Bioflavonoids as DNA Topoisomerase II Poisons

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DESCRIPTION (provided by applicant): Bioflavonoids are potent topoisomerase II poisons and are believed to be chemopreventative in adults. However, they have also been implicated in the initiation of acute myeloid leukemia's (AMLs) in utero. The overall goal of this proposal is to further define the mechanism by which bioflavonoids alter the catalytic activity of human topoisomerase II and their potential role in the initiation of carcinogenesis. The specific aims for this proposal are to: (1) Delineate the mechanism by which bioflavonoids alter the catalytic function of human type II topoisomerases via in vitro enzymological studies that are used to examine DNA cleavage and ligation. Mutagenesis and NMR studies will be employed to define the site of interaction of bioflavonoids on the enzyme. (2) Determine the role of topoisomerase II alpha and beta in mediating the cytotoxic and genotoxic effects of bioflavonoids in human cells by using siRNA. The role of each isoform in the initiation of bioflavonoid-induced MIL gene translocations in cultured human cells will be examined via cloning and PCR approaches. This project will further our understanding of the chemopreventative and cytotoxic properties of bioflavonoids and potentially lead to the utilization of these compounds as chemotherpeutic agents.