Identification of a novel small molecule to inhibit gastric cancer cells growth

Abstract

Abstract A majority of gastric cancer (GC) patients die from tumor metastasis or recurrence as GC is not sensitive to radiotherapy and chemotherapy. It is in desperate need to develop new therapeutic agents. In this study, we screened a novel compound against gastric cancer cells and subsequently investigated the molecular mechanisms. Gastric cancer AGS cells were used as models to determine the cytotoxic effect of 450 compounds (10 µM) from the Topscience Preclinical Compound Library by CCK-8 assay. Our studies demonstrated that 32 compounds showed inhibitory effect on the growth of AGS cells, with ZM-241385 be the most potent one, which killed all the AGS cells at 48h. Next, ZM-241385 was shown to induce autophagy in AGS cells by the activation of AMPK pathway. In addition, ZM-241385 induced cell apoptosis dependent on caspase 3, caspase 8 and caspase 9. Finally, inhibition of autophagy by chloroquine augmented ZM-241385 induced apoptotic cell death, indicating that autophagy exerts a protective role against ZM-241385 induced apoptosis. Together, our data indicate that we have screened a novel compound which inhibits AGS cell proliferation by inducing cell apoptosis and activates autophagy which, however, attenuates ZM-241385 induced apoptosis.