Abstract
Vesicular stomatitis virus (VSV) matrix protein (MP) can induce in vitro apoptosis of tumor cells in the absence of other viral components. Here, the antitumor activity of VSV-MP against lung adenocarcinoma was investigated in vivo. A pVAX-plasmid DNA encoding VSV-MP and control empty vectors (pVAX) were constructed and wrapped-up with liposome. A549 and Spc-A1 human lung adenocarcinoma cells were transfected with liposomal-VSV-MP (Lip-MP) or Lip-pVAX and then examined for cell viability or apoptosis using Hoechst/propidium iodide staining by flow cytometry, and further demonstrated by caspase/poly ADP-ribose polymerase (PARP) cleavage analysis. For the in vivo study, A549 and Spc-A1 lung carcinoma models in nude mice were established and randomly assigned into three groups to receive eight 2-weekly intravenous administrations of medium alone as control, Lip-pVAX or Lip-MP, respectively. Subsequently, Lip-MP significantly reduced tumor growth and prolonged the survival of tumor-bearing mice compared with Lip-pVAX and control agents (P<0.05), with much higher apoptosis index of both in vivo and in vitro tumor cells, respectively (P<0.05). In addition, in vivo antitumoral effect was associated with natural killer-(NK) cell congregation without evidence of toxicity. These observations suggest that systemically delivering Lip-MP has a specific dual antitumor activity in human lung adenocarcinoma by inducing apoptosis and possibly stimulating NK-cell responses, it may provide a clue for developing new therapeutic approaches against human lung adenocarcinoma.
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References
Peacock CD, Watkins DN . Cancer stem cells and the ontogeny of lung cancer. J Clin Oncol 2008; 26: 2883–2889.
Navada S, Lai P, Schwartz AG, Oton AB, Gooding WE, Taioli E . Temporal trends in small cell lung cancer: analysis of the national Surveillance Epidemiology and End-Results (SEER) database [abstract 7082]. J Clin Oncol 2006; 24 (Suppl): 384S.
Sher T, Dy GK, Adjei AA . Small cell lung cancer. Mayo Clin Proc 2008; 83: 355–367.
Franceschi S, Bidoli E . The epidemiology of lung cancer. Ann Oncol 1999; 10 (Suppl 5): S3–S6.
Koyama AH . Induction of apoptotic DNA fragmentation by the infection of vesicular stomatitis virus. Virus Res 1995; 37: 285–290.
Balachandran S, Barber GN . Defective translational control facilitates vesicular stomatitis virus oncolysis. Cancer Cell 2004; 5: 51–65.
Stojdl DF, Lichty B, Knowles S, Marius R, Atkins H, Sonenberg N . Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nat Med 2000; 6: 821–825.
Fernandez M, Porosnicu M, Markovic D, Barber GN . Genetically engineered vesicular stomatitis virus in gene therapy: application for treatment of malignant disease. J Virol 2002; 76: 895–904.
Ebert O, Shinozaki K, Huang TG, Savontaus MJ, GarcÃa-Sastre A, Woo SL . Oncolytic vesicular stomatitis virus for treatment of orthotopic hepatocellular carcinoma in immune-competent rats. Cancer Res 2003; 63: 3605–3611.
Shinozaki K, Ebert O . Koumioti C Oncolysis of multifocal hepatocellular carcinoma in the rat liver by hepatic artery infusion of vesicular stomatitis virus. Mol Ther 2004; 9: 368–376.
Li Q, Wei YQ, Wen YJ, Zhao X, Tian L, Yang L . Induction of apoptosis and tumor regression by vesicular stomatitis virus in the presence of gemcitabine in lung cancer. Int J Cancer 2004; 112: 143–149.
Ahmed M, Cramer SD, Lyles DS . Sensitivity of prostate tumors to wild type and M protein mutant vesicular stomatitis viruses. Virol 2004; 330: 34–49.
Ebert O, Harbaran S, Shinozaki K, Woo SL . Systemic therapy of experimental breast cancer metastases by mutant vesicular stomatitis virus in immune-competent mice. Cancer Gen Ther 2005; 12: 350–358.
Letchworth GJ, Rodriguez LL, Del CBJ . Vesicular stomatitis. Vet J 1999; 157: 239–260.
Black BL, Lyles DS . Vesicular stomatitis virus matrix protein inhibits host cell-directed transcription of target genes in vivo. J Virol 1992; 66: 4058–4064.
Black BL, Rhodes RB, McKenzie M, Lyles DS . The role of vesicular stomatitis virus matrix protein in inhibition of hostdirected gene expression is genetically separable from its function in virus assembly. J Virol 1993; 67: 4814–4821.
Paik SY, Banerjea AC, Harmison GG, Chen CJ, Schubert M . Inducible and conditional inhibition of human immunodeficiency virus proviral expression by vesicular stomatitis matrix protein. J Virol 1995; 69: 3529–3537.
Ferran MC, Lucas-Lenard JM . The vesicular stomatitis virus matrix protein inhibits transcription from the human beta interferon promoter. J Virol 1997; 71: 371–377.
Ahmed M, Lyles DS . Effect of vesicular stomatitis virus matrix protein on transcription directed by host RNA II polymerasesI, and III. J Virol 1998; 72: 8413–8419.
Yuan H, Yoza BK, Lyles DS . Inhibition of host RNA polymerase II-dependent transcription by vesicular stomatitis virus results from inactivation of TFIID. Virology 1998; 251: 83–92.
Yuan H, Puckett S, Lyles DS . Inhibition of host transcription by vesicular stomatitis virus involves a novel mechanism that is independent of phosphorylation of TATA-Binding protein (TBP) or association of TBP with TBP-associated factor subunits. J Virol 2001; 75: 4453–4458.
Ahmed M, McKenzie MO, Puckett S . Ability of the matrix protein of vesicular stomatitis virus to suppress beta interferon gene expression is genetically correlated with the inhibition of host RNA and protein synthesis. J Virol 2003; 77: 4646–4657.
Her LS, Lund E, Dahlberg JE . Inhibition of Ran guanosine triphosphatase dependent nuclear transport by the matrix protein of vesicular stomatitis virus. Science 1997; 276: 1845–1848.
Petersen JM, Her LS, Varvel V . The matrix protein of vesicular stomatitis virus inhibits nucleocytoplasmic transport when it is in the nucleus and associated with nuclear pore complexes. Mol Cell Biol 2000; 20: 8590–8601.
Kobbe CV, Deursen JMV, Rodrigues JP, Sitterlin D, Bachi A, Wu X et al. Vesicular stomatitis virus matrix protein inhibits host cell gene expression by targeting the nucleoporin Nup98. Mol Cell 2000; 6: 1243–1252.
Blondel D, Harmison GG, Schubert M . Role of matrix protein in cytopathogenesis of vesicular stomatitis virus. J Virol 1990; 64: 1716–1725.
Melki R, Gaudin Y, Blondel D . Interaction between tubulin and the viral matrix protein of vesicular stomatitis virus: possible implications in the viral cytopathic effect. Virology 1994; 202: 339–347.
Lin X, Chen X, Wei Y, Zhao J, Fan L, Wen Y et al. Efficient inhibition of intraperitoneal human ovarian cancer growth and prolonged survival by gene transfer of vesicular stomatitis virus matrix protein in nude mice. Gynecol Oncol 2007; 104: 540–546.
Zhong Q, Wen YJ, Yang HS, Luo H, Fu AF, Yang F et al. Efficient inhibition of cisplatin-resistant human ovarian cancer growth and prolonged survival by gene transferred vesicular stomatitis virus matrix protein in nude mice. Ann Oncol 2008; 19: 1584–1591.
Shi W, Tang Q, Chen X, Cheng P, Jiang P, Jing X et al. Antitumor and antimetastatic activities of vesicular stomatitis virus matrix protein in a murine model of breast cancer. J Mol Med 2009; 87: 493–506.
Bell JC, Lichty B, Stojdl D . Getting oncolytic virus therapies off the ground. Cancer Cell 2003; 4: 7–11.
Acknowledgements
This work was supported by National 973 Project (No. 2010CB529900) and National Natural Science Foundation (No. 30973452).
Author contributions: Xiaomei Jing, Wei Shi, Qingqing Tang contributed to the experimental work, data analysis and manuscript writing; Yanjun Wen and Jiong Li contributed to the construction of expression vector and preparation of liposome; Xiancheng Chen was engaged in devising the project and revising the manuscript.
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Jing, XM., Wen, YJ., Shi, W. et al. VSV-MP gene therapy strategy inhibits tumor growth in nude mice model of human lung adenocarcinoma. Cancer Gene Ther 19, 101–109 (2012). https://doi.org/10.1038/cgt.2011.71
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DOI: https://doi.org/10.1038/cgt.2011.71
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