b) lowering of prostate-specific antigen levels, (c) lowering of insulin-like growth factor-I levels, and (d) circulating levels of serum insulin-like growth factor binding protein-3 compared with results of single-agent treatment. CONCLUSIONS: These data suggest synergistic and/or additive effects of combinatorial chemopreventive agents and underscore the need for rational design of human clinical trials.

 

Anticancer Res. 2006 Jul-Aug;26(4A):2525-30.Links

    Mechanisms of vitamin D-mediated growth inhibition in prostate cancer cells: inhibition of the prostaglandin pathway.

    Moreno J, Krishnan AV, Peehl DM, Feldman D.

    Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.

    Calcitriol (1,25-dihydroxyvitamin D3), the active form of vitamin D, promotes growth inhibition and differentiation in prostate cancer (PCa) cells. To unravel the molecular pathways of calcitriol actions, cDNA microarray analysis was used to identify novel calcitriol target genes including two that play key roles in the metabolism of prostaglandins (PGs), known stimulators of PCa growth and progression. Calcitriol significantly decreases the expression of the PG synthesizing cyclooxygenase-2 (COX-2) gene, while increasing that of PG inactivating 15-prostaglandin dehydrogenase (15-PGDH). Calcitriol also inhibits the expression of the PG receptors EP2 and FP. It reduces the levels of biologically active PGs and inhibits PG actions in PCa cells, thereby decreasing the proliferative stimulus of PGs. We postulate that the regulation of the PG pathway contributes to the growth inhibitory actions of calcitriol. We also propose that calcitriol can be combined with non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit COX enzyme activity, as a potential therapeutic strategy in PCa.

 

J Bone Miner Res. 2007 Dec;22 Suppl 2:V74-80.Click here to read Links

    Calcitriol as a chemopreventive and therapeutic agent in prostate cancer: role of anti-inflammatory activity.

    Krishnan AV, Moreno J, Nonn L, Swami S, Peehl DM, Feldman D.

    Department of Medicine, Division of Endocrinology, Stanford University School of Medicine, Stanford, California, USA.

    Calcitriol, the hormonally active form of vitamin D, inhibits the growth and development of several cancers. Inflammation has been implicated in the development and progression of many cancers, including prostate cancer (PCa). Recent research from our laboratory suggests that calcitriol exhibits anti-inflammatory actions that may contribute to its inhibitory effects in PCa. We found that calcitriol inhibits the synthesis and actions of pro-inflammatory prostaglandins (PGs) by three mechanisms: (1) inhibition of the expression of cyclooxygenase-2 (COX-2), the enzyme that synthesizes PGs, (2) induction of the expression of 15-prostaglandin dehydrogenase (15-PGDH), the enzyme that inactivates PGs, and (3) decreasing the expression of prostaglandin E and prostaglandin F PG receptors, which are the mediators of PG signaling. The combination of calcitriol and nonsteroidal anti-inflammatory drugs (NSAIDs) result in a synergistic inhibition of PCa cell growth and offers a potential therapeutic strategy. Acting on a separate anti-inflammatory pathway, calcitriol induces the expression of mitogen-activated protein kinase phosphatase 5 (MKP5), a member of a family of phosphatases that are negative regulators of MAP kinases, causing the selective dephosphorylation and inactivation of the stress-activated protein kinase p38. Because p38 activation may be both procarcinogenic and promote inflammation, this calcitriol action, especially coupled with the inhibition of the PG pathway, may contribute to the chemopreventive activity of calcitriol. We conclude that calcitriol exerts several anti-inflammatory actions in prostate cells, which contribute to its potential as a chemopreventive and therapeutic agent in PCa.

 

Am J Geriatr Pharmacother. 2007 Mar;5(1):1-8.Links

    Prevalence of vitamin D insufficiency in elderly ambulatory outpatients in Denver, Colorado.

    Linnebur SA, Vondracek SF, Vande Griend JP, Ruscin JM, McDermott MT.

    Department of Clinical Pharmacy, University of Colorado at Denver and Health Sciences Center; Denver, Colorado 80262, USA. sunny.linnebur@uchsc.edu

    BACKGROUND: Vitamin D insufficiency is common in the elderly. However, previous studies have utilized 25-hydroxvvitamin D (25[OH]D) concentrations as low as <16 ng/mL for defining vitamin D insufficiency. Moreover, most of the studies have been conducted in European patients, in certain geographic areas of the United States, or in institutionalized elderly. OBJECTIVE: The goal of this study was to characterize vitamin D concentrations in ambulatory elderly living in metropolitan Denver, Colorado, utilizing 25(OH)D concentrations <32 ng/mL as the definition for vitamin D insufficiency. METHODS: Ambulatory older adults (aged 65-89 years) with clinic visits during December 2005 and January 2006 were enrolled. Serum concentrations of 25(OH)D, parathyroid hormone (PTH), calcium, phosphorus, creatinine, and albumin were measured; height and weight were also measured. Data regarding dietary and over-the-counter vitamin D intake were collected, as well as information on body mass index, history of osteoporosis, osteoporosis treatment, and history of falls and fractures. RESULTS: Eighty patients (mean [SD] age, 77.8 [5.3] years; age range, 66-89 years) completed the study; there were no dropouts. The majority of patients were white (88%) and female (68%). Fifty-nine (74%) were found to have vitamin D insufficiency. Mean total and over-the-counter vitamin D intake was significantly higher in sufficient (P < 0.01) and insufficient (P < 0.05) patients compared with deficient patients, but dietary intake did not differ significantly between groups. The majority of patients who were vitamin D insufficient consumed more than the recommended 400 to 600 IU/d of vitamin D. Obese patients were found to have significantly lower 25(OH)D concentrations (P < 0.001) and higher PTH concentrations (P = 0.04) than nonobese patients. CONCLUSIONS: Vitamin D insufficiency is prevalent in ambulatory, and especially obese, elderly living in Denver, Colorado, despite vitamin D intake consistent with national recommendations. Dietary intake of vitamin D appeared to be unreliable to prevent insufficiency. Based on our results, along with other published data, we feel that national recommendations for vitamin D intake in the elderly should be increased to at least 800 to 1000 IU/d of over-the-counter supplemental cholecalciferol.

 

J Nutr. 2007 Jan;137(1 Suppl):205S-210S.Click here to read Links

    Calcitriol and genistein actions to inhibit the prostaglandin pathway: potential combination therapy to treat prostate cancer.

    Swami S, Krishnan AV, Moreno J, Bhattacharyya RB, Peehl DM, Feldman D.

    Department of Medicine, Division of Endocrinology, Stanford University School of Medicine, Stanford, CA 94305, USA.

    We present an overview of the prostaglandin (PG) pathway as a novel target for the treatment of prostate cancer (PCa) using a combination of calcitriol and genistein, both of which have known antiproliferative properties. Calcitriol inhibits the PG pathway in PCa cells in 3 separate ways: by decreasing cyclooxygenase-2 (COX-2) expression, stimulating 15-hydroxyprostaglandin dehydrogenase (15-PGDH) expression, and decreasing EP (PGE2) and FP (PGF(2alpha)) receptors. These actions of calcitriol result in reduced levels of biologically active PGE2, leading ultimately to growth inhibition of the PCa cells. We also demonstrate the advantages of using calcitriol in combination with genistein for the treatment of PCa. Genistein, a major component of soy, is a potent inhibitor of the activity of CYP24, the enzyme that initiates the degradation of calcitriol. This leads to increased half-life of bioactive calcitriol, thereby enhancing all of calcitriol's actions including those on the PG pathway. In addition to inhibiting CYP24 enzyme activity, genistein has its own independent actions on the PG pathway in PCa cells. Like calcitriol it inhibits COX-2 expression and activity, leading to decreased synthesis of PGE2. It also inhibits the EP and FP receptors, thereby reducing the biological function of PGE2. Thus, the combination of calcitriol and genistein acts additively to inhibit the PG pathway. Both calcitriol and genistein are relatively safe and have little toxicity associated with their intake. We postulate that the combination of calcitriol and genistein is an attractive therapeutic option for the treatment of PCa.