Ethonafide-induced cytotoxicity is mediated by topoisomerase II inhibition in prostate cancer cells.

Abstract	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 IIalpha and -beta. In addition, ethonafide induced a potent G(2) cell cycle arrest in the DU 145 human prostate cancer cell line. By creating stable cell lines with decreased expression of topoisomerase IIalpha or -beta, we found that a decrease in topoisomerase IIalpha 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 IIalpha-specific in the DU 145 human prostate cancer cell line.
Authors	Alan Pourpak, Terry H Landowski, Robert T Dorr
Journal	The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 321 Issue 3 Pg. 1109-17 (Jun 2007) ISSN: 0022-3565 [Print] United States
PMID	17351106 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antigens, Neoplasm Antineoplastic Agents DNA, Catenated DNA, Kinetoplast DNA-Binding Proteins Isoquinolines Naphthalimides Quinoxalines Taxoids Topoisomerase II Inhibitors XK 469 Docetaxel Mitoxantrone DNA Topoisomerases, Type II 2-(2'-(dimethylamino)ethyl)-1,2-dihydro-7-ethoxydibenz(de,h)isoquinoline-1,3-dione Melphalan
Topics	Animals Antigens, Neoplasm (genetics, metabolism) Antineoplastic Agents (pharmacology) Cell Cycle (drug effects) Cell Line, Tumor Cell Survival (drug effects) DNA Breaks, Double-Stranded (drug effects) DNA Topoisomerases, Type II (genetics, metabolism) DNA, Catenated (metabolism) DNA, Kinetoplast (metabolism) DNA-Binding Proteins (antagonists & inhibitors, genetics, metabolism) Docetaxel Humans Isoquinolines (pharmacology, therapeutic use) Male Melphalan (pharmacology) Mice Mice, SCID Mitoxantrone (pharmacology) Naphthalimides (pharmacology) Prostatic Neoplasms (metabolism, pathology, prevention & control) Protein Binding (drug effects) Quinoxalines (pharmacology) RNA Interference Taxoids (pharmacology) Topoisomerase II Inhibitors Xenograft Model Antitumor Assays

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