title: Novel compound PS-101 exhibits selective inhibition in non-small-cell lung cancer cell by blocking the EGFR-driven antiapoptotic pathway.
abstract: 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.
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmacy, Guangxi Normal University, Guilin 541004, China.
authors.forename: Guo-Hai
authors.initials: GH
authors.lastname: Zhang
authors.forename: Le-Jing
authors.initials: LJ
authors.lastname: Cai
authors.forename: Yan-Fei
authors.initials: YF
authors.lastname: Wang
authors.forename: Yuan-Hua
authors.initials: YH
authors.lastname: Zhou
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: An
authors.forename: Yan-Cheng
authors.initials: YC
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Peng
authors.forename: Zhen-Feng
authors.initials: ZF
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
mesh_terms: D000606:Amino Sugars / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D017931:DNA Primers; D015536:Down-Regulation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D009285:Naphthoquinones / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D000606:Amino Sugars; D000970:Antineoplastic Agents; D017931:DNA Primers; D009285:Naphthoquinones; C585911:PS-101; D066246:ErbB Receptors
keywords: Antiapoptotic pathway; EGFR; Inhibition selectivity; Non-small cell lung cancer; PS-101