Review Article Efficacy and Safety of Pomegranate Medicinal Products for Cancer
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Crossref Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2015, Article ID 258598, 15 pages http://dx.doi.org/10.1155/2015/258598 Review Article Efficacy and Safety of Pomegranate Medicinal Products for Cancer Christian Vlachojannis,1 Benno F. Zimmermann,2,3 and Sigrun Chrubasik-Hausmann1 1 Institute of Forensic Medicine, University of Freiburg, Albertstr. 9, 79104 Freiburg, Germany 2Institute of Nutrition and Food Sciences, Food Technology and Food Biotechnology, University of Bonn, Romerstraße¨ 164, 53117 Bonn, Germany 3Institut Prof. Dr. Georg Kurz GmbH, Eupener Straße 161, 50933 Koln,¨ Germany Correspondence should be addressed to Sigrun Chrubasik-Hausmann; [email protected] Received 25 February 2014; Revised 8 July 2014; Accepted 2 September 2014 Academic Editor: Junhua Zhang Copyright © 2015 Christian Vlachojannis et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preclinical in vitro and in vivo studies demonstrate potent effects of pomegranate preparations in cancer cell lines and animal models with chemically induced cancers. We have carried out one systematic review of the effectiveness of pomegranate products in the treatment of cancer and another on their safety. The PubMed search provided 162 references for pomegranate and cancer and 122 references for pomegranate and safety/toxicity. We identified 4 clinical studies investigating 3 pomegranate products, of which one was inappropriate because of the low polyphenol content. The evidence of clinical effectiveness was poor because the quality ofthe studies was poor. Although there is no concern over safety with the doses used in the clinical studies, pomegranate preparations may be harmful by inducing synthetic drug metabolism through activation of liver enzymes. We have analysed various pomegranate products for their content of anthocyanins, punicalagin, and ellagic acid in order to compare them with the benchmark doses from published data. If the amount of coactive constituents is not declared, patients risk not benefiting from the putative pomegranate effects. Moreover, pomegranate end products are affected by many determinants. Their declaration should be incorporated into the regulatory guidance and controlled before pomegranate products enter the market. 1. Introduction about twice the antiproliferative effect shown by polyphenols from fresh pomegranate juice. They also inhibited the activity Pomegranate products are amongst most promising anti- of aromatase and 17--hydroxysteroid dehydrogenase type 1 tumorigenic dietary supplements. The polyphenol fraction by 60–80% and inhibited chemically induced formation of of pomegranate exerts antiproliferative and proapoptotic cancerous lesions in a murine mammary gland organ culture effects in a number of cancer cell lines1 [ ]. Various medi- by about 50% [8] However, a specific purified polyphenol ators of carcinogenesis are inhibited by the pomegranate compound and pomegranate seed oil were more effective active principle in vitro, for example, vascular endothelial than fermented juice in this in vitro test [9]. The isolated growth factor [2], insulin-like growth factors [3], cytokine- ellagitannins, punicalagin, and ellagic acid also had a high stimulated NF-B[4], and others [5, 6]. Fermentation is a antiproliferative activity against various cancer cell lines [10, new technology that enriches coactive compounds [7]. Fer- 11]. mentation of pomegranate juice with Lactobacillus plantarum The aromatase enzyme, which converts androgen to increased the concentration of ellagic acid and enhanced estrogen, plays a key role in breast cancer. Tamoxifen is theantimicrobialactivityofthejuice.Bothfreshandfer- the usual antiestrogen therapy for hormone-receptor-positive mented juices inhibited the growth of K562 tumor cells breast cancer in premenopausal women, though it carries [7]. Polyphenols from fermented pomegranate juice showed a risk of development of resistance [12]. Pomegranate fruit 2 Evidence-Based Complementary and Alternative Medicine extracts enhanced the action of tamoxifen in both tamoxifen- cancer” and “pomegranate prostate” and, on June 29, sensitive and tamoxifenresistant breast cancer cells, through “pomegranate safety” and “pomegranate toxicity,” the ref- the inhibition of cell viability by inducing the cell-death erence lists of articles were searched by hand for other machinery [13]. publications. No methodological filter was applied and the The polyphenols also inhibited the expression of genes for search was not limited by language. The full manuscript key androgen-synthesizing enzymes and androgen receptors, was retrieved for each record that had a chance of meet- suggesting that the pomegranate polyphenols (mainly the ing the review criteria (clinical trial, safety investigation). oligomeric punicalagin and the monomeric ellagic acid) Two authors (Christian Vlachojannis and Sigrun Chrubasik- affect androgen-independent prostate cancer cells and the Hausmann) extracted the data independently and evaluated subset of human prostate cancer cells where the androgen the quality of the studies and the strength of the evidence of receptor is upregulated [4, 14]. In investigations of the anti- clinical effectiveness using the same criteria as in previous invasive effects of ellagic acid in androgen-independent reviews [25–35]. Briefly, the assessment of quality was based human and rat prostate cancer cell lines in vitro,ellagic on “yes” or “no” answers to the following questions: was or acid significantly inhibited the motility and invasion of cells were examined in migration and invasion assays. The secretion of matrix metalloproteinases from androgen-independent (i) patients included on the basis of specified eligibility humanandratprostatecancercelllinesandtheproteolytic criteria; activity of collagenase/gelatinase were significantly reduced, (ii) randomization appropriate; indicating that the anti-invasive potential of prostate cancer cellsismediatedviaproteaseactivity[15]. (iii) treatment allocation concealed; Although all pomegranate-derived materials contribute to a greater or lesser extent to the anticancer effect of (iv) baseline values of the groups similar pomegranate, the polyphenol fraction and supercritical CO2- (v) outcome measures and control interventions explic- extracted seed oil were more potent than cold-pressed itly described; pomegranateseedoilininhibitinggrowthofprostatecancer xenografts in athymic mice [16]. Pomegranate juice was more (vi) cointerventions comparable; effective than compounds isolated from the juice [17]. (vii) outcome measures relevant; In immunodeficient mice, pomegranate juice and extract inhibited tumor-associated angiogenesis and slowed the (viii) adverse events fully described; growth of prostate cancer [18]. Oral infusion of pomegranate fruit extract resulted not only in a dose-dependent inhibition (ix) attrition of patients from the study (the “drop-outs”) of tumor growth, but also in a decrease of prostate-specific fully described; antigen (PSA) levels in mice implanted with androgen- (x) sample size based on a priori power calculation; responsive cancer cells [19]. Tumor reductions were also seen in mice with induced lung, colon, and skin cancers [1]. (xi) analysis by intention-to-treat in the event of attrition Of the polyphenols, the chemopreventive pomegranate of patients during the study; ellagitannins (e.g., punicalagin and punicalin) are metab- olized during absorption. One of the metabolites, ellagic (xii) point estimates and measures of variability presented acid, is further metabolized by the colonic microflora to for the primary outcome measure; urolithin A. Both ellagic acid and urolithin A contribute (xiii) studies undertaken over an appropriate time-course to the mechanism of anticancer action, but urolithin was to demonstrate the putative effect. less effective in inhibiting cancer cell proliferation20 [ –22]. There was no difference in metabolite production between For observational studies, some of the questions are not pomegranate juice and extracts thereof [23], though inactive applicable but the inability to supply a “yes” answer itself ellagitannin-derived metabolites are also produced by the marksan“absenceofquality”insystematicreviewsofthis colonic microflora24 [ ]. This may account for individual sort. Potential disagreements were discussed and resolved by differences in the response to pomegranate consumption. referring to the original protocol. Theaimofthisstudywastosummarizedataontheclin- Adding up the “yes” answers applicable to each study ical effectiveness and safety of pomegranate preparations for gaveitatotalscore(TS)outofamaximumof13.Evidence the treatment of cancer and to analyse various pomegranate of effectiveness was defined as (i) “strong”: pooling of data preparations for their content of coactive compounds in order from at least 2 confirmatory studies demonstrating a clinically tofindoutthedoserequiredforananticancereffectin relevant effect; patients suffering from prostate cancer. (ii) “moderate”: consistent findings from one confir- matory study with a clinically relevant effect, multiple 2. Methods exploratory studies of high internal validity (TS 10 and higher), or both; 2.1. Systematic