Quinolone analogue inhibits tubulin polymerization and induces apoptosis via Cdk1-involved signaling pathways

Ying Cheng Chen, Pin Hsuan Lu, Shiow Lin Pan, Che Ming Teng, Sheng Chu Kuo, Tsung Ping Lin, Yunn Fang Ho, Yu Chun Huang, Jih Hwa Guh

研究成果: 雜誌貢獻文章同行評審

56 引文 斯高帕斯(Scopus)

摘要

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 IC50 values were 0.85, 1.81, 3.32, 0.90 and 1.53 μM, 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 (36 h) 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.
原文英語
頁(從 - 到)10-19
頁數10
期刊Biochemical Pharmacology
74
發行號1
DOIs
出版狀態已發佈 - 6月 30 2007
對外發佈

ASJC Scopus subject areas

  • 生物化學
  • 藥理

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