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

Fethia Ben Yebdri1, Julien Van Grevenynghe, Vera A Tang

  • 1Department of Medicine, Lady Davis Institute-Jewish General Hospital, McGill University, Montréal, Québec, Canada.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|August 30, 2013
PubMed

Insights

Triptolide enhances oncolytic virus therapy by blocking the antiviral response in cancer cells. This combination therapy promotes virus replication and cancer cell death, improving treatment outcomes.

Area of Science:

  • Oncology
  • Virology
  • Immunology

Background:

  • Oncolytic viruses (OVs) show promise for cancer treatment.
  • Combining OVs with cytotoxic agents may improve efficacy.
  • OV-resistant cancer cells present a therapeutic challenge.

Purpose of the Study:

  • To investigate triptolide's potential to enhance vesicular stomatitis virus (VSV) oncolysis in OV-resistant cancer cells.
  • To elucidate the mechanisms by which triptolide affects VSV replication and cancer cell apoptosis.

Main Methods:

  • In vitro and in vivo studies using prostate cancer cell line PC3 and mouse xenograft models.
  • Assessed VSV replication, type I interferon (IFN) signaling, and apoptosis markers (annexin-V, cleaved caspase-3, BCL2).
  • Treated cells and animals with triptolide and VSV, alone and in combination.

Main Results:

  • Triptolide significantly increased VSV replication in VSV-resistant cancer cells in a dose- and time-dependent manner.
  • Triptolide inhibited the innate antiviral response by blocking type I IFN signaling downstream of IRF3.
  • Combination therapy with VSV and triptolide enhanced virus-mediated apoptosis and delayed tumor growth in vivo.
  • Treated animals showed prolonged survival in xenograft models.

Conclusions:

  • Triptolide sensitizes prostate cancer cells to VSV replication by inhibiting IFN production.
  • Triptolide enhances VSV-mediated apoptosis in resistant cancer cells.
  • The combination of VSV and triptolide represents a promising strategy for overcoming OV resistance in cancer therapy.

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