Novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivative, MHY-449,             induces apoptosis and cell cycle arrest in HCT116 human colon cancer cells.
Colorectal cancer (CRC) is the second most frequent cancer in men and the             third most common cancer in women in Korea. In spite of the significant advances             in conventional therapeutic approaches to CRC, most patients ultimately die of             their disease. There is a need to develop novel preventive approaches for this             malignancy. This study was carried out to investigate the anticancer effect of             the diastereoisomeric compounds, MHY-449 and MHY-450, novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one             derivatives, on HCT116 human colon cancer cells. MHY-449 exhibited more potent             cytotoxicity than MHY-450, against HCT116 cells. Treatment of cells with MHY-449             resulted in growth inhibition and induction of apoptosis in a concentration-dependent             manner, and inhibition of proliferation in a time-dependent manner. The induction             of apoptosis was observed by decreased cell viability, DNA fragmentation, activation             of protein levels involved in death receptors. Moreover, activation of caspase-3,             -8 and -9 and cleavage of poly(ADP-ribose) polymerase and alteration in the ratio             of Bax/Bcl-2 protein expression was observed. MHY-449 induced G2/M phase arrest             in the cell cycle progression which was observed by flow cytometry analysis, and             a decrease in the protein expression of cyclin B1 and its activating partners             Cdc25c and Cdc2. MHY-449 also caused increase in the expression levels of p53,             a tumor suppressor gene, and p21WAF1/CIP and p27KIP, G2/M phase inhibitors. These             results suggest that MHY-449 may be a useful candidate for chemo-prevention and/or             treatment of colon cancer.
Division of Pharmacy, College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 609-735, Republic of Korea.
Hye Jung
HJ
Hwang
Yong Jung
YJ
Kang
Mohammad Akbar
MA
Hossain
Dong Hwan
DH
Kim
Jung Yoon
JY
Jang
Sun Hwa
SH
Lee
Jeong-Hyun
JH
Yoon
Hyung Ryong
HR
Moon
Hyung Sik
HS
Kim
Hae Young
HY
Chung
Nam Deuk
ND
Kim
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001572:Benzofurans / Q000494:pharmacology* / Q000633:toxicity; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D009287:Naphthyridines / Q000494:pharmacology* / Q000633:toxicity; D015398:Signal Transduction
D051017:Apoptosis Regulatory Proteins; D001572:Benzofurans; D018797:Cell Cycle Proteins; C579798:MHY-449; D009287:Naphthyridines; D020169:Caspases