Resveratrol Mobilizes Endogenous Copper in Human Peripheral Lymphocytes Leading to Oxidative DNA Breakage: A Putative Mechanism for Chemoprevention of Cancer

Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202002, India.
Pharmaceutical Research (Impact Factor: 3.42). 06/2010; 27(6):979-88. DOI: 10.1007/s11095-010-0055-4
Source: PubMed


Plant polyphenols are important components of human diet, and a number of them are considered to possess chemopreventive and therapeutic properties against cancer. They are recognized as naturally occurring anti-oxidants but also act as pro-oxidants catalyzing DNA degradation in the presence of metal ions such as copper. The plant polyphenol resveratrol confers resistance to plants against fungal agents and has been implicated as a cancer chemopreventive agent. Of particular interest is the observation that resveratrol has been found to induce apoptosis in cancer cell lines but not in normal cells. Over the last few years, we have shown that resveratrol is capable of causing DNA breakage in cells such as human lymphocytes. Such cellular DNA breakage is inhibited by copper specific chelators but not by iron and zinc chelating agents. Similar results are obtained by using permeabilized cells or with isolated nuclei, indicating that chromatin-bound copper is mobilized in this reaction. It is well established that tissue, cellular and serum copper levels are considerably elevated in various malignancies. Therefore, cancer cells may be more subject to electron transfer between copper ions and resveratrol to generate reactive oxygen species responsible for DNA cleavage. The results are in support of our hypothesis that anti-cancer mechanism of plant polyphenols involves mobilization of endogenous copper and the consequent pro-oxidant action. Such a mechanism better explains the anti-cancer effects of resveratrol, as it accounts for the preferential cytotoxicity towards cancer cells.

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    • "In spite of the numerous reports showing antioxidation as chemopreventive activity for berries and several of their constituents , we must recall that these chemicals may also have opposite effects; for example, flavonoids, such as apigenin and quercetin, as well as tannins are known to have DNA strand breaking abilities [39]. Resveratrol and ascorbic acid have also been reported to possibly cause DNA breakage through the generation of ROS [40] [41]. Heterogeneous effects of quercetin have also been reported; low doses were found to increase the production of micronuclei and chromosomal aberrations, contrary to the protective effect shown against mitomycin C genotoxicity with a high dose [42]. "
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    ABSTRACT: Blueberry is a plant with a number of nutritional and biomedical capabilities. In the present study we initially evaluated the capacity of its juice (BJ) to inhibit the number of aberrant crypts (AC) induced with azoxymethane (AOM) in mouse. BJ was administered daily by the oral route to three groups of animals during four weeks (1.6, 4.1, and 15.0 íµí¼‡L/g), respectively, while AOM (10 mg/kg) was intraperitoneally injected to the mentioned groups, twice a week, in weeks two and three of the assay. We also included two control groups of mice, one administered distilled water and the other the high dose of BJ. A significant increase of AC was observed in the AOM treated animals, and a mean protection of 75.6% was determined with the two low doses of BJ tested; however, the high dose of the juice administered together with AOM increased the number of crypts more than four times the value observed in animals administered only AOM. Furthermore, we determined the antioxidant potential of BJ with an ex vivo DPPH assay and found a dose-dependent decrease with a mean of 19.5%. We also determined the DNA oxidation/antioxidation by identifying 8-hydroxy-2 í®í° -deoxyguanosine adducts and found a mean decrease of 44.3% with the BJ administration with respect to the level induced by AOM. Our results show a complex differential effect of BJ related to the tested doses, opening the need to further evaluate a number of factors so as to determine the possibility of a cocarcinogenic potential.
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    • "A redox reaction of the polyphenols and Cu(II) in the ternary complex may occur leading to the reduction of Cu(II) to Cu(I), whose reoxidation generates a variety of ROS [2]. This has been attributed as a primary reason behind the cytotoxic potential of several polyphenols including resveratrol [16] [17]. Extensive work has been carried out on the health benefits of resveratrol and the associated mechanism of its action [18]. "
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