| Backgroud and AIM: Hepatocellular carcinoma (HCC) become the most common formof cancer-associated mortality in China and one of the leading causes of death in theworld. Although sorafenib, a multi-target and multi-kinase inhibitor, currently sets thenew standard for advanced HCC, the tumor response rates are actually quite low. Theepigenetic control of gene expression by the histone deacetylases (HDAC) family hasbeen revealed to play critical roles in cancer progression and chemoresistance, andHDAC inhibitors (HDACIs) are emerging as a new class of potential anticancer agents.However, whether HDACIs can sensitize HCC cells for sorafenib treatment remainslargely unexplored. The aim of this study is to clarify whether histone deacetylaseinhibitors histone deacetylase inhibitors (HDACIs) can sensitize hepatocellularcarcinoma (HCC) cells to sorafenib treatment.METHODS: Bax, Bcl-2, ATG5-ATG12, p21, and p27protein levels in Hep3B, HepG2,and PLC/PRF/5cells were examined by Western blot. CCK8and a fluorometriccaspase-3assay were used to examine cellular viability and apoptosis levels. The effectof Beclin-1on sensitization of HCC cells to sorafenib was examined by transfectingBeclin-1siRNA into Hep3B, HepG2, and PLC/PRF/5cells.RESULTS: Autophagy inhibition enhances the inhibitory effects of vorinostat andsorafenib alone or in combination on HCC cell growth. Vorinostat and sorafenibsynergistically induced apoptosis and cell cycle alterations. Western blot data indicatedthat HDACIs and Beclin-1knockdown increased the p53acetylation level. Theknockdown of Beclin-1enhanced the synergistic effect of the combination of vorinostatwith sorafenib.CONCLUSION: Our data demonstrate that hepatoma cell lines are more sensitive to sorafenib combined with HDACIs and the potentiation is further enhanced by theinhibition of autophagy, suggesting autophagy may play a compensatory role in themechanism of treatment. |
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