title: YM155 inhibits topoisomerase function.
abstract: YM155 (sepantronium bromide) has been evaluated in clinical trials as a survivin suppressant, but despite positive signals from early work, later studies were negative. Clarification of the mechanism of action of YM155 is important for its further development. YM155 affects cells in a cell cycle-specific manner. When cells are in G1, YM155 prevented their progression through the S phase, leaving the cells at G1/S when exposed to YM155. Passage through mitosis from G2 is also defective following YM155 exposure. In this study, YM155 did not behave like a typical DNA intercalator in viscosity, circular dichroism, and absorption spectroscopy studies. In addition, molecular modeling experiments ruled out YM155 DNA interaction to produce DNA intercalation. We show that YM155 inhibited topoisomerase 2α decatenation and topoisomerase 1-mediated cleavage of DNA, suggesting that YM155 inhibits the enzyme function. Consistent with these findings, DNA double-strand break repair was also inhibited by YM155.
authors.affiliation: aCancer Center, Georgia Regents University Cancer Center bDepartment of Surgery cDepartment of ENT Surgery, Center for Biotechnology and Genomic Medicine dDepartment of Medicine, Medical College of Georgia, Augusta eDepartment of Chemistry, Georgia State University, Atlanta, Georgia, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Hong
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Ren
authors.forename: Jeane
authors.initials: J
authors.lastname: Silva
authors.forename: Ananya
authors.initials: A
authors.lastname: Paul
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
authors.forename: Carsten
authors.initials: C
authors.lastname: Schroeder
authors.forename: Paul
authors.initials: P
authors.lastname: Weinberger
authors.forename: John
authors.initials: J
authors.lastname: Janik
authors.forename: Zhonglin
authors.initials: Z
authors.lastname: Hao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D053960:DNA Breaks; D004260:DNA Repair; D004261:DNA Replication / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009285:Naphthoquinones / Q000494:pharmacology*; D059003:Topoisomerase Inhibitors / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D009285:Naphthoquinones; D059003:Topoisomerase Inhibitors; C523798:sepantronium