Histone Deacetylase Inhibitors Augment Antitumor Efficacy of Herpes-based Oncolytic Viruses

• Published in: Molecular therapy Vol. 16; no. 9; pp. 1546 - 1555
• Main Authors: Otsuki, Akihiro, Patel, Ankita, Kasai, Kazue, Suzuki, Masataka, Kurozumi, Kazuhiko, Antonio Chiocca, E, Saeki, Yoshinaga
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2008; Elsevier Limited
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Brain Neoplasms - genetics; Brain Neoplasms - therapy; Brain Neoplasms - virology; Butyrates - therapeutic use; Cancer; Cytotoxicity; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors - therapeutic use; Gene expression; Gene therapy; Genetic Therapy; Genetic Vectors - therapeutic use; Glioma - drug therapy; Glioma - genetics; Glioma - virology; Herpes viruses; Herpesviridae Infections - drug therapy; Herpesviridae Infections - genetics; Herpesviridae Infections - virology; Herpesvirus 1, Human - genetics; Herpesvirus 1, Human - metabolism; Histone Deacetylase Inhibitors; Humans; Immunotherapy; Infections; Interferon beta-1a; Interferon-beta - therapeutic use; Kinases; Melanoma - drug therapy; Melanoma - genetics; Melanoma - virology; Mice; Mice, Nude; Neurosciences; Oncology; Oncolytic Viruses; Propagation; Proteins; Recombinant Proteins - therapeutic use; Tumor Cells, Cultured; Valproic Acid - therapeutic use; Viral infections; Virus Replication - drug effects; Xenograft Model Antitumor Assays; United States > US; Ohio
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1038/mt.2008.155

Replication-conditional (oncolytic) mutants of herpes simplex virus (HSV), are considered promising therapeutic alternatives for human malignancies, and chemotherapeutic adjuvants are increasingly sought to augment their efficacy. Histone deacetylase (HDAC) inhibitors are a new class of antineoplastic agents because of their potent activity in growth arrest, differentiation, and apoptotic death of cancer cells. The ability of the HDAC inhibitors to upregulate exogenous transgene expression and inhibit interferon (IFN) responses prompted our exploration of their use in improving the antitumor efficacy of oncolytic HSV. We discovered that the yield of viral progeny increased significantly when cultured glioma cells were treated with HDAC inhibitors before viral infection. Valproic acid (VPA), a commonly used antiepileptic agent with HDAC inhibitory activity, proved most effective when used to treat glioma cells before viral infection, but not concomitantly with viral infection. Pretreatment with VPA inhibited the induction of several IFN-responsive antiviral genes, augmented the transcriptional level of viral genes, and improved viral propagation, even in the presence of type I IFNs. Moreover, VPA pretreatment improved the propagation and therapeutic efficacy of oncolytic HSV in a human glioma xenograft model in vivo. These findings indicate that HDAC inhibitors can improve the efficacy of tumor virotherapies.