Triptolide-mediated inhibition of interferon signaling enhances vesicular stomatitis virus-based oncolysis

Mol Ther. 2013 Nov;21(11):2043-53. doi: 10.1038/mt.2013.187. Epub 2013 Aug 28.


Preclinical and clinical trials demonstrated that use of oncolytic viruses (OVs) is 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 this study, we investigated the capacity of triptolide - a natural anticancer 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, triptolide (TPL) inhibited the innate antiviral response by blocking type I interferon (IFN) signaling, downstream of IRF3 activation. Furthermore, triptolide-enhanced VSV-induced 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 mammary adenocarcinoma and PC3 mouse xenograft models, combination treatment with VSV and triptolide delayed tumor growth and prolonged survival of tumor-bearing 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology
  • Apoptosis
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Diterpenes / pharmacology*
  • Epoxy Compounds / pharmacology
  • Female
  • HEK293 Cells
  • Humans
  • Interferons / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Neoplasms / virology
  • Neoplasms, Experimental
  • Oncolytic Virotherapy / methods*
  • Oncolytic Viruses / genetics
  • Oncolytic Viruses / immunology
  • Oncolytic Viruses / physiology*
  • Phenanthrenes / pharmacology*
  • Signal Transduction / drug effects*
  • Vesicular stomatitis Indiana virus / genetics
  • Vesicular stomatitis Indiana virus / immunology
  • Vesicular stomatitis Indiana virus / physiology*
  • Virus Replication
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents, Alkylating
  • Diterpenes
  • Epoxy Compounds
  • Phenanthrenes
  • triptolide
  • Interferons