TY - JOUR T1 - Ethonafide-Induced Cytotoxicity Is Mediated by Topoisomerase II Inhibition in Prostate Cancer Cells JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1109 LP - 1117 DO - 10.1124/jpet.106.117457 VL - 321 IS - 3 AU - Alan Pourpak AU - Terry H. Landowski AU - Robert T. Dorr Y1 - 2007/06/01 UR - http://jpet.aspetjournals.org/content/321/3/1109.abstract N2 - Ethonafide is an anthracene-containing derivative of amonafide that belongs to the azonafide series of anticancer agents. The lack of cross-resistance in multidrug-resistant cancer cell lines and the absence of a quinone and hydroquinone moiety make ethonafide a potentially less cardiotoxic replacement for existing anthracene-containing anticancer agents. For this study, we investigated the anticancer activity and mechanism of ethonafide in human prostate cancer cell lines. Ethonafide was cytotoxic against three human prostate cancer cell lines at nanomolar concentrations. Ethonafide was found to be better tolerated and more effective at inhibiting tumor growth compared with mitoxantrone in a human xenograft tumor regression mouse model. Mechanistically, we found that ethonafide inhibited topoisomerase II activity by stabilizing the enzyme-DNA complex, involving both topoisomerase IIα and -β. In addition, ethonafide induced a potent G2 cell cycle arrest in the DU 145 human prostate cancer cell line. By creating stable cell lines with decreased expression of topoisomerase IIα or -β, we found that a decrease in topoisomerase IIα protein expression renders the cell line resistant to ethonafide. The decrease in sensitivity to ethonafide was associated with a decrease in DNA damage and an increase in DNA repair as measured by the neutral comet assay. These data demonstrate that ethonafide is a topoisomerase II poison and that it is topoisomerase IIα-specific in the DU 145 human prostate cancer cell line. The American Society for Pharmacology and Experimental Therapeutics ER -