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.

• Authors: Mi Kyeong Kim, Yong Jung Kang, Dong Hwan Kim, Mohammad Akbar Hossain, Jung Yoon Jang, Sun Hwa Lee, Jeong-Hyun Yoon, Pusoon Chun, Hyung Ryong Moon, Hyung Sik Kim, Hae Young Chung, Nam Deuk Kim
• Journal: International journal of oncology (Int J Oncol) Vol. 44 Issue 1 Pg. 256-64 (Jan 2014) ISSN: 1791-2423 [Electronic] Greece
• PMID: 24190633 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclin B1
• Hydroxamic Acids
• N1-hydroxy-N8-(4-phenoxyphenyl)octanediamide
• NF-kappa B
• Phenyl Ethers
• Pimelic Acids
• rho GTP-Binding Proteins

Topics

• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Proliferation (drug effects)
• Colonic Neoplasms (drug therapy, genetics, pathology)
• Cyclin B1 (biosynthesis)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• HCT116 Cells
• Humans
• Hydroxamic Acids (administration & dosage)
• NF-kappa B (genetics, metabolism)
• Phenyl Ethers (administration & dosage)
• Pimelic Acids (administration & dosage)
• rho GTP-Binding Proteins (biosynthesis)