Chemoprevention of Human Prostate Cancer by Oral Administration of Green Tea Catechins in Volunteers with High-Grade Prostate Intraepithelial Neoplasia: A Preliminary Report from a One-Year Proof-of-Principle Study

Department of Medicina Sperimentale, Sezione di Biochimica, University of Parma, Via Volturno 39, 43100 Parma, Italy.
Cancer Research (Impact Factor: 9.33). 02/2006; 66(2):1234-40. DOI: 10.1158/0008-5472.CAN-05-1145
Source: PubMed


Green tea catechins (GTCs) proved to be effective in inhibiting cancer growth in several experimental models. Recent studies showed that 30% of men with high-grade prostate intraepithelial neoplasia (HG-PIN) would develop prostate cancer (CaP) within 1 year after repeated biopsy. This prompted us to do a proof-of-principle clinical trial to assess the safety and efficacy of GTCs for the chemoprevention of CaP in HG-PIN volunteers. The purity and content of GTCs preparations were assessed by high-performance liquid chromatography [(-)-epigallocathechin, 5.5%; (-)-epicatechin, 12.24%; (-)-epigallocatechin-3-gallate, 51.88%; (-)-epicatechin-3-gallate, 6.12%; total GTCs, 75.7%; caffeine, <1%]. Sixty volunteers with HG-PIN, who were made aware of the study details, agreed to sign an informed consent form and were enrolled in this double-blind, placebo-controlled study. Daily treatment consisted of three GTCs capsules, 200 mg each (total 600 mg/d). After 1 year, only one tumor was diagnosed among the 30 GTCs-treated men (incidence, approximately 3%), whereas nine cancers were found among the 30 placebo-treated men (incidence, 30%). Total prostate-specific antigen did not change significantly between the two arms, but GTCs-treated men showed values constantly lower with respect to placebo-treated ones. International Prostate Symptom Score and quality of life scores of GTCs-treated men with coexistent benign prostate hyperplasia improved, reaching statistical significance in the case of International Prostate Symptom Scores. No significant side effects or adverse effects were documented. To our knowledge, this is the first study showing that GTCs are safe and very effective for treating premalignant lesions before CaP develops. As a secondary observation, administration of GTCs also reduced lower urinary tract symptoms, suggesting that these compounds might also be of help for treating the symptoms of benign prostate hyperplasia.

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    • "Among these, EGCG is the most abundant and has been shown to exhibit antioxidative and chemo-preventive properties against various types of cancers because of its potent capacity for inhibiting cancer cell growth through several signaling pathways [5] [6] [7]. Epidemiological studies have revealed that GT consumption is inversely associated with the progression of prostate cancer and the risk of breast cancer recurrence [8] [9]. Steele et al. have shown that GT activates detoxification enzymes, such as glutathione S-transferase and quinone reductase, thus protecting against carcinogenesis [10]. "
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    ABSTRACT: Green tea (GT)-based chemoprevention has shown promising results in various cancer models. However, the effective dose may not be far from the toxic dose because of inefficient systemic delivery and limited bio-availability of GT polyphenols. We have used GT polyphenols to successfully reduce gold to corresponding gold nanoparticles (NPs) in a single step; a process that fulfils all criteria of green nanotechnology as no "man-made" chemical other than gold acids are used. GT and (-) - epigallocatechin-3-gallate (EGCG) conjugated gold NPs (diameters <50 nm), showed remarkable stability, significantly rapid cellular uptake and excellent in vitro anti-oxidant activities. These NPs were observed to be selectively toxic towards cancer cells (Ehrlich's Ascites Carcinoma and MCF-7) while showing absolutely no lethality towards normal primary mouse hepatocytes. In cancer cells, NPs altered the redox status and limited Nrf2 activation by almost 50%. These NPs significantly decreased nuclear translocation of NF-κB, coupled with decreased phosphorylation of IĸB and down-regulation of NF-κB-dependent anti-apoptotic proteins Bcl2 and Akt in a dose-dependent manner, triggering onset of apoptosis. Culturing normal hepatocytes with tumor-conditioned media prompted apoptosis by increasing reactive oxygen species (ROS) and depleting the anti-oxidant defense mechanism of hepatocytes. Pre-treatment with NPs protected hepatocytes from tumor-induced cellular damage by scavenging excess ROS, increasing the levels of reduced glutathione and anti-oxidant enzymes. There was evidence of decreased Bax/Bcl2 ratio and active Caspase 3 levels in these hepatocytes, indicating apoptosis escape. Nanoformulations of GT-based polyphenols might serve as an operative platform for effective delivery, increased bio-availability, enhanced effects and minimal chemotherapy-associated toxicities. Copyright © 2015 Elsevier Inc. All rights reserved.
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    • "Clinical studies have been conducted evaluating the effects of EGCG and green tea catechins in conditions such as cancer, hyperlipidemia, diabetes, and many *Address correspondence to this author at the Therapeutic Research Center, 1 Davis Square, Somerville, MA 02144, USA; Tel: (617) 591-3316; E-mail: more [5] [7] [8] [9] [10]. No consensus on an optimal EGCG dose or intake level currently exists; however, evidence suggests that higher green tea catechin levels and specifically EGCG are needed for therapeutic effects. "
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    • "These data in combination with our previous reports [24], [27] and others [55] provide further evidence that these natural compounds have clinical potential for not only targeting tumor epithelial cells, but also for targeting the surrounding tumor microenvironment. Furthermore, an earlier study supported that green tea catechin consumption consisting, in part, of EGCG could slow progression from high grade prostatic intraepithelial neoplasia (HGPIN) to prostate cancer [56]. Combinations of EGCG and luteolin could prove to be even more effective than green tea catechin treatments alone. "
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