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

Research output: Contribution to journalArticle

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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

Fingerprint

Quinolones
Tubulin
Polymerization
Apoptosis
Chemical activation
Cells
Caspases
Microtubules
Caspase 2
Prometaphase
G2 Phase Cell Cycle Checkpoints
Cyclin B1
Phosphorylation
Spindle Apparatus
Caspase 8
P-Glycoprotein
Turbidity
2-phenyl-4-oxohydroquinoline
Alkaloids
Non-Small Cell Lung Carcinoma

Keywords

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

ASJC Scopus subject areas

  • Pharmacology

Cite this

Quinolone analogue inhibits tubulin polymerization and induces apoptosis via Cdk1-involved signaling pathways. / Chen, Ying Cheng; Lu, Pin Hsuan; Pan, Shiow Lin; Teng, Che Ming; Kuo, Sheng Chu; Lin, Tsung Ping; Ho, Yunn Fang; Huang, Yu Chun; Guh, Jih Hwa.

In: Biochemical Pharmacology, Vol. 74, No. 1, 30.06.2007, p. 10-19.

Research output: Contribution to journalArticle

Chen, Ying Cheng ; Lu, Pin Hsuan ; Pan, Shiow Lin ; Teng, Che Ming ; Kuo, Sheng Chu ; Lin, Tsung Ping ; Ho, Yunn Fang ; Huang, Yu Chun ; Guh, Jih Hwa. / Quinolone analogue inhibits tubulin polymerization and induces apoptosis via Cdk1-involved signaling pathways. In: Biochemical Pharmacology. 2007 ; Vol. 74, No. 1. pp. 10-19.
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AU - Kuo, Sheng Chu

AU - Lin, Tsung Ping

AU - Ho, Yunn Fang

AU - Huang, Yu Chun

AU - Guh, Jih Hwa

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