Inhibition of autophagy signiﬁcantly enhances combination therapy with sorafenib and HDAC inhibitors for human hepatoma cells

Hang Yuan; Ai-Jun Li; Sen-Lin Ma; Long-Jiu Cui; Bin Wu; Lei Yin; Meng-Chao Wu

doi:10.3748/wjg.v20.i17.4953

Inhibition of autophagy signiﬁcantly enhances combination therapy with sorafenib and HDAC inhibitors for human hepatoma cells

World J Gastroenterol. 2014 May 7;20(17):4953-62. doi: 10.3748/wjg.v20.i17.4953.

Authors

Hang Yuan¹, Ai-Jun Li¹, Sen-Lin Ma¹, Long-Jiu Cui¹, Bin Wu¹, Lei Yin¹, Meng-Chao Wu¹

Affiliation

¹ Hang Yuan, Ai-Jun Li, Sen-Lin Ma, Long-Jiu Cui, Bin Wu, Lei Yin, Meng-Chao Wu, Department of the 2 Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.

Abstract

Aim: To clarify whether histone deacetylase inhibitors histone deacetylase inhibitors (HDACIs) can sensitize hepatocellular carcinoma (HCC) cells to sorafenib treatment.

Methods: Bax, Bcl-2, ATG5-ATG12, p21, and p27 protein levels in Hep3B, HepG2, and PLC/PRF/5 cells were examined by Western blot. CCK8 and a fluorometric caspase-3 assay were used to examine cellular viability and apoptosis levels. The effect of Beclin-1 on sensitization of HCC cells to sorafenib was examined by transfecting Beclin-1 siRNA into Hep3B, HepG2, and PLC/PRF/5 cells.

Results: Autophagy inhibition enhances the inhibitory effects of vorinostat and sorafenib alone or in combination on HCC cell growth. Vorinostat and sorafenib synergistically induced apoptosis and cell cycle alterations. Western blot data indicated that HDACIs and Beclin-1 knockdown increased the p53 acetylation level. The knockdown of Beclin-1 enhanced the synergistic effect of the combination of vorinostat with sorafenib.

Conclusion: HDACIs can sensitize HCC cells to sorafenib treatment by regulating the acetylation level of Beclin-1.

Keywords: Autophagy; Chemoresistance; Hepatocellular carcinoma; Histone deacetylase inhibitors; Sorafenib.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism
Autophagy*
Beclin-1
Carcinoma, Hepatocellular / enzymology
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / pathology*
Cell Cycle Checkpoints / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Synergism
Gene Expression Regulation, Neoplastic
Hep G2 Cells
Histone Deacetylase Inhibitors / pharmacology
Humans
Hydroxamic Acids / pharmacology
Liver Neoplasms / enzymology
Liver Neoplasms / genetics
Liver Neoplasms / pathology*
Membrane Proteins / genetics
Membrane Proteins / metabolism
Niacinamide / analogs & derivatives
Niacinamide / pharmacology
Phenylurea Compounds / pharmacology
Protein Kinase Inhibitors / pharmacology
RNA Interference
Sorafenib
Transfection
Tumor Suppressor Protein p53 / metabolism
Vorinostat

Substances

Apoptosis Regulatory Proteins
BECN1 protein, human
Beclin-1
Histone Deacetylase Inhibitors
Hydroxamic Acids
Membrane Proteins
Phenylurea Compounds
Protein Kinase Inhibitors
TP53 protein, human
Tumor Suppressor Protein p53
Niacinamide
Vorinostat
Sorafenib