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

Int J Oncol. 2012 Dec;41(6):2057-64. doi: 10.3892/ijo.2012.1659. Epub 2012 Oct 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism
  • Benzofurans / pharmacology*
  • Benzofurans / toxicity
  • Caspases / metabolism
  • Cell Cycle Checkpoints / drug effects*
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Colonic Neoplasms / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • HCT116 Cells
  • Humans
  • Naphthyridines / pharmacology*
  • Naphthyridines / toxicity
  • Signal Transduction


  • Apoptosis Regulatory Proteins
  • Benzofurans
  • Cell Cycle Proteins
  • MHY-449
  • Naphthyridines
  • Caspases