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Novel ferrocenyl derivatives exert anti-cancer effect in human lung cancer cells in vitro via inducing G1-phase arrest and senescence

   
@article{APS7938,
	author = {Ying Li and Han-lin Ma and Lei Han and Wei-yong Liu and Bao-xiang Zhao and Shang-li Zhang and Jun-ying Miao},
	title = {Novel ferrocenyl derivatives exert anti-cancer effect in human lung cancer cells in vitro via inducing G1-phase arrest and senescence},
	journal = {Acta Pharmacologica Sinica},
	volume = {34},
	number = {7},
	year = {2016},
	keywords = {},
	abstract = {Ying LI1, #, Han-lin MA1, #, Lei HAN1, Wei-yong LIU2, Bao-xiang ZHAO2, *, Shang-li ZHANG1, Jun-ying MIAO1, *
1Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, Institute of Developmental Biology, School of Life Science, Shandong University, Ji-nan 250100, China; 2School of Chemistry and Chemical Engineering, Shandong University, Ji-nan 250100, China
 
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-β-galactosidase (SA-β-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 µmol/L) caused significant decrease of A549 cell viability, while other 4 compounds had no effect on the cells.  Compounds 5b, 5d, and 5e (80 µmol/L) induced G1-phase arrest (increased the G1 population by 22.6%, 24.23%, and 26.53%, respectively), and markedly increased SA-β-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 G1-phase arrest and senescence through ROS/p38 MAP-kinase pathway.

Keywords: human lung cancer; ferrocene; triazoles; cell cycle arrest; apoptosis; senescence; senescence-associated-β-galactosidase; ROS; p38
 
This work was financially supported by the National Natural Science Foundation of China (No 31270877, 90813022, 20972088, 31070735, and 81021001) and the National 973 Research Project (No 2011CB503906).
# These authors contributed equally to this work. 
* To whom correspondence should be addressed.
E-mail miaojy@sdu.edu.cn (Jun-ying MIAO); bxzhao@sdu.edu.cn (Bao-xiang ZHAO)
Received 2012-11-05    Accepted 2013-02-17},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/7938}
}