Novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivative, MHY-449, induces cell cycle arrest and apoptosis via the downregulation of Akt in human lung cancer cells.
The anticancer properties of MHY-449, a novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivative, in various human cancer cell lines have been previously reported. The aim of the present study was to investigate the activities of MHY-449 on human lung cancer cells in order to elucidate its underlying molecular mechanisms of action. The result showed that MHY-449 treatment inhibited cell growth in a time- and concentration‑dependent manner. Specifically, MHY-449 induced cell cycle arrest at the S phase, and the resulting increased sub-G1 fraction led to the induction of apoptosis, as determined by flow cytometric analysis and DNA fragmentation. In addition, MHY-449 was shown to induce alterations in the ratio of Bax/Bcl-2 protein expression, and contribute to the loss of mitochondrial membrane potential. These cellular events then triggered the caspase cascade and subsequent poly(ADP‑ribose) polymerase cleavage. The apoptotic cell death induced by MHY-449 was inhibited by pretreatment with Z-VAD‑FMK, a pan-caspase inhibitor. Moreover, MHY-449 downregulated the phosphorylation of Akt, and the phosphatidylinositol-3 kinase/Akt inhibitor LY294002 was found to enhance its induction of apoptosis. Taken together, the results suggested that MHY-449 exerts anticancer effects by promoting cell cycle arrest and apoptosis via the downregulation of Akt. Based on these data, MHY-449 serves as a potential candidate in the chemoprevention and/or treatment of lung cancer.
College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
Hyun Sook
HS
Lim
College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
Yong Jung
YJ
Kang
College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
Bokyung
B
Sung
College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
Seon Hee
SH
Kim
College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
Min Jeong
MJ
Kim
College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
Hye Rim
HR
Kim
College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
Seong Jin
SJ
Kim
Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan 614-052, Republic of Korea.
Yung Hyun
YH
Choi
College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
Hyung Ryong
HR
Moon
College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
Hae Young
HY
Chung
College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
Nam Deuk
ND
Kim
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001572:Benzofurans / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D009287:Naphthyridines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
D000970:Antineoplastic Agents; D001572:Benzofurans; D002867:Chromones; C579798:MHY-449; D009025:Morpholines; D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one