title: Quinolone analogue inhibits tubulin polymerization and induces apoptosis via Cdk1-involved signaling pathways.
abstract: Cancer chemotherapeutic agents that interfere with tubulin/microtubule function are in extensive use. Quinolone is a common structure in alkaloids and its related components exhibit several pharmacological activities. In this study, we have identified the anticancer mechanisms of 2-phenyl-4-quinolone. 2-Phenyl-4-quinolone displayed anti-proliferative effect in several cancer types, including hormone-resistant prostate cancer PC-3, hepatocellular carcinoma Hep3B and HepG2, non-small cell lung cancer A549 and P-glycoprotein-rich breast cancer NCI/ADR-RES cells. The IC(50) values were 0.85, 1.81, 3.32, 0.90 and 1.53 microM, respectively. 2-Phenyl-4-quinolone caused G2/M arrest of the cell-cycle and a subsequent apoptosis. The turbidity assay showed an inhibitory effect on tubulin polymerization. After immunochemical examination, the data demonstrated that the microtubules were arranged irregularly into dipolarity showing prometaphase-like states. Furthermore, 2-Phenyl-4-quinolone induced the Mcl-1 cleavage, the phosphorylation of Bcl-2 and Bcl-xL (12-h treatment), and the caspase activation including caspase-8, -2 and -3 (24-h treatment). The exposure of cells to 2-phenyl-4-quinolone caused Cdk1 activation by several observations, namely (i) elevation of cyclin B1 expression, (ii) dephosphorylation on inhibitory Tyr-15 of Cdk1, and (iii) dephosphorylation on Ser-216 of Cdc25c. Moreover, a long-term treatment (36h) caused the release reaction and subsequent nuclear translocation of AIF. In summary, it is suggested that 2-phenyl-4-quinolone displays anticancer effect through the dysregulation of mitotic spindles and induction of mitotic arrest. Furthermore, participation of cell-cycle regulators, Bcl-2 family of proteins, activation of caspases and release of AIF may mutually cross-regulate the apoptotic signaling cascades induced by 2-phenyl-4-quinolone.
authors.affiliation: School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ying-Cheng
authors.initials: YC
authors.lastname: Chen
authors.forename: Pin-Hsuan
authors.initials: PH
authors.lastname: Lu
authors.forename: Shiow-Lin
authors.initials: SL
authors.lastname: Pan
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.forename: Tsung-Ping
authors.initials: TP
authors.lastname: Lin
authors.forename: Yunn-Fang
authors.initials: YF
authors.lastname: Ho
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Huang
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D014404:Tubulin / Q000187:drug effects* / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D015363:Quinolones; D014404:Tubulin; D050257:Tubulin Modulators; C084179:2-phenyl-4-oxohydroquinoline; D014750:Vincristine; D016203:CDC2 Protein Kinase; D017239:Paclitaxel