A novel hydroxamic acid derivative, MHY218, induces apoptosis and cell cycle arrest through downregulation of NF-κB in HCT116 human colon cancer cells

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 p21(WAF1/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.

MHY218-induced apoptotic cell death is enhanced by the inhibition of autophagy in AGS human gastric cancer cells

“…It was found to cause apoptosis in SKOV-3 ovarian cancer cells. This histone deacetylase (HDAC) inhibitor exhibits growth inhibitory effects in several tumor cell lines, including ovarian, breast, and colon cancer cells (10)(11)(12). Two studies in animals have shown that MHY218 has antineoplastic activities against tamoxifen-resistant breast cancer and ovarian cancer (10,11).…”

“…The anticancer mechanisms of MHY218 are still under investigation, and few studies have reported its effects on cell death. It has been shown to induce the pro-apoptotic Bax protein, inhibit the anti-apoptotic Bcl-2 protein (10)(11)(12), and suppress the nuclear translocation of nuclear factor-κB (NF-κB) (12). Thus, modulations of the NF-κB-regulated genes such as cyclooxygenase-2, matrix metalloproteinase-9, 5-lipoxygenase (12), and HDACs (10,11) have been implicated in MHY218-induced apoptotic cell death.…”

“…It has been shown to induce the pro-apoptotic Bax protein, inhibit the anti-apoptotic Bcl-2 protein (10)(11)(12), and suppress the nuclear translocation of nuclear factor-κB (NF-κB) (12). Thus, modulations of the NF-κB-regulated genes such as cyclooxygenase-2, matrix metalloproteinase-9, 5-lipoxygenase (12), and HDACs (10,11) have been implicated in MHY218-induced apoptotic cell death. In addition, this synthetic hydroxamic acid derivative induces G2/M phase arrest in cells, and this is most likely mediated through the regulation of cyclin B1 and its activating partners Cdc25C and Cdc2, and a G2/M phase inhibitor p21 WAF1/CIP1 (10)(11)(12).…”

“…Thus, modulations of the NF-κB-regulated genes such as cyclooxygenase-2, matrix metalloproteinase-9, 5-lipoxygenase (12), and HDACs (10,11) have been implicated in MHY218-induced apoptotic cell death. In addition, this synthetic hydroxamic acid derivative induces G2/M phase arrest in cells, and this is most likely mediated through the regulation of cyclin B1 and its activating partners Cdc25C and Cdc2, and a G2/M phase inhibitor p21 WAF1/CIP1 (10)(11)(12). MHY218 has been shown to significantly inhibit the growth of tumors in mice bearing human ovarian cancer (10).…”

Evaluation of preventive and therapeutic activity of novel non-steroidal anti-inflammatory drug, CG100649, in colon cancer: Increased expression of TNF-related apoptosis-inducing ligand receptors enhance the apoptotic response to combination treatment with TRAIL

“…Colon cancer is one of the most common solid tumors and frequent cause of cancer-related mortality worldwide (1,2). Despite significant progress in conventional therapeutic approaches to colon cancer, most patients eventually succumb to their disease.…”