| ABSTRACT: |
|
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
topoisomerases. The minimum concentration required to inhibit > or =
50% of catalytic activity (IC50) of ellagic acid was determined at 0.6 and
0.7 micrograms/ml for topo I and topo II, respectively. Flavellagic acid's
IC50 was determined at 3.0 and 3.6 micrograms/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 topo I and topo II
poisons from stabilizing the cleavable complex, suggesting 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 properties of ellagic
acid, a mechanistic model for the documented anticarcinogenic effects of
the agent is proposed. |