CS1 is a novel topoisomerase IIα inhibitor with favorable drug resistance profiles

  • Biochem Biophys Res Commun. 2014 Oct 24;453(3):302-8. doi: 10.1016/j.bbrc.2014.09.042.
Yan Shen  1 ,  Wang Chen  1 ,  Baobing Zhao  1 ,  Huilin Hao  1 ,  Zhenyu Li  1 ,  Chunhua Lu  1 ,  Yuemao Shen  2
Affiliations
  • 1. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
  • 2. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China. Electronic address: [email protected].
PMID: 25242524 DOI: 10.1016/j.bbrc.2014.09.042
Abstract

DNA Topoisomerase II (Topo II) is an essential nuclear enzyme and a validated target for Anticancer agent screening. CS1, a novel 2-phenylnaphthalene, had potent cytotoxicity against nine tested tumor cell lines and showed 6-10-fold less toxicity against normal cell lines compared with etoposide. In addition, CS1 showed potential anti-multidrug resistance capabilities. kDNA decatenation, DNA relaxation and cleavage complex assays indicated that CS1 acted as a nonintercalating Topoisomerase IIα (Topo IIα) inhibitor by stabilizing the DNA-Topo IIα cleavage complex. CS1 also induced DNA breaks in MDA-MB-231 cells evidenced by comet tails and the accumulation of γH2AX foci. The ability of CS1 in inducing DNA breaks mediated by Topo II resulted in G2/M phase arrest and Apoptosis. Moreover, CS1 exhibited dramatic in vivo antitumor activity and lower toxicity compared with etoposide. This work supports the development of CS1 as a promising candidate for the treatment of Cancer by targeting Topo IIα.

Keywords
2-Phenylnaphthalene; DNA breaks; Multidrug resistance; Topoisomerase II inhibitor.
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