STAT3 inhibition reduces toxicity of oncolytic VSV and provides a potentially synergistic combination therapy for hepatocellular carcinoma.
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.
II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
S
S
Marozin
II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
J
J
Altomonte
II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
K A
KA
Muñoz-Álvarez
Medizinische Klinik und Poliklinik II, University Hospital Grosshadern, University of Munich, Munich, Germany.
A
A
Rizzani
Medizinische Klinik und Poliklinik II, University Hospital Grosshadern, University of Munich, Munich, Germany.
E N
EN
De Toni
Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, University Hospital Grosshadern, University of Munich, Munich, Germany.
W E
WE
Thasler
II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
R M
RM
Schmid
II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
O
O
Ebert
D000636:Aminosalicylic Acids / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000628:therapy* / Q000821:virology; D003131:Combined Modality Therapy; D006801:Humans; D008113:Liver Neoplasms / Q000628:therapy* / Q000821:virology; D008297:Male; D051379:Mice; D050130:Oncolytic Virotherapy / Q000009:adverse effects; D051381:Rats; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D014721:Vesicular stomatitis Indiana virus
D000636:Aminosalicylic Acids; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; C520337:NSC 74859; D050796:STAT3 Transcription Factor