MHY-449, a novel dihydrobenzofuro[4,5-b][1,8] naphthyridin-6-one derivative, mediates oxidative stress-induced apoptosis in AGS human gastric cancer cells

Abstract

MHY-449 is a novel dihydrobenzofuro[4,5-b][1,8] naphthyridin-6-one derivative designed and synthesized as a potential anticancer agent. The present study aimed to examine the anticancer activity and underlying mechanism of MHY-449. The cell viability assay performed in AGS human gastric carcinoma cells demonstrated that MHY-449 inhibited cell proliferation in a concentration-dependent manner. MHY-449 induced AGS cell death via apoptosis. The underlying molecular mechanism of MHY-449-mediated apoptosis was also investigated. MHY-449 promoted the upregulation of Fas and Fas-ligand, and activation of caspase-8, suggesting the involvement of a Fas-mediated extrinsic pathway in MHY-449-induced apoptosis. In addition, it was found that MHY-449-induced apoptosis was accompanied by the upregulation of Bax, p21WAF1/CIP1, p27KIP1, and p53 and suppression of Bcl-2. MHY-449 exposure activated the caspase cascade and subsequent poly(ADP-ribose) polymerase (PARP) cleavage. Furthermore, the pan-caspase inhibitor, Z-VAD-FMK, significantly attenuated MHY-449-induced apoptosis, indicating that the apoptosis was caspase-dependent. Moreover, the apoptogenic effect of MHY-449 was reactive oxygen species (ROS)-dependent. This result was confirmed by the induction of ROS by MHY-449 and by evidence that the scavenging of ROS by N-acetyl-L-cysteine inhibited MHY-449-induced cell death. Taken together, these results demonstrated that MHY-449 triggers apoptosis via caspase activation and ROS production. This result provides a novel mechanistic explanation and a basis for developing this compound as a novel candidate for human cancer therapy.