title: CFS-1686 causes cell cycle arrest at intra-S phase by interference of interaction of topoisomerase 1 with DNA.
abstract: CFS-1686 (chemical name (E)-N-(2-(diethylamino)ethyl)-4-(2-(2-(5-nitrofuran-2-yl)vinyl)quinolin-4-ylamino)benzamide) inhibits cell proliferation and triggers late apoptosis in prostate cancer cell lines. Comparing the effect of CFS-1686 on cell cycle progression with the topoisomerase 1 inhibitor camptothecin revealed that CFS-1686 and camptothecin reduced DNA synthesis in S-phase, resulting in cell cycle arrest at the intra-S phase and G1-S boundary, respectively. The DNA damage in CFS-1686 and camptothecin treated cells was evaluated by the level of ATM phosphorylation, γH2AX, and γH2AX foci, showing that camptothecin was more effective than CFS-1686. However, despite its lower DNA damage capacity, CFS-1686 demonstrated 4-fold higher inhibition of topoisomerase 1 than camptothecin in a DNA relaxation assay. Unlike camptothecin, CFS-1686 demonstrated no activity on topoisomerase 1 in a DNA cleavage assay, but nevertheless it reduced the camptothecin-induced DNA cleavage of topoisomerase 1 in a dose-dependent manner. Our results indicate that CFS-1686 might bind to topoisomerase 1 to inhibit this enzyme from interacting with DNA relaxation activity, unlike campothecin's induction of a topoisomerase 1-DNA cleavage complex. Finally, we used a computer docking strategy to localize the potential binding site of CFS-1686 to topoisomerase 1, further indicating that CFS-1686 might inhibit the binding of Top1 to DNA.
authors.affiliation: Bone and Joint Research Center, National Cheng Kung University, Tainan, Taiwan; Medical Device R & D Core Laboratory, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan.
authors.forename: Ru-Wei
authors.initials: RW
authors.lastname: Lin
authors.affiliation: Department of Life Sciences, National University of Kaohsiung, Kaohsiung, Taiwan.
authors.forename: Chia-Ning
authors.initials: CN
authors.lastname: Yang
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: ShengYu
authors.initials: S
authors.lastname: Ku
authors.affiliation: Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Cheng-Jung
authors.initials: CJ
authors.lastname: Ho
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Shih-Bo
authors.initials: SB
authors.lastname: Huang
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Min-Chi
authors.initials: MC
authors.lastname: Yang
authors.affiliation: Department of Life Sciences, National University of Kaohsiung, Kaohsiung, Taiwan.
authors.forename: Hsin-Wen
authors.initials: HW
authors.lastname: Chang
authors.affiliation: Department of Biochemistry, School of Medical, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chun-Mao
authors.initials: CM
authors.lastname: Lin
authors.affiliation: Department of Biochemistry, School of Medical, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jaulang
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Department of Medical and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yeh-Long
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Department of Medical and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Cherg-Chyi
authors.initials: CC
authors.lastname: Tzeng
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chihuei
authors.initials: C
authors.lastname: Wang
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002166:Camptothecin / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism*; D006801:Humans; D008297:Male; D008954:Models, Biological; D062105:Molecular Docking Simulation; D016196:S Phase / Q000187:drug effects*
chemical_list: D000634:Aminoquinolines; D001549:Benzamides; C000599713:CFS-1686; D004273:DNA, Neoplasm; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin