THE DIETARY ANTICANCER AGENT ELLAGIC ACID IS A POTENT INHIBITOR OF DNA TOPOISOMERASES IN-VITRO

Ellagic acid and 12 related agents have been tested for their ability to inhibit the activities of human DNA topoisomerase (topo) I and II. Using specific in vitro assays, we found ellagic acid and flavellagic acid to be potent inhibitors of the catalytic activities of the two to poisomerases. The minimum concentration required to inhibit greater th an or equal to 50% of catalytic activity (IC50) of ellagic acid was de termined at 0.6 and 0.7 mu g/ml for topo I and topo II, respectively. Flavellagic acid's IC50 was determined at 3.0 and 3.6 mu g/ml for topo I and topo II, respectively. Unlike topoisomerase poisons, these two plant phenols did not trap the enzyme-DNA reaction intermediate, known as the cleavable complex. In contrast, ellagic acid prevented other t opo I and topo II poisons from stabilizing the cleavable complex, sugg esting that the mode of its action is that of an antagonist. Structure -activity studies identified the 3,3'-hydroxyl groups and the lactone groups as the most essential elements for the topoisomerase inhibitory actions of plant phenols. On the basis of these findings and other pr operties of ellagic acid, a mechanistic model for the documented antic arcinogenic effects of the agent is proposed.