Triptolide Mediated-Inhibition of Interferon Signaling Enhances Vesicular Stomatitis Virus based Oncolysis

Preclinical and clinical trials demonstrated that oncolytic viruses (OVs) are a promising new therapeutic approach to treat multiple types of cancer. To further improve their viral oncolysis, experimental strategies are now combining OVs with different cytotoxic compounds. In the current study, we investigated the capacity of triptolide - a natural anti-cancer molecule - to enhance vesicular stomatitis virus (VSV) oncolysis in OV-resistant cancer cells. Triptolide treatment increased VSV replication in the human prostate cancer cell line PC3 and in other VSV-resistant cells in a dose and time-dependent manner in vitro and in vivo. Mechanistically, TPL inhibited the innate antiviral response by blocking the type I interferon (IFN) signaling, downstream of IRF3 activation. Furthermore, triptolide enhanced VSVinduced apoptosis in a dose dependent fashion in VSV-resistant cells, as measured by annexin-V, cleaved caspase-3 and B-cell lymphoma 2 staining. In vivo, using the TSA and PC3 mouse xenograft models, combination treatment with VSV and triptolide delayed tumor growth and prolonged survival of tumorbearing animals by enhancing viral replication. Together, these results demonstrate that triptolide inhibition of IFN production sensitizes prostate cancer cells to VSV replication and virus-mediated apoptosis