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


CONCLUSIONS
HDACIs can sensitize HCC cells to sorafenib treatment by regulating the acetylation level of Beclin-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.
Hang
H
Yuan
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.
Ai-Jun
AJ
Li
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.
Sen-Lin
SL
Ma
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.
Long-Jiu
LJ
Cui
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.
Bin
B
Wu
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.
Lei
L
Yin
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.
Meng-Chao
MC
Wu
D000107:Acetylation; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D000077157:Sorafenib; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000077337:Vorinostat
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D009536:Niacinamide; D000077337:Vorinostat; D000077157:Sorafenib
Autophagy; Chemoresistance; Hepatocellular carcinoma; Histone deacetylase inhibitors; Sorafenib