Evodiamine, a dual catalytic inhibitor of type I and II topoisomerases, exhibits enhanced inhibition against camptothecin resistant cells

DNA topoisomerases are nuclear enzymes that are the targets for several anticancerdrugs. In this study we investigated the antiproliferative activity against human leukaemia cell lines and the effects on topoisomerase I and II of evodiamine, which is a quinazolinocarboline alkaloid isolated from the fruit of a traditional Chinese medicinal plant, Evodia rutaecarpa. We report here the anti-proliferative activity against human leukaemia cells K562, THP-1, CCRF-CEM and CCRF-CEM/C1 and the inhibitory mechanism on human topoisomerases I and II, important anti-cancer drugs targets, of evodiamine. Evodiamine failed to trap [Topo-DNA] complexes and induce any detectable DNA damage in cells, was unable to bind or intercalate DNA, and arrested cells in the G(2)/M phase. The results suggest evodiamine is a dual catalytic inhibitor of topoisomerases land II, with IC50 of 60.74 and 78.81 mu M, respectively. The improved toxicity towards camptothecin resistant cells further supports its inhibitory mechanism which is different from camptothecin, and its therapeutic potential. (C) 2012 Elsevier GmbH. All rights reserved.