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3,3'-Diindolylmethane Is a Novel Topoisomerase II Catalytic Inhibitor That Induces S-Phase Retardation and Mitotic Delay in Human Hepatoma HepG2 Cells

Department of Nutritional Sciences and Toxicology (Y.G., L.F.B.) and Department of Molecular and Cell Biology (G.L.F.), University of California, Berkeley, Berkeley, California

Epidemiological evidence suggests that high consumption of Brassica genus vegetables, such as broccoli, cabbage, and Brussels sprouts, is very effective in reducing the risks of several types of cancers. 3,3'-Diindolylmethane (DIM), one of the most abundant and biologically active dietary compounds derived from Brassica genus vegetables, displays remarkable antitumor activity against several experimental tumors. In the present study, we demonstrate for the first time that DIM is a novel catalytic topoisomerase II inhibitor. In supercoiled DNA relaxation assay and kinetoplast DNA decatenation assay, DIM strongly inhibited DNA topoisomerase II and also partially inhibited DNA topoisomerases I and II. DIM did not stabilize DNA cleavage complex and did not prevent etoposide-induced DNA cleavage complex formation. Further experiments showed that DIM inhibited topoisomerase II-catalyzed ATP hydrolysis, which is a necessary step for the enzyme turnover. In cultured human hepatoma HepG2 cells, DIM blocked DNA synthesis and mitosis in a concentration-dependent manner, which was consistent with the outcome of topoisomerase inhibition in these cell-cycle phases. Our results identified a new mode of action for this intriguing dietary component that might be exploited for therapeutic development.

Address correspondence to: Dr. Leonard F. Bjeldanes, Department of Nutritional Sciences and Toxicology, 119 Morgan Hall, University of California, Berkeley, CA 94720-3104. E-mail: lfb{at}nature.berkeley.edu