The Prooxidant Action of Dietary Antioxidants Leading to Cellular DNA Breakage and Anticancer Effects: Implications for Chemotherapeutic Action Against Cancer
ABSTRACT Plant-derived dietary antioxidants have attracted considerable interest in recent past for their ability to induce apoptosis and regression of tumors in animal models. While it is believed that the antioxidant properties of these agents may contribute to lowering the risk of cancer induction by impeding oxidative injury to DNA, it could not account for apoptosis induction and chemotherapeutic observations. In this article, we show that dietary antioxidants can alternatively switch to a prooxidant action in the presence of transition metals such as copper. Such a prooxidant action leads to strand breaks in cellular DNA and growth inhibition in cancer cells. Further, the cellular DNA breakage and anticancer effects were found to be significantly enhanced in the presence of copper ions. Moreover, inhibition of antioxidant-induced DNA strand breaks and oxidative stress by Cu(I)-specific chelators bathocuproine and neocuproine demonstrated the role of endogenous copper in the induction of the prooxidant mechanism. Since it is well established that tissue, cellular, and serum copper levels are considerably elevated in various malignancies, such a prooxidant cytotoxic mechanism better explains the anticancer activity of dietary antioxidants against cancer cells.
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ABSTRACT: Plant-derived polyphenols, a prominent class of phytochemicals, are considered important components of human diet. A number of them are known to possess chemopreventive and therapeutic properties against various diseases including cancer. Several studies using cancer cell lines and animal models of carcinogenesis have shown that a wide range of polyphenols possess anticancer and apoptosis-inducing properties. Notably, an important aspect of the chemopreventive action of polyphenols is their differential activity in selectively targeting cancer cells while sparing normal cells. However, the mechanism through which polyphenols modulate their cancer cell selective anticancer effects has not been clearly delineated. In this regard, identification of a definitive anticancer mechanism of polyphenols would contribute to establish them as potent lead compounds for the synthesis of novel anticancer drugs. Although polyphenols are generally recognized as antioxidants, they also act as prooxidants inducing DNA degradation in the presence of metal ions such as copper. Based on our own observations and those of others, a mechanism for the anticancer properties of polyphenols that involves mobilization of chromatin-bound copper and consequent prooxidant action leading to cell death, was proposed. Since it is known that tissue and cellular copper levels are significantly elevated in a number of malignancies, cancer cells would be more subject to redox cycling between copper ions and polyphenols to generate reactive oxygen species (ROS) responsible for DNA breakage. This review discusses such a copper-dependent prooxidant mechanism of action of polyphenols that accounts for their observed chemopreventive properties, as also for their preferential cytotoxicity towards cancer cells.Current drug targets 11/2012; · 3.93 Impact Factor