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Published on: April 15, 2016
Overexpression of Smac by an Armed Vesicular Stomatitis Virus Overcomes Tumor Resistance
Weike Li1, Ravi Chakra Turaga2, Xin Li2
1Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA.
Abstract:
Despite reports of successful clinical cases, many tumors appear to resist infection by oncolytic viruses (OVs). To circumvent this problem, an armed vesicular stomatitis virus was constructed by inserting a transgene to express Smac/DIABLO during virus infection (VSV-S). Endogenous Smac in HeLa cells was diminished during wtVSV infection, whereas the Smac level was enhanced during VSV-S infection. Apoptosis was readily induced by VSV-S, but not wtVSV, infection. More importantly, the tumor volume was reduced to a larger extent when xenografts of 4T1 cells in BALB/c mice and OV-resistant T-47D cells in nude mice were intratumorally injected with VSV-S. VSV-S represents a novel mechanism to overcome tumor resistance, resulting in more significant tumor regression due to enhanced apoptosis.
Insights
This study introduces an armed oncolytic virus (VSV-S) that overcomes tumor resistance by enhancing Smac/DIABLO expression. VSV-S effectively induced apoptosis and significantly reduced tumor volume in preclinical models.
Area of Science:
- Oncolytic virotherapy
- Cancer biology
- Molecular virology
Background:
- Tumor resistance to oncolytic viruses (OVs) limits their clinical efficacy.
- Endogenous Smac/DIABLO levels decrease during wild-type VSV infection, potentially contributing to resistance.
Purpose of the Study:
- To engineer an oncolytic virus expressing Smac/DIABLO to overcome tumor resistance.
- To evaluate the efficacy of the engineered virus in inducing apoptosis and reducing tumor growth.
Main Methods:
- Construction of an armed vesicular stomatitis virus (VSV-S) expressing Smac/DIABLO.
- Assessment of Smac/DIABLO levels in infected cells.
- Evaluation of apoptosis induction by VSV-S and wild-type VSV (wtVSV).
- Intratumoral injection of VSV-S into xenograft models (4T1 and T-47D cells).
Main Results:
- VSV-S infection enhanced Smac/DIABLO levels compared to wtVSV infection.
- VSV-S robustly induced apoptosis, whereas wtVSV did not.
- Significant reduction in tumor volume was observed in mice treated with VSV-S.
Conclusions:
- VSV-S represents a novel strategy to overcome oncolytic virus resistance in tumors.
- Enhanced apoptosis mediated by VSV-S leads to improved tumor regression.
- This armed oncolytic virus shows promise for enhanced cancer therapy.
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