TY - JOUR T1 - 3,3′-Diindolylmethane Is a Novel Topoisomerase IIα Catalytic Inhibitor That Induces S-Phase Retardation and Mitotic Delay in Human Hepatoma HepG2 Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1320 LP - 1327 DO - 10.1124/mol.105.018978 VL - 69 IS - 4 AU - Yixuan Gong AU - Gary L. Firestone AU - Leonard F. Bjeldanes Y1 - 2006/04/01 UR - http://molpharm.aspetjournals.org/content/69/4/1320.abstract N2 - 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 IIα inhibitor. In supercoiled DNA relaxation assay and kinetoplast DNA decatenation assay, DIM strongly inhibited DNA topoisomerase IIα and also partially inhibited DNA topoisomerases I and IIβ. DIM did not stabilize DNA cleavage complex and did not prevent etoposide-induced DNA cleavage complex formation. Further experiments showed that DIM inhibited topoisomerase IIα-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. ER -