Superoxide dismutases (SOD) are a class of essential enzymes responsible for the elimination of the toxic free radical, superoxide (O2-), and thus protect cells from oxidative stress. Inhibition of SOD impairs the ability of cells to cope with free radicals, and may provide a new strategy to kill cancer cells by mechanisms involving free radical O2- induced apoptotic cell death. However, specific SOD inhibitors with anticancer activity are not readily available for testing this new strategy. The applicant recently discovered that certain estrogen derivatives inhibited both the cellular copper/zinc-containing superoxide dismutase (CuZnSOD) and the mitochondrial manganese-containing superoxide dismutatase (MnSOD), and preferentially induced apoptosis in cancer cells but not in normal human lymphocytes. Based on these observations, the applicants propose to test the hypothesis of targeting SOD by the estrogen derivatives as a new strategy for cancer therapy. The objectives of this proposal are to investigate the biological consequences of SOD inhibition, to investigate the mechanisms by which the estrogen derivatives inhibit SOD, and to design new mechanism-based strategies to enhance the anticancer activity of the SOD-targeting compounds. Specifically, new molecular biology techniques and pharmacological/biochemical approaches will be employed to investigate the role of SOD inhibition in causing cell death by the estrogen derivatives, and to examine the free radical-mediated damage to membrane lipids, DNA, and relevant proteins such as cytochrome c. Changes in gene expression profiles associated with the estrogen derivative-induced apoptosis will be analyzed by cDNA micro-array technology. They will also use biochemical approaches to characterize the kinetics of SOD inhibition by estrogen derivatives. Laboratory investigations will be combined with computer-assisted molecular simulation technology to determine the structure-function relationship during SOD inhibition. Furthermore, the possibility of combining the SOD inhibitors with radiation and other agents such as anthracyclines that produce free radicals in cells as new strategies to enhance the anticancer activity will be tested. They anticipate that this research project will further our understanding of the mechanisms of SOD inhibition and its biological consequences, and will provide a basis both for the rational design of more potent/selective SOD inhibitors suitable for cancer therapy, and for the development of new mechanism-based strategies to enhance anticancer activity and selectivity.
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