DNC News

DNC News: Prostate Cancer and Pomegranate Juice

 

Jacob Schor, ND

August 29, 2006

Subject: Pomegranate juice triples PSA doubling time in trial of men with metastatic prostate cancer.

 

 

A study on the effect of regular consumption of pomegranate juice on advanced prostate cancer was published this July in Clinical Cancer Research. The results were very impressive.

 

Several earlier studies should be mentioned to put this new study in context. In the fall of 2004, Albrecht and his colleagues at the Institute of Anatomy and Cell Biology in Marburg , Germany reported the results of their experiments testing various pomegranate extracts on prostate cancer cells. They tested oil from the seeds, fermented juice, and pericarp extracts (that red shell that holds the seeds) against prostate cancer both in live animals and in 'test tubes.' The different extracts had varying effects on different types of prostate cancer cells but they were able to report, “Overall, this study demonstrates significant antitumor activity of pomegranate-derived materials against human prostate cancer.” [i]

 

Malik and his colleagues at the University of Wisconsin in Madison have published two studies that are of interest to this discussion. The first, published in October of 2005, reported on their initial work using pomegranate juice in various experiments to determine its effect on prostate cancer cells. One of the things they were able to do was to convince me that cell biology is more complex than it was 30 years ago. Take this section of the abstract:

“Immunoblot analysis revealed that PFE treatment of PC3 cells resulted in (i) induction of Bax and Bak (proapoptotic); (ii) down-regulation of Bcl-X(L) and Bcl-2 (antiapoptotic); (iii) induction of WAF1/p21 and KIP1/p27; (iv) a decrease in cyclins D1, D2, and E; and (v) a decrease in cyclin-dependent kinase (cdk) 2, cdk4, and cdk6 expression. These data establish the involvement of the cyclin kinase inhibitor-cyclin-cdk network during the antiproliferative effects of PFE”

try and explain that in simple English. Luckily they do intersperse an occasional sentence that can is more comprehensible:

“Oral administration of PFE (0.1% and 0.2%, wt/vol) to athymic nude mice implanted with androgen-sensitive CWR22Rnu1 cells resulted in a significant inhibition in tumor growth concomitant with a significant decrease in serum prostate-specific antigen levels.”

Which can be translated to:

“Pomegranate juice given to mice with prostate cancer stopped the tumors from growing and lowered PSA test numbers.”

Malik's second study on pomegranate juice and prostate cancer was published in February of 2006. [ii] It appears he had help in writing this abstract as it is almost comprehensible to this reader. Here it is in only slightly edited form:

“Prostate cancer is the second leading cause of cancer-related deaths among U.S. males with a similar trend in many Western countries. [Prostate cancer] 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 prostate cancer 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 [in other words, juice] ……. resulted in inhibition of cell growth followed by apoptosis of highly aggressive human prostate carcinoma ….. cells. ……… Further, we showed that oral administration of a human acceptable dose of [pomegranate juice] to [mice with prostate cancer tumors] 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 [prostate cancer] patients, because it suggests that pomegranate consumption may retard [prostate cancer] progression, which may prolong the survival and quality of life of the patients.”

These earlier studies require mentioning because without this background readers may not believe the current study's results. In July, 2006, Panchuk and his colleagues from the Urology Department at the UCLA School of Medicine reported on a clinical trial in which they had men with metastatic prostate cancer drink 8 ounces of pomegranate juice each day. This study was placebo controlled. In other words they had a control group of men with similar disease drinking some other red fluid each day that wasn't pomegranate juice so they could compare the results.

Advanced prostate cancer is monitored by watching the PSA test numbers. As the tumors grow, the PSA numbers increase. The length of time that it takes for an individual patient's PSA numbers to double, say go from 4 to 8, is a good measure of how fast the disease is progressing. This length of time is referred to as PSA doubling time.

The average PSA doubling time, again that's how fast the disease is progressing, was 15 months for the control group of guys drinking red juice. For the guys who got the pomegranate juice, the PSA doubling time increased to 54 months. That's more than 3 times as long. [iii]

The researchers report that the treatment, drinking a glass of pomegranate juice each day, was 'well tolerated' and without 'adverse side effects reported.' This must be something of an understatement when you compare this to the other treatments that are available for metastatic cancer.

The full text of Panchuk's Study can be found at: http://pomwonderful.com/pdf/Clinical_Cancer_Research.pdf

 

This needs to be said again. Drinking pomegranate juice slowed the prostate cancer growth to less than one third the rate of the guys who didn't drink the juice. It took more than three times as long for tumors to grow to the same size because of the juice.

 

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References:

 

 

[i] J Med Food. 2004 Fall;7(3):274-83. Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion of human prostate cancer cells. Albrecht M, Jiang W, Kumi-Diaka J, Lansky EP, Gommersall LM, Patel A, Mansel RE, Neeman I, Geldof AA, Campbell MJ.

Institute of Anatomy and Cell Biology, Philipps University , Marburg , Germany .

We completed a multicenter study of the effects of pomegranate cold-pressed (Oil) or supercritical CO(2)-extracted (S) seed oil, fermented juice polyphenols (W), and pericarp polyphenols (P) on human prostate cancer cell xenograft growth in vivo, and/or proliferation, cell cycle distribution, apoptosis, gene expression, and invasion across Matrigel, in vitro. Oil, W, and P each acutely inhibited in vitro proliferation of LNCaP, PC-3, and DU 145 human cancer cell lines. The dose of P required to inhibit cell proliferation of the prostate cancer cell line LNCaP by 50% (ED(50)) was 70 microg/mL, whereas normal prostate epithelial cells (hPrEC) were significantly less affected (ED(50) = 250 g/mL). These effects were mediated by changes in both cell cycle distribution and induction of apoptosis. For example, the androgen-independent cell line DU 145 showed a significant increase from 11% to 22% in G(2)/M cells (P <.05) by treatment with Oil (35 microg/mL) with a modest induction of apoptosis. In other cell lines/treatments, the apoptotic response predominated, for example, in PC-3 cells treated with P, at least partially through a caspase 3-mediated pathway. These cellular effects coincided with rapid changes in mRNA levels of gene targets. Thus, 4-hour treatment of DU 145 cells with Oil (35 microg/mL) resulted in significant 2.3 +/- 0.001-fold (mean +/- SEM) up-regulation of the cyclin-dependent kinase inhibitor p21((waf1/cip1)) (P <.01) and 0.6 +/- 0.14-fold down-regulation of c-myc (P <.05). In parallel, all agents potently suppressed PC-3 invasion through Matrigel, and furthermore P and S demonstrated potent inhibition of PC-3 xenograft growth in athymic mice. Overall, this study demonstrates significant antitumor activity of pomegranate-derived materials against human prostate cancer.

PMID: 15383219 [PubMed - indexed for MEDLINE]

 

[ii] Cell Cycle. 2006 Feb;5(4):371-3. Epub 2006 Feb 15 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.

PMID: 16479165 [PubMed - indexed for MEDLINE]

 

[iii] Clin Cancer Res. 2006 Jul 1;12(13):4018-26 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.

PMID: 16818701 [PubMed - in process]

 


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