Abstract
Colorectal cancer (CRC) is one of the most common malignant diseases and frequent cause of cancer deaths in the world. 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 MHY218, a hydroxamic acid derivative, in HCT116 human colon cancer cells. Treatment of cells with MHY218 resulted in growth inhibition and induction of apoptosis in a concentration-dependent manner. MHY218 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. MHY218 also caused an increase in the expression levels of p21WAF1/CIP1, a G2/M phase inhibitor, in a p53-independent pathway. The induction of apoptosis was observed by decreased viability, DNA fragmentation, cleavage of poly(ADP-ribose) polymerase, alteration in the ratio of Bax/Bcl-2 protein expression, and activation of caspase-3, -8 and -9. In addition, MHY218 treatment showed downregulation of the expression levels of the transcription factor nuclear factor-kappa B (NF-κB) in the nucleus, which has been reported to be implicated in the apoptotic cell death of several types of cancer cells, suppression of TNF-α-induced NF-κB activation, inhibition of cyclooxygenase-2 expression, repression of matrix metalloproteinase-9 activation and decrease of 5-lipoxygenase in a concentration-dependent manner. These results suggest that MHY218 may be a useful candidate to be used in the chemoprevention and/or treatment of colon cancer.