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

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51 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)10-19
Number of pages10
JournalBiochemical Pharmacology
Volume74
Issue number1
DOIs
Publication statusPublished - Jun 30 2007
Externally publishedYes

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Keywords

  • AIF
  • Bcl-2 family of proteins
  • Caspase
  • Cdk1
  • Mitotic arrest
  • Quinolone

ASJC Scopus subject areas

  • Pharmacology

Cite this

Chen, Y. C., Lu, P. H., Pan, S. L., Teng, C. M., Kuo, S. C., Lin, T. P., Ho, Y. F., Huang, Y. C., & Guh, J. H. (2007). Quinolone analogue inhibits tubulin polymerization and induces apoptosis via Cdk1-involved signaling pathways. Biochemical Pharmacology, 74(1), 10-19. https://doi.org/10.1016/j.bcp.2007.03.015