title: CS1 is a novel topoisomerase IIα inhibitor with favorable drug resistance profiles.
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.
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
authors.forename: Wang
authors.initials: W
authors.lastname: Chen
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
authors.forename: Baobing
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
authors.forename: Huilin
authors.initials: H
authors.lastname: Hao
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.affiliation: 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: yshen@sdu.edu.cn.
authors.forename: Yuemao
authors.initials: Y
authors.lastname: Shen
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D002396:Catechols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D020868:Gene Silencing; D006801:Humans; D009284:Naphthols / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D002396:Catechols; D004268:DNA-Binding Proteins; D009284:Naphthols; D034741:RNA, Small Interfering; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II
keywords: 2-Phenylnaphthalene; DNA breaks; Multidrug resistance; Topoisomerase II inhibitor