Abstract
BackgroundHistone 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.MethodsThe 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.ResultsCKD-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.ConclusionCKD-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.
Highlights
Histone deacetylase inhibitors (HDACIs) have distinctive epigenetic targets involved in hepatocarcinogenesis and chemoresistance
We demonstrated that CKD-5 has consistent anti-tumor effects in various Hepatocellular carcinoma (HCC) cell lines and xenograft mice models, which is further potentiated when combined with sorafenib
CKD-5 affected cell viability and apoptosis in HCC cell lines CKD-5 treatment decreased SNU-761 and SNU-3085 cell proliferation in both normoxic and hypoxic conditions in a dose-dependent manner after 24-h incubation (Fig. 1a), and the anti-tumor effect was further enhanced after 48-h incubation (Fig. 1b)
Summary
Histone deacetylase inhibitors (HDACIs) have distinctive epigenetic targets involved in hepatocarcinogenesis and chemoresistance. There have been limitations in treating advanced HCC patients with sorafenib because it has demonstrated limited survival benefits with low tumor response rates, suggesting the existence of sorafenib-resistance [3]. To overcome these limitations of sorafenib, combination therapies with various treatment modalities such as locoregional treatment [4,5,6], conventional chemotherapy [7,8,9], and novel targeted agents [10,11,12] have been tried
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