Quinolone analogue inhibits tubulin polymerization and induces apoptosis via Cdk1-involved signaling pathways
| Autor: | Yu-Chun Huang, Ying Cheng Chen, Tsung Ping Lin, Yunn-Fang Ho, Shiow Lin Pan, Pin Hsuan Lu, Sheng-Chu Kuo, Che-Ming Teng, Jih-Hwa Guh |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
G2 Phase
Programmed cell death Paclitaxel Cell Survival Antineoplastic Agents Apoptosis Quinolones Biochemistry Dephosphorylation Tubulin Microtubule Cell Line Tumor Neoplasms CDC2 Protein Kinase Humans Mitosis Caspase Cell Proliferation Pharmacology Cyclin-dependent kinase 1 Dose-Response Relationship Drug biology Cell Cycle Tubulin Modulators Vincristine biology.protein Cancer research Drug Screening Assays Antitumor |
| Zdroj: | Biochemical Pharmacology. 74:10-19 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/j.bcp.2007.03.015 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect