Distinct novel quinazolinone exhibits selective inhibition in MGC-803 cancer cells by dictating mutant p53 function.

The mutant p53 proteins and their corresponding cellular response can be manipulated by novel quinazolinone derivatives 4-8 (a-i) in p53 mutant cancer cells. Of the two most potent compounds, 4a exhibited promising broad-spectrum anti-cancer effects, whereas 6c showed selective and exclusive inhibition activity in p53 mutant cancer cell lines but low toxicity to wild-type p53 cancer cell A375 and normal lung fibroblast WI-38 cells. Furthermore, 6c exhibited a more sophisticated mechanism for cell-destructive response by causing S/G2 phase arrest effect and cell size reduction. Compared with the cellular response of 6b and genetic background of cell lines studied, p53 mutation was found to be the key factor and main target for 6c evoked cell-destructive response. Molecular mechanism studies indicated that p53 phosphorylation and acetylation dual-targeting inhibitor 6c exerted anti-cancer activities with a special mechanism in evoking cell apoptosis by arresting mutant p53 function to trigger the deregulation of Cdk2 caused Bim-mediated apoptosis. To the best of our knowledge, 6c is the first quinazolinone derivative to dictate mutant p53 function for apoptotic cell death.

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

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.