title: Triptolide-mediated inhibition of interferon signaling enhances vesicular stomatitis virus-based oncolysis.
abstract: 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.
authors.affiliation: Department of Medicine, Lady Davis Institute-Jewish General Hospital, McGill University, Montréal, Québec, Canada.
authors.forename: Fethia
authors.initials: F
authors.lastname: Ben Yebdri
authors.forename: Julien
authors.initials: J
authors.lastname: Van Grevenynghe
authors.forename: Vera A
authors.initials: VA
authors.lastname: Tang
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Goulet
authors.forename: Jian Hui
authors.initials: JH
authors.lastname: Wu
authors.forename: David F
authors.initials: DF
authors.lastname: Stojdl
authors.forename: John
authors.initials: J
authors.lastname: Hiscott
authors.forename: Rongtuan
authors.initials: R
authors.lastname: Lin
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004224:Diterpenes / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007372:Interferons / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000276:immunology / Q000628:therapy* / Q000821:virology; D009374:Neoplasms, Experimental; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D010616:Phenanthrenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; C001899:triptolide; D007372:Interferons