title: Identification of a small-molecule inhibitor of DNA topoisomerase II by proteomic profiling.
abstract: BNS-22, a chemically synthesized derivative of the natural plant product GUT-70, has antiproliferative activity against human cancer cells, the mechanism of which is unknown. Here, we identify a target of BNS-22 by proteomic profiling analysis, which suggests that BNS-22 belongs to the same cluster as ICRF-193, a DNA topoisomerase II (TOP2) catalytic inhibitor. BNS-22 inhibits kinetoplast DNA decatenation that is mediated by human TOP2α and TOP2β in vitro at an IC(50) of 2.8 and 0.42 μM, respectively. BNS-22 does not affect DNA damage and antagonizes TOP2 poison-mediated DNA damage. Like ICRF-193, BNS-22 induces mitotic abnormalities, characterized by impairments in chromosome alignment and segregation, thereby causing polyploidy in HeLa cells. These results indicate that BNS-22 targets TOP2 and acts as its catalytic inhibitor.
authors.affiliation: Chemical Biology Core Facility, Chemical Biology Department, RIKEN Advanced Science Institute, Saitama 351-0198, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawatani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayama
authors.forename: Makoto
authors.initials: M
authors.lastname: Muroi
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
authors.forename: Taira
authors.initials: T
authors.lastname: Maekawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
mesh_terms: D016000:Cluster Analysis; D003374:Coumarins / Q000737:chemistry* / Q000633:toxicity; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D006367:HeLa Cells; D006801:Humans; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D011804:Quinolines / Q000737:chemistry* / Q000633:toxicity; D008941:Spindle Apparatus / Q000187:drug effects; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000633:toxicity
chemical_list: C562063:BNS 22; D003374:Coumarins; D020543:Proteome; D011804:Quinolines; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II