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

DC Field Value Language
dc.contributor.authorChang, Young-
dc.contributor.authorLee, Yun Bin-
dc.contributor.authorCho, Eun Ju-
dc.contributor.authorLee, Jeong-Hoon-
dc.contributor.authorYu, Su Jong-
dc.contributor.authorKim, Yoon Jun-
dc.contributor.authorYoon, Jung-Hwan-
dc.date.accessioned2021-01-12T05:19:31Z-
dc.date.available2021-01-12T14:34:11Z-
dc.date.issued2020-10-15-
dc.identifier.citationBMC Cancer. 2020 Oct 15;20(1):1001ko_KR
dc.identifier.issn1471-2407-
dc.identifier.urihttps://hdl.handle.net/10371/171614-
dc.description.abstractBackground
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.
ko_KR
dc.description.sponsorshipThis study was supported by a grant from Chong Kun Dang Pharmaceutical Corp. (Seoul, Korea). The funder had no role in study design, experiments, analysis and interpretation of data, decision to publish, or preparation of the manuscript.ko_KR
dc.language.isoenko_KR
dc.publisherBMCko_KR
dc.titleCKD-5, a novel pan-histone deacetylase inhibitor, synergistically enhances the efficacy of sorafenib for hepatocellular carcinomako_KR
dc.typeArticleko_KR
dc.contributor.AlternativeAuthor창영-
dc.contributor.AlternativeAuthor이윤빈-
dc.contributor.AlternativeAuthor조은주-
dc.contributor.AlternativeAuthor이정훈-
dc.contributor.AlternativeAuthor유수종-
dc.contributor.AlternativeAuthor김윤준-
dc.contributor.AlternativeAuthor윤정환-
dc.identifier.doi10.1186/s12885-020-07471-3-
dc.citation.journaltitleBMC Cancerko_KR
dc.language.rfc3066en-
dc.rights.holderThe Author(s)-
dc.date.updated2020-10-18T03:17:36Z-
dc.citation.number1ko_KR
dc.citation.startpage1001ko_KR
dc.citation.volume20ko_KR
Appears in Collections:
Seoul National University(서울대학교)Seoul National University Bulletin(서울대학교 요람) Seoul National University Bulletin, 1965-1966 (서울대학교 요람)
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