TANNINS AS POTENT INHIBITORS OF DNA TOPOISOMERASE-II INVITRO

Fifty-two out of 60 tannins, including gallo-, ellagi-, condensed, and complex tannins, are inhibitors of human DNA topoisomerase II in vitr o. Thirty-six compounds that completely inhibited enzyme activity at a concentration of 500 nM or less, as assessed by ATP-dependent unknott ing of P4 phage DNA, were at least 100-fold more potent than the clini cally useful antitumor agent etoposide (VP-16). Relative inhibitory ac tivity was primarily related to the number of phenolic hydroxyl groups (galloyl and hexahydroxydiphenoyl moieties) found in the active struc tures, with more groups generally conferring increased potencies. Unli ke VP-16 and some DNA intercalative agents that stabilize the topoisom erase II-DNA cleavage intermediate, none of the active compounds induc ed protein-linked DNA breaks in cultured cells. Some of the tannins re duced VP-1 6-induced protein-linked DNA breaks by 20% or more, but one of these compounds, (-)-epicatechin, was not an inhibitor in vitro. O ur data suggest that some tannins, such as sangiin H-6, that are poten t inhibitors of catalytic double DNA-strand passage in vitro may targe t intracellular enzyme activity in a similar fashion to known poisons that interfere with formation of the enzyme-DNA covalent intermediate.