Inhibition of gastric cancer cell growth by a PI3K-mTOR dual inhibitor GSK1059615

Abstract

Gastric cancer (GC) is a common malignancy. Developing novel and efficient anti-GC agents is urgent. GSK1059615 is a PI3K (phosphatidylinositol 3-kinase) and mTOR (mammalian target of rapamycin) dual inhibitor. It activity in human GC cells is tested here. In AGS cells and primary human GC cells, GSK1059615 potently inhibited cell growth, survival, proliferation and cell cycle progression. Further, significant apoptosis activation was detected in GSK1059615-treated GC cells. Contrarily in the primary human gastric epithelial cells, GSK1059615 failed to induce significant cytotoxicity and apoptosis. GSK1059615 blocked PI3K-AKT-mTOR cascade activation, inducing microRNA-9 downregulation but LMX1A (LIM homeobox transcription factor 1α) upregulation in GC cells. Significantly, GSK1059615 administration (i.p., daily, at 10 or 30 mg/kg) in nude mice potently inhibited subcutaneous AGS xenograft growth. AKT-mTOR inhibition and LMX1A upregulation were detected in AGS xenograft tissues with GSK1059615 administration. Together, we conclude that GSK1059615 inhibits GC cell growth in vitro and in vivo.

Keywords: GSK1059615; Gastric cancer; PI3K-AKT-mTOR cascade; microRNA-9-LMX1A cascade.