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Pomegranate Juice Slows PSA Rise in Men With Recurrent Prostate CancerPomegranate juice prolongs post-surgery PSA doubling time, drives down cancer cell proliferation and causes prostate cancer cells to self-destruct, according to a study published in the July 1 issue of Clinical Cancer Research. PSA (prostate specific antigen) is a protein marker for prostate cancer. In men who have been treated for prostate cancer by surgery or radiation, a rise in PSA (prostate specific antigen) is a sign of cancer recurrence. The faster a man's PSA levels rise after treatment, the greater his risk of dying of prostate cancer. In a clinical study at the Jonsson Cancer Center at UCLA, men with rising PSA after surgery or radiation treatment who drank pomegranate juice saw their PSA doubling time slow down to about 54 months. By comparison, prior to their drinking the daily doses of eight-ounce pomegranate juice, the men's PSA levels had been doubling more than twice as fast, on average in just 15 months. "The velocity of the increase in PSA is decreased by 35 percent among those who drank the pomegranate juice," said Allan Pantuck, M.D., associate professor, Department of Urology, David Geffen School of Medicine, UCLA, and lead author of the paper. "We are hoping that pomegranate juice offers a novel strategy for prolonging the doubling time in men who have been treated for prostate cancer," Dr. Pantuck added. Dr. Pantuck's team included Louis Ignarro, Ph.D., the Nobel laureate who identified a signalling molecule in the cardiovascular system as nitric oxide (NO). Ignarro's discoveries concerning NO are used in fighting heart disease and led to the invention of Viagra. Pantuck, Ignarro and their colleagues suggest that what explains the pomegranate effect on PSA velocity is the role of inflammation in cancer and the antioxidant and anti-inflammatory effects of pomegranate polyphenols. "Pomegranate is high in antioxidants, and there is good evidence that inflammation plays an important role in prostate cancer," Dr. Pantuck said. As with vitamin C and other antioxidants, Pantuck said, ellagic acid, works to quench molecules that oxidate, or add oxygen, to cellular and circulatory proteins and fats, altering their biological function. Ellagic acid is "a primary antioxidant in pomegranate juice," After drinking 8 oz of the juice every day the patients all had ellagic acid in their urine, detected by liquid chromatography-mass spectrometry. "By quenching oxidative species with antioxidants, you are basically preserving circulating nitric oxide, so it can have a greater biologic effect," Dr. Pantuck said. "By decreasing the amount of free radicals, you are probably decreasing the circulating factors that are destroying nitric oxide." Backed up by a survey of previous literature the Puntack team says that by preserving nitric oxide and increasing it over the baseline levels, the antioxidants combat inflammation. Chronic inflammation has been linked to many cancers, including prostate cancer. Studies have shown, Pantuck et al point out, that abnormal increase (proliferation) in epithelial cells is increased by inflammation. About 15% of all cancers can be related to chronic inflammation. Population studies have found an increased risk for prostate cancer in men who have a prior history of sexually transmitted disease or prostatitis. Inflammation in the microenvironment of the prostate cancer cell may stimulate the multistep process of carcinogenesis by up-regulating the production of proinflammatory cytokines and their signaling pathways, they write. In fact, "proliferative inflammatory atrophy has recently been proposed as a precursor to prostatic intraepithelial neoplasia (PIN) and prostate cancer." "Inflammation can result in persistent oxidative stress in cancer cells and the reactive oxygen species may lend cancer cells a survival advantage," they continue. "Mild levels of oxidative stress stimulate cancer cell proliferation and increase mutation rates through DNA damage" and/or through other changes that affect the cell and, indirectly, genes. De Marzo et al., they note, "have shown the loss of glutathione S-transferase P1 as an early event in prostate tumors that sets the stage for stimulation of growth by oxygen radicals." Oxidative stress has also been shown to increase cancer cell growth and cell division "by increasing the sensitivity of growth factor receptors and by altering transcription factor activity." Pantuck and his colleagues examined antioxidant characteristics of the fruit juice and in the patients' blood. Tests detected a 23 percent increase in nitric oxide in blood from patients who had drunk 8 oz pomegranate juice a day for 9 months. Two thirds of patients assayed had an increase compared with baseline. These studies were conducted in Dr. Ignarro's UCLA laboratory. To measure the effects of pomegranate juice treatment on cancer cell growth in blood drawn from each individual patient at baseline and posttreatment, they took the indivual "before" and "after" bloods and mixed them with culture containing human prostate cancer cells (LNCaP cell line) using a specially designed cell culture assay system. Blood drawn from the men after the regimen of daily 8oz of pomegranate juice showed a net decrease of almost 30 percent in the numbers of prostate cancer cells generated. Similarly, the "after" blood decreased cell proliferation by 12 percent and induced 17 percent more programmed cancer cell death, or apoptosis, than sera drawn from the men prior to treatment. As for levels of nitric oxide, they took concentrations of nitrite and nitrate as anindirect measurement of nitric oxide (NO) production, since "Plasmanitrite and nitrate represent the two stable oxidation productsof NO in solution, and determination of both anions representsan accurate quantitative measure of NO produced." They found that compared with baseline, there was a 23% increase in serum NOmetabolites measured in patients' serum at 9 months with two thirdsof patients assayed having an increase compared with baseline. "There was a significant negative correlation betweenbaseline PSA and baseline nitrite level." Pomegranate contains hormones (see right sidebar down page). An earlier study (PNAS, 2005), which Dr. Ignarro edited on behalf of a group in Wisconsin, found that pomegranate downregulates the androgen receptor on prostate cancer cells. But Dr. Pantuck's team found no effect of pomegranate juice on the men's testosterone levels. "The lack of any observed effect on serum androgen levels," Pantuck writes, "suggests that the effect is not primarily hormonal in nature." Further, the authors say, there's no reason to believe that polyphenols "artifactually" affect PSA, e.g. lower PSA alone without any change in the cancer. "This is supported by a separate pharmacokinetic study (data not shown), in which there was no relationship between circulating ellagic acid and PSA when both were serially and simultaneously measured after pomegranate juice consumption." Dr. Pantuck says that clinical trials with more precise design are necessary to confirm the biological role the fruit plays in prolonging or preventing recurrence of prostate cancer in men. "We don't believe we are curing anyone from prostate cancer," he said. "In our initial trial, although a third of patients experienced a decrease in their PSA during the study, nobody's PSA went to zero. "The PSA doubling time, however, was longer. For many men, this may extend the years after surgery or radiation that they remain recurrence free and their life expectancy is extended. They may be able to prevent the need to undergo additional therapies, such as radiation, hormonal or chemotherapies." Study methods and resultsA phase II, Simon two-stage clinical trial for men with rising PSA after surgery or radiotherapy was conducted. The study recruited the target number of 48 participants over a period of 13 months in two stages after efficacy criteria were met. Two patients withdrew participation before their first evaluation, leaving 46 patients evaluable for treatment response. Of the patients enrolled, 68% were originally treated by radical prostatectomy, 10% by external beam radiotherapy, 10% by brachytherapy, 7% by surgery and radiation, and 5% by cryotherapy. The original Gleason scores were read as intermediate ( 5-7 ) in 94% of patients, whereas 6% had Gleason 4 cancers. All patients were clinical or pathologic N 0 and M 0, and 63% were clinically or pathologically staged with organ-confined disease, whereas 37% had locally advanced cancers extending into the periprostatic or seminal vesicle tissues. At study entry, median PSA for the cohort was 1.05 ng/mL (average, 2.23 ± 2.58 ng/mL). A series of PSA measurements before study entry determined each patient's baseline PSA doubling time (PSADT). Each patient had a minimum of three pretreatment PSA values measured over a minimum of 6 months before study entry. Patients were treated with 8 ounces of pomegranate juice by mouth daily (Wonderful variety, equivalent to 570 mg total polyphenol gallic acid equivalents daily) until meeting disease progression end points. Patients were followed in 3-month intervals for serum PSA, and blood and urine were collected for laboratory studies. In addition measurements were made of the effect of pomegranate on the patients' hormone levels (testosterone, estradiol, sex hormone-binding globulin, dehydroepiandrosterone, insulin-like growth factor, and androstenedione). In stage I of this trial, 24 patients were treated of whom 2 patients were objective responders, with PSA declines of 85% and 50%. In the first responder, the PSA rose to a maximal value at 6 months on study, followed by the 85% decrease in PSA level, which did not return to its peak until 21 months. The second responder has maintained a 57% reduction in peak PSA at 33 months on study. In addition to these 2 subjects, 6 of the first 24 patients progressed by PSA criteria. Of the 46 patients analyzed from both stages, 16 (35%) achieved a decrease in PSA during treatment (median, 18%; average, 27%; range, 5-85%). Of these 46 patients, a total of 4 met objective response criteria and achieved a PSA decline >50%, meeting efficacy criteria to justify future clinical testing. The slope of their mean log PSA decreased 35%, from 0.066 ± 0.007 (mean {lambda} ± SE) at baseline down to 0.043 ± 0.007 (mean . " Each individual thin line represents the log PSA by time for one subject, pretreatment and posttreatment (month 0 = baseline treatment), with the average slope of the entire cohort plotted in thick black line. The PSA values tend to increase, but the increase rate (slope) decreased. The slope of the mean log PSA of the entire cohort decreased 35%, from 0.066 ± 0.007 (mean {lambda} ± SE) at baseline down to 0.043 (mean {lambda} ± SE) on treatment (P < 0.001)." Comparisons between baseline and posttreatment PSADT were calculated at multiple time points. At 15 months, there were 28 patients with sufficient data points for meaningful analysis. At 15 months, the average pretreatment baseline PSADT was estimated to be 14.3 ± 10.8 months, whereas the posttreatment PSADT was 25.5 ± 33.5 months (P = 0.048). At 24 months, the average PSADT for 39 patients before intervention was 15.0 ± 11.1 months (median, 11.5 months). At 24 months, 7 subjects had negative slopes (PSA was decreasing); therefore, no PSADT could be estimated in these patients who were therefore excluded from analysis at this time point. Note that by excluding patients with a declining PSA from the PSADT calculation the actual PSADT will be underestimated. In the remaining evaluable patients, the PSADT was 37.0 ± 53.0 months (median, 19.9 months). The 22-month prolongation in PSADT reached statistical significance (signed rank sum test, P = 0.0001). Due to the large number of patients who continued to have stable disease at 18 months of treatment, the protocol was amended to permit patients to continue treatment until meeting disease progression criteria. At 33 months, 3 additional patients were able to be included for analysis, as their PSA values had increased to the point that they developed positive PSA slopes, allowing their PSADT to be estimated. At 33 months, the estimate of the average PSADT before intervention was 15.6 ± 10.8 months (median, 11.5 months), whereas the average posttreatment PSADT was 54.7 ± 102 months (median, 28.7 months; P < 0.001). During the study, 83% of patients achieved an improvement in PSADT (i.e., either prestudy PSADT > 0 and poststudy PSADT < 0 or poststudy PSADT > prestudy PSADT) after intervention. Baseline tumor stage stage showed some correlation with the change of PSADT, but this did not reach statistical significance. There were no serious adverse events reported and the treatment was well tolerated, and no patients developed metastatic disease on study. Pomegranate juice processing. Pomegranate juice was provided by the Pom Wonderful Company (Los Angeles, CA). Pomegranates were handpicked, washed, chilled to 4°C, and stored in tanks. The fruit was then crushed, squeezed, and treated enzymatically with pectinase to yield the juice and byproducts, which included the inner and outer peels and the seeds. Flavonoids constitute 40% (anthocyanins, catechins, and phenols) of total polyphenols in pomegranate juice (28). The pomegranate juice was filtered, pasteurized, concentrated, and stored at -20°C until use. Determination of ellagic acid and ellagic acid metabolites by liquid chromatography-electrospray ionization/mass spectrometry.Plasma from the centrifugation of collected whole blood and aliquoted urine [1.3 mL urine with 30 µL ascorbic acid/EDTA solution (20% ascorbic acid, 0.1% EDTA, NaH 2 PO 4 0.04 mmol/L (pH 3.6-final pH 2))] were collected at each study time point and stored immediately at -80°C. The high-performance liquid chromatography system and conditions for liquid chromatography-electrospray ionization/mass spectrometry are as described previously. These studies were paid for by the Lynda and Stewart Resnick Revocable Trust. The Resnicks are the owners of the POM Wonderful Company. Additional NIH funding (P50CA92131 and IR01CA100938) supported portions of the science conducted in the course of these experiments. The mission of the American Association for Cancer Research is to prevent and cure cancer. AACR publishes five major peer-reviewed journals Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers and Prevention, as well as CR, a magazine about people and progress in cancer. ReferencesClinical Cancer Research Vol. 12, 4018-4026, July 1, 2006 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 ≤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. Pomegranate juice protects nitric oxide against oxidative destruction and enhances the biological actions of nitric oxide. Ignarro LJ, Byrns RE, Sumi D, de Nigris F, Napoli C. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Nitric Oxide. 2006 Apr 18. Inflammation and cancer: role of phagocyte-generated oxidants in carcinogenesis SA Weitzman and LI Gordon Department of Medicine, Northwestern University Medical School, Chicago, IL 60611. Prostate cancer prevention through pomegranate fruit. Department of Dermatology, University of Wisconsin, Madison 53706, USA. Cell Cycle 2006 Feb;5(4) Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Arshi Malik , Farrukh Afa, Sami Sarfaraz , Vaqar M. Adhami , Deeba N. Syed , and Hasan Mukhtar. Department of Dermatology, University of Wisconsin, Madison, WI 53706 PNAS October 11, 2005vol. 102 no. 41 14813-14818 In vitro antiproliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice. Nutr Biochem. 2005 Jun;16(6):360-7. Heber D, et al. Center for Human Nutrition, David Geffen School of Medicine, UC, Los Angeles Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion of human prostate cancer cells. Journal of Medicinal Food Sep 2004, Vol. 7, No. 3: 274-283 Albrecht M, et al. Institute of Anatomy and Cell Biology, Philipps University, Marburg, Germany Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells. Adams LS, Seeram NP, Aggarwal BB, Takada Y, Sand D, Heber D. J Agric Food Chem. 2006 Feb 8;54(3):980-5. Rapid dereplication of estrogenic compounds in pomegranate (Punica granatum) using on-line biochemical detection coupled to mass spectrometry. Phytochemistry. 2004 Jan;65(2):233-41. van Elswijk DA, Schobel UP, Lansky EP, Irth H, van der Greef J. Kiadis, Niels Bohrweg 11-13, 2333 AC, Leiden, The Netherlands .pdf full text Preliminary studies on the anti-angiogenic potential of pomegranate fractions in vitro and in vivo. Angiogenesis. 2003;6(2):121-8. Toi M, Bando H, Ramachandran C, Melnick SJ, Imai A, Fife RS, Carr RE, Oikawa T, Lansky EP. Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan. Chemopreventive and adjuvant therapeutic potential of Homepage :
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 The pomegranate researchersAllan Pantuck, M.D. "has had a longstanding clinical interest in alternative and complementary medicine in treating cancer patients. He has conducted--or been a part of--several research studies focusing on prostate and kidney cancer." More on his publications. Team member Louis J. Ignarro won the Louis J. Ignarro Autobiography David Heber, MD, PhD Professor, UCLA Department of Medicine-Division of Clinical Nutrition is Director, NIH Center for Dietary Supplement Research in Botanicals (CDSRB) Inflammation as a cause of canceris a key part of the new study's outlook. Among works cited is: Inflammation and cancer: role of phagocyte-generated oxidants in carcinogenesis SA Weitzman and LI Gordon Department of Medicine, Northwestern University Medical School, Chicago, IL 60611. advertisement  Eat to Beat Prostate Cancer CookbookAuthor: David Ricketts; Buy New: $12.97 David has a recipe for
Nitric Oxide: The New Hero of Human Biology Other studies that report effects of pomegranate on prostate cancerProstate cancer prevention through pomegranate fruit. Department of Dermatology, University of Wisconsin, Madison 53706, USA. Cell Cycle 2006 Feb;5(4) Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Proc Natl Acad Sci U S A. 2005 Oct Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion of human prostate cancer cells. Journal of Medicinal Food Sep 2004, Vol. 7, No. 3: 274-283 Albrecht M, et al. Institute of Anatomy and Cell Biology, Philipps University, Marburg, Germany. More pomegranate newsPomegranate Juice Fights Heart Disease, Study Says Stefan Lovgren for National Geographic News March 22, 2005 Pomegranate Seed Oil Causes Breast Cancer Cells to Self-Destruct. American Technion Society August 21, 2001 Rimonest Ltd. - the Science of the Pomegranate Want to comment?
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± SE) on treatment (P < 0.001; Fig. 1 )
