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: Guo-Hai Zhang, Le-Jing Cai, Yan-Fei Wang, Yuan-Hua Zhou, Yun-Feng An, Yan-Cheng Liu, Yan Peng, Zhen-Feng Chen, Hong Liang
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 86 Issue 12 Pg. 1721-30 (Dec 15 2013) ISSN: 1873-2968 [Electronic] England
• PMID: 24161785 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Amino Sugars
• Antineoplastic Agents
• DNA Primers
• Naphthoquinones
• PS-101
• ErbB Receptors

Topics

• Amino Sugars (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Base Sequence
• Carcinoma, Non-Small-Cell Lung (metabolism, pathology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• DNA Primers
• Down-Regulation
• ErbB Receptors (antagonists & inhibitors, genetics)
• Humans
• Lung Neoplasms (metabolism, pathology)
• Naphthoquinones (pharmacology)
• Real-Time Polymerase Chain Reaction
• Transcription, Genetic