期刊
MOLECULAR CARCINOGENESIS
卷 57, 期 10, 页码 1383-1395出版社
WILEY
DOI: 10.1002/mc.22852
关键词
anticancer agent; colorectal cancer; combination therapy; HDAC6; HDAC6-selective inhibitor
资金
- Graduate School of Yonsei University Research Scholarship Grants
- National Research Foundation of Korea (NRF) [2016R1D1A1A02937071]
- National Research Foundation of Korea [2016R1D1A1A02937071] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Although histone deacetylase inhibitors (HDACi) alone could be clinically useful, these are most recently used in combination with other anticancer agents in clinical trials for cancer treatment. Recently, we reported the anticancer activity of an HDAC6-selective inhibitor A452 toward various cancer cell types. This study aims to present a potent synergistic antiproliferative effect of A452/anticancer agent treatment in colorectal cancer cells (CRC) cells, independently of the p53 status. A452 in combination with irinotecan, or SAHA is more potent than either drug alone in the apoptotic pathway as evidenced by activated caspase-3 and PARP, increased Bak and pp38, decreased Bcl-xL, pERK, and pAKT, and induced apoptotic cells. Furthermore, A452 enhances DNA damage induced by anticancer agents as indicated by the increased accumulation of H2AX and the activation of the checkpoint kinase Chk2. The silencing of HDAC6 enhances the cell growth inhibition and cell death caused by anticancer agents. In addition, A452 induces the synergistic suppression of cell migration and invasion. This study suggests a mechanism by which HDAC6-selective inhibition can enhance the efficacy of specific anticancer agents in CRC cells.
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