期刊
ANTICANCER RESEARCH
卷 39, 期 12, 页码 6731-6741出版社
INT INST ANTICANCER RESEARCH
DOI: 10.21873/anticanres.13888
关键词
Histone deacetylase 6; glioblastoma; temozolomide resistance; DNA mismatch repair; MutSa
类别
资金
- National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2016R1D1A1A 02937071, 2018R1A6A1A03023718, 2019R1I1A1A01058601, 2019R1A2C1008619]
- National Research Foundation of Korea [2019R1I1A1A01058601] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Background/Aim: Histone deacetylase 6 (HDAC6) is considered as one of the most promising targets in drug development for cancer therapy. Drug resistance is a major cause of treatment failure in many cancers including glioblastoma (GBM), the most lethal malignant tumor. The role of HDAC6 in GBM resistance and its underlying mechanisms have not been well elucidated. Herein, we investigated the function of HDAC6 in modulating GBM resistance. Materials and Methods: The anticancer effects of four structurally distinct selective HDAC6 inhibitors were addressed using western blot, flow cytometry, CCK-8 assay, and CI in temozolomide (TMZ)-resistant GBM cells. Results: We showed that HDAC6-selecitve inhibitors block activation of the EGFR and p53 pathways in TMZ-resistant GBM cells. Importantly, the inhibition of HDAC6 correlates with increased levels of MSH2 and MSH6, key DNA mismatch repair proteins, in TMZ-resistant GBM cells. In addition to the MSH, HDAC6 inhibitors decrease MGMT expression in TMZ-resistant GBM cells. Furthermore, HDAC6 inhibitors increase TMZ sensitivity and efficiently induce apoptosis in TMZ-resistant GBM cells. Conclusion: Selective inhibition of HDAC6 may be a promising strategy for the treatment of TMZ-resistant GBM.
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