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STAT3 inhibition reduces toxicity of oncolytic VSV and provides a potentially synergistic combination therapy for hepatocellular carcinoma

Cancer Gene Therapy volume 22, pages 317–325 (2015)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is a refractory malignancy with a high mortality and increasing worldwide incidence rates, including the United States and central Europe. In this study, we demonstrate that a specific inhibitor of signal transducer and activator of transcription 3 (STAT3), NSC74859, efficiently reduces HCC cell proliferation and can be successfully combined with oncolytic virotherapy using vesicular stomatitis virus (VSV). The potential benefits of this combination treatment are strengthened by the ability of NSC74859 to protect primary hepatocytes and nervous system cells against virus-induced cytotoxicity, with an elevation of the VSV maximum tolerated dose in mice. Hereby we propose a strategy for improving the current regimen for HCC treatment and seek to further explore the molecular mechanisms underlying selective oncolytic specificity of VSV.

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Acknowledgements

We thank Dr Douglas Lyles and Dr Asit Pattnaik for providing anti-VSV and anti-VSV M antibodies. We also thank Miss Maren Ilowski and Miss Barbara Donabauer for primary human hepatocyte isolation. We thank Dr Katharina Eisenaecher for useful suggestions on IP-10 ELISA. This work is supported in part by the German Cancer Aid (Max-Eder Research Program), the Federal Ministry of Education and Research (Grant 01GU0505) and the Deutsche Forschungsgemeinschaft (DFG) under Grant Agreement No. SFB 824 subprojects C7, Z1, Z2 and Z3.

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Authors and Affiliations

  1. II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

    S Marozin, J Altomonte, K A Muñoz-Álvarez, R M Schmid & O Ebert

  2. Medizinische Klinik und Poliklinik II, University Hospital Grosshadern, University of Munich, Munich, Germany

    A Rizzani & E N De Toni

  3. Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, University Hospital Grosshadern, University of Munich, Munich, Germany

    W E Thasler

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  1. S Marozin
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Correspondence to O Ebert.

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Marozin, S., Altomonte, J., Muñoz-Álvarez, K. et al. STAT3 inhibition reduces toxicity of oncolytic VSV and provides a potentially synergistic combination therapy for hepatocellular carcinoma. Cancer Gene Ther 22, 317–325 (2015). https://doi.org/10.1038/cgt.2015.23

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