Novel compound PS-101 exhibits selective inhibition in non-small-cell lung cancer cell by blocking the EGFR-driven antiapoptotic pathway

作者：Zhang, Guo-Hai; Cai, Le-Jing; Wang, Yan-Fei; Zhou, Yuan-Hua; An, Yun-Feng; Liu, Yan-Cheng; Peng, Yan^*; Chen, Zhen-Feng; Liang, Hong

来源：Biochemical Pharmacology, 2013, 86(12): 1721-1730.

DOI：10.1016/j.bcp.2013.10.013

• PS-101
• Inhibition selectivity
• EGFR
• Antiapoptotic pathway
• Non-small cell lung cancer

This study investigated the anticancer effect of a novel compound PS-101 in human lung cancer cells. By phenotype screening, PS-101 exhibited highly selective inhibition in EGFR-overexpressed non-small cell lung cancer cells NCI-H460 and A549 while displaying no obvious toxicity to normal hepatic cell HL-7702, lung fibroblast cell WI-38, liver cancer cell BEL-7404 and gastric cancer cell MCG-803. A combination of cell viability assay, immunoblotting, and RNA interference revealed that PS-101 induced EGFR-dependent inhibition selectivity. Further studies showed that PS-101 caused cell cycle arrest at G1 phase, changed cell size, induced apoptosis and led to cell death by increasing the proportion of sub-G1 cells. Molecular mechanism studies suggested that blocking the EGFR-driven antiapoptotic pathway is essential for PS-101-induced apoptosis. The contribution of blocking the EGFR-driven antiapoptotic pathway was verified through examines abundance of likely candidate proteins and RNA interference. The root cause for increase in BAD and decrease in Bcl-2 which altogether initiated caspase-dependent apoptosis were predominantly due to down-regulation the expression of EGFR after PS-101 treatment. PS-101 strongly down-regulated the EGFR expression to trigger proapototic protein BAD increase and antiproapototic protein Bcl-2 decrease, which altogether actived effector caspase-3/9 to initiate cell apoptisis. Taken together, these results suggest that PS-101 may be a potential candidate for cancer therapy against human lung cancer.

• 出版日期2013-12-15
• 单位广西师范大学