Pourpak Alan, Landowski Terry H, Dorr Robert T
Department of Pharmacology, Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, USA.
J Pharmacol Exp Ther. 2007 Jun;321(3):1109-17. doi: 10.1124/jpet.106.117457. Epub 2007 Mar 9.
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.
乙磺酰亚胺是氨磺酰亚胺的一种含蒽衍生物，属于氮杂磺酰亚胺系列抗癌药物。多药耐药癌细胞系中缺乏交叉耐药性，且不存在醌和对苯二酚部分，这使得乙磺酰亚胺成为现有含蒽抗癌药物潜在心脏毒性较小的替代品。在本研究中，我们研究了乙磺酰亚胺在人前列腺癌细胞系中的抗癌活性和作用机制。乙磺酰亚胺在纳摩尔浓度下对三种人前列腺癌细胞系具有细胞毒性。在人异种移植肿瘤消退小鼠模型中，发现乙磺酰亚胺与米托蒽醌相比耐受性更好，抑制肿瘤生长更有效。从机制上讲，我们发现乙磺酰亚胺通过稳定酶 - DNA复合物来抑制拓扑异构酶II活性，该复合物涉及拓扑异构酶IIα和 - β。此外，乙磺酰亚胺在DU 145人前列腺癌细胞系中诱导了强烈的G(2)期细胞周期阻滞。通过创建拓扑异构酶IIα或 - β表达降低的稳定细胞系，我们发现拓扑异构酶IIα蛋白表达的降低使细胞系对乙磺酰亚胺产生抗性。通过中性彗星试验测量，对乙磺酰亚胺敏感性的降低与DNA损伤的减少和DNA修复的增加有关。这些数据表明乙磺酰亚胺是一种拓扑异构酶II毒药，并且在DU 145人前列腺癌细胞系中它是拓扑异构酶IIα特异性的。
