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

被引：26

作者：

Ben Yebdri, Fethia ^{[1
]}

Van Grevenynghe, Julien ^{[1
,2
]}

Tang, Vera A. ^{[3
]}

Goulet, Marie-Line ^{[1
]}

Wu, Jian Hui ^{[1
]}

Stojdl, David F. ^{[3
]}

Hiscott, John ^{[1
,2
]}

Lin, Rongtuan ^{[1
]}

机构：

[1] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Med, Montreal, PQ H3T 1E2, Canada

[2] VGTI Florida, Div Infect Dis, Port St Lucie, FL USA

[3] Univ Ottawa, Dept Pediat, Childrens Hosp, Eastern Ontario Res Inst, Ottawa, ON K1N 6N5, Canada

来源：

MOLECULAR THERAPY | 2013年 / 21卷 / 11期

基金：

加拿大健康研究院;

关键词：

CHRONIC LYMPHOCYTIC-LEUKEMIA; KAPPA-B ACTIVATION; CANCER-CELLS; TRIPTERYGIUM-WILFORDII; EXTRACELLULAR ATP; SOLID TUMORS; PATHWAY; APOPTOSIS; REPLICATION; ANTICANCER;

D O I：

10.1038/mt.2013.187

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：2043 / 2053

页数：11

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