Sang-ki Park, Hye-Yeon Kang, C. Kwon
Apr 1, 2008
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Influential Citations
18
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Quality indicators
Journal
Anti-Cancer Drugs
Abstract
9-Anilinoacridine contains a tricyclic and planar aromatic structure that enables DNA intercalation and inhibition of topoisomerase II. Two recently developed sulfide derivatives of 9-anilinoacridines, 2-({4-[4-(acridin-9-ylamino)phenylthio]phenyl}(2-hydroxyethyl)amino)ethan-1-ol (CK0402) and 3-({4-[4-(acridin-9-ylamino)phenylthio]phenyl}(3-hydroxypropyl)amino)propan-1-ol (CK0403), displayed potent cytotoxic activity in multiple cancer cell lines. In-vitro enzymatic assay demonstrated that CK0402 and CK0403 directly inhibit decatenation reaction of topoisomerase II&agr;. Cells exposed to CK0403 showed DNA fragmentation, and activation of caspase-3 and caspase-2, indicating that it triggers caspase-dependent apoptosis. This was further supported by the fact that cytotoxicity of these drugs is attenuated by pharmacological inhibition of caspases with z-VAD-FMK. Studies with wild-type and p53−/− primary mouse embryonic fibroblasts demonstrated that p53 does not play a significant role in cell death process initiated by this kind of drug. In addition, pharmacological inhibition of poly(ADP-ribose) polymerase-1activity moderately enhanced cytotoxic activity of sulfide 9-anilinoacridine, suggesting that poly(ADP-ribose) polymerase-1 may have a protective function against 9-anilinoacridine-induced cell death process.