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.

[1]  Guido Kroemer,et al.  Caspase-independent cell death , 2005, Nature Medicine.

[2]  T. Tenev,et al.  The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. , 2011, Molecular cell.

[3]  L K Miller,et al.  An exegesis of IAPs: salvation and surprises from BIR motifs. , 1999, Trends in cell biology.

[4]  Seamus J. Martin,et al.  Apoptosis‐associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl‐2 , 2001, The EMBO journal.

[5]  H. Ji,et al.  Interferon-β-armed oncolytic adenovirus induces both apoptosis and necroptosis in cancer cells. , 2012, Acta biochimica et biophysica Sinica.

[6]  M. Millenson,et al.  Cancer- and chemotherapy-induced anemia. , 2012, Journal of the National Comprehensive Cancer Network : JNCCN.

[7]  Aaron Fenster,et al.  Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans , 2011, Nature.

[8]  Lawrence M Wein,et al.  Validation and analysis of a mathematical model of a replication-competent oncolytic virus for cancer treatment: implications for virus design and delivery. , 2003, Cancer research.

[9]  J C Reed,et al.  IAP family proteins--suppressors of apoptosis. , 1999, Genes & development.

[10]  A. Gambotto,et al.  Expression of X‐linked inhibitor‐of‐apoptosis protein in hepatocellular carcinoma promotes metastasis and tumor recurrence , 2008, Hepatology.

[11]  M. Jordan,et al.  Microtubules as a target for anticancer drugs , 2004, Nature Reviews Cancer.

[12]  Jian Yu,et al.  Role of Smac in Determining the Chemotherapeutic Response of Esophageal Squamous Cell Carcinoma , 2011, Clinical Cancer Research.

[13]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[14]  D. Kirn,et al.  Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer , 2009, Nature Reviews Cancer.

[15]  C. Qian,et al.  Enhanced sensitivity of hepatocellular carcinoma cells to chemotherapy with a Smac-armed oncolytic adenovirus , 2007, Acta Pharmacologica Sinica.

[16]  A. Alcamí,et al.  Vaccinia Virus-Mediated Inhibition of Type I Interferon Responses Is a Multifactorial Process Involving the Soluble Type I Interferon Receptor B18 and Intracellular Components , 2008, Journal of Virology.

[17]  J. Meléndez-Zajgla,et al.  Role of Smac/DIABLO in cancer progression , 2008, Journal of experimental & clinical cancer research : CR.

[18]  M. Vitale,et al.  Differential kinetics of propidium iodide uptake in apoptotic and necrotic thymocytes , 1993, Histochemistry.

[19]  Josepa Ribes,et al.  Primary liver cancer: worldwide incidence and trends. , 2004, Gastroenterology.

[20]  Robert B Sim,et al.  Extracellular enveloped vaccinia virus is resistant to complement because of incorporation of host complement control proteins into its envelope. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Chunying Du,et al.  Smac/DIABLO Selectively Reduces the Levels of c-IAP1 and c-IAP2 but Not That of XIAP and Livin in HeLa Cells* , 2004, Journal of Biological Chemistry.

[22]  Alexei Degterev,et al.  Identification of RIP1 kinase as a specific cellular target of necrostatins. , 2008, Nature chemical biology.

[23]  Xin-Yuan Liu,et al.  Lithium Down-regulates Histone Deacetylase 1 (HDAC1) and Induces Degradation of Mutant Huntingtin* , 2013, The Journal of Biological Chemistry.

[24]  G. Bjørkøy,et al.  p62/SQSTM1 Binds Directly to Atg8/LC3 to Facilitate Degradation of Ubiquitinated Protein Aggregates by Autophagy* , 2007, Journal of Biological Chemistry.

[25]  D. Kirn,et al.  Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963. , 2007, The Journal of clinical investigation.

[26]  Xiaodong Wang,et al.  Structural and biochemical basis of apoptotic activation by Smac/DIABLO , 2000, Nature.

[27]  S. Vadhan-Raj.  Management of chemotherapy-induced thrombocytopenia: current status of thrombopoietic agents. , 2009, Seminars in hematology.

[28]  F. Falkner,et al.  Evaluation of the thymidine kinase (tk) locus as an insertion site in the highly attenuated vaccinia MVA strain , 2005, Archives of Virology.

[29]  A. Jemal,et al.  Cancer statistics, 2013 , 2013, CA: a cancer journal for clinicians.

[30]  C. Qian,et al.  Complete elimination of colorectal tumor xenograft by combined manganese superoxide dismutase with tumor necrosis factor-related apoptosis-inducing ligand gene virotherapy. , 2006, Cancer research.

[31]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[32]  M. Bertrand,et al.  The Ripoptosome: death decision in the cytosol. , 2011, Molecular cell.

[33]  F. Chan,et al.  Phosphorylation-Driven Assembly of the RIP1-RIP3 Complex Regulates Programmed Necrosis and Virus-Induced Inflammation , 2009, Cell.

[34]  M. Roizen,et al.  Hallmarks of Cancer: The Next Generation , 2012 .

[35]  Michael Weller,et al.  Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo , 2002, Nature Medicine.