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CKD-5, a novel pan-histone deacetylase inhibitor, synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma

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Authors
Chang, Young; Lee, Yun Bin; Cho, Eun Ju; Lee, Jeong-Hoon; Yu, Su Jong; Kim, Yoon Jun; Yoon, Jung-Hwan
Issue Date
2020-10-15
Publisher
BMC
Citation
BMC Cancer. 2020 Oct 15;20(1):1001
Abstract
Background
Histone deacetylase inhibitors (HDACIs) have distinctive epigenetic targets involved in hepatocarcinogenesis and chemoresistance. A recent phase I/II study reported the possibility of HDACI as a chemosensitizer in sorafenib-resistant patients. In this study, we evaluated whether CKD-5, a novel pan-HDACI, can potentiate the efficacy of sorafenib.

Methods
The anticancer effect of CKD-5 with and without sorafenib was evaluated in vitro using an MTS assay with human HCC cells (SNU-3058 and SNU-761) under both normoxic and hypoxic conditions. Microarray analysis was performed to investigate the mechanism of cell death, which was also evaluated by small interfering RNA (siRNA) transfection and subsequent immunoblot assays. In vivo experiments were conducted using two different murine HCC models. C3H mice implanted with MH134 cells and C57BL/6 mice implanted with RIL-175 cells were treated with weekly CKD-5 with and without sorafenib for 2 weeks.

Results
CKD-5 treatment significantly suppressed human HCC cell growth in both normoxic and hypoxic conditions. Microarray analysis and real-time PCR showed that CKD-5 treatment significantly increased peripherin expression in HCC cells and that downregulation of peripherin by siRNA decreased CKD-5-induced apoptosis. The combination of CKD-5 and sorafenib decreased cell viability more effectively than sorafenib or CKD-5 monotherapy in human and murine HCC cells. The effectiveness of the combination therapy was consistently demonstrated in the animal models. Histological and biochemical analyses demonstrated good tolerance of CKD-5 plus sorafenib in vivo.


Conclusion
CKD-5 may enhance sorafenib efficacy through epigenetic regulation. The combination of CKD-5 and sorafenib might be a novel therapeutic option for the treatment of HCC.
ISSN
1471-2407
Language
English
URI
https://hdl.handle.net/10371/171614
DOI
https://doi.org/10.1186/s12885-020-07471-3
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Seoul National University(서울대학교)Seoul National University Bulletin(서울대학교 요람) Seoul National University Bulletin, 1965-1966 (서울대학교 요람)
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