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

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.

A multidimensional platform of patient-derived tumors identifies drug susceptibilities for clinical lenvatinib resistance

“…Romidepsin has confirmed activity as a potent and selective inhibitor of HDAC1 and HDAC2 and was shown to re-sensitize acute myeloid leukemia to chemotherapy by eradicating leukemia stem cell marker (CD123) positive cells 51 . Previous studies have shown some pan-histone deacetylase inhibitors including resminnostat, CKD-5 and entinostat displayed synergistic effects on TKI-sensitive liver cancer cells 52 , 53 , 54 , 55 . Based on the WGS analysis from our patient-derived lenvatinib-resistant cells, HDAC2 was altered with duplication during the formation of lenvatinib resistance and romidepsin exhibited the most potent antitumor activity in both PDC and PDO models.…”

Role of the Intermediate Filament Protein Peripherin in Health and Disease

“…The combination therapy with CKD-5 and sorafenib decreased HCC cell viability. CKD-5 probably acts by repressing PRC2 [ 54 ].…”

Resistance to Antiangiogenic Therapy in Hepatocellular Carcinoma: From Molecular Mechanisms to Clinical Impact

“…CKD-5 is a pan-histone deacetylase inhibitor (HDACI) which has been shown to be more effective in inhibiting, together with sorafenib, HCC cells compared to panobinostat, which is an HDACI already approved for multiple myeloma treatment [ 102 ]. Ibrutinib, a TKI of BTK and ErbB family members, by inactivating downstream Akt and MAPK pathways, is also a potential partner for sorafenib in treating HCC by modulating immune cells in the stroma through BTK inhibition [ 103 ].…”