title: 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, p21(WAF1/CIP1), p27(KIP1), 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.
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Seon Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Yong Jung
authors.initials: YJ
authors.lastname: Kang
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Bokyung
authors.initials: B
authors.lastname: Sung
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Dong Hwan
authors.initials: DH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Hyun Sook
authors.initials: HS
authors.lastname: Lim
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Hye Rim
authors.initials: HR
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Seong Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Jeong-Hyun
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Hyung Ryong
authors.initials: HR
authors.lastname: Moon
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Nam Deuk
authors.initials: ND
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009287:Naphthyridines / Q000008:administration & dosage*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D001572:Benzofurans; D053222:Fas Ligand Protein; C579798:MHY-449; D009287:Naphthyridines; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species