SMAC-armed vaccinia virus induces both apoptosis and necroptosis and synergizes the efficiency of vinblastine in HCC.
Hepatocellular carcinoma (HCC) has particularly high incidence rate in Asia and its resistance to the chemotherapeutic drugs and cell death make it intractable. Vaccinia virus (VV) is a potential vehicle and has been widely used in cancer therapy. SMAC/DIABLO is a critical factor in activating caspases and eliminating inhibition of IAPs when the programmed cell death is promoted. In this study, we constructed a tumor-targeted vaccinia virus carrying SMAC/DIABLO gene that was knocked in the region of viral thymidine kinase gene (VV-SMAC). Our results showed that VV-SMAC efficiently infected and destroyed HCC cells via triggering both caspase-dependent apoptosis and necroptosis with depletion of IAPs. Furthermore, ripoptosome, a prerequisite complex of necroptosis, was assembled and induced by VV-SMAC. In addition, the combination of VV-SMAC and vinblastine represented a synergistic effect on HCC cells. In summary, our data suggest that VV-SMAC is a potential candidate and combination of VV-SMAC and vinblastine may provide a new avenue in treatment of HCC.
Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Room 217, Building No. 6, Xiasha, Hangzhou, 310018, China.
Qiang
Q
Pan
Yuanyong
Y
Huang
Lieyang
L
Chen
JinFa
J
Gu
Xiumei
X
Zhou
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology* / Q000821:virology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000821:virology*; D024101:Mitochondrial Proteins; D009336:Necrosis; D013937:Thymidine Kinase / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D014616:Vaccinia virus / Q000201:enzymology* / Q000235:genetics*; D014747:Vinblastine / Q000494:pharmacology* / Q000627:therapeutic use
D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D014747:Vinblastine; D013937:Thymidine Kinase