Novel ferrocenyl derivatives exert anti-cancer effect in human lung cancer cells in vitro via inducing G(1)-phase arrest and senescence

作者：Li Ying; Ma Han lin; Han Lei; Liu Wei yong; Zhao Bao xiang^*; Zhang Shang li; Miao Jun ying

来源：Acta Pharmacologica Sinica, 2013, 34(7): 960-968.

DOI：10.1038/aps.2013.19

• human lung cancer
• ferrocene
• triazoles
• cell cycle arrest
• apoptosis
• senescence
• senescence-associated-beta-galactosidase
• ROS
• p38

Aim: To investigate the effects of 7 novel 1-ferrocenyl-2-(5-phenyl-1H-1,2,4-triazol-3-ylthio) ethanone derivatives on human lung cancer cells in vitro and to determine the mechanisms of action.
Methods: A549 human lung cancer cells were examined. Cell viability was analyzed with MTT assay. Cell apoptosis and senescence were examined using Hoechst 33258 and senescence-associated-beta-galactosidase (SA-beta-gal) staining, respectively. LDH release was measured using a detection kit. Cell cycle was analyzed using a flow cytometer. Intracellular ROS level was measured with the 2',7'-dichlorodihydrofluorescein probe. Phosphorylation of p38 was determined using Western blot.
Results: Compounds 5b, 5d, and 5e (40 and 80 mu mol/L) caused significant decrease of A549 cell viability, while other 4 compounds had no effect on the cells. Compounds 5b, 5d, and 5e (80 mu mol/L) induced G(1)-phase arrest (increased the G(1) population by 22.6%, 24.23%, and 26.53%, respectively), and markedly increased SA-beta-gal-positive cells. However, the compounds did not cause nuclear DNA fragmentation and chromatin condensation in A549 cells. Nor did they affect the release of LDH from the cells. The compounds significantly elevated the intracellular ROS level, decreased the mitochondrial membrane potential, and increased p38 phosphorylation in the cells. In the presence of the antioxidant and free radical scavenger N-acetyl-L-cysteine (10 mmol/L), above effects of compounds 5b, 5d, and 5e were abolished.
Conclusion: The compounds 5b, 5d, and 5e cause neither apoptosis nor necrosis of A549 cells, but exert anti-cancer effect via inducing G(1)-phase arrest and senescence through ROS/p38 MAP-kinase pathway.

• 出版日期2013-7
• 单位山东大学