Anti-tumor efficacy of oncolytic reovirus against gastrointestinal stromal tumor cells
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Yusuke Inagaki1, Eiji Kubota1, Yoshinori Mori2, Mineyoshi Aoyama3, Hiromi Kataoka1, Randal N. Johnston4 and Takashi Joh1
1Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-Ku, Nagoya, Japan
2Department of Gastroenterology, Nagoya City West Medical Center, Kita-Ku, Nagoya, Japan
3Department of Pathobiology, Nagoya City University Graduate School of Pharmaceutical Sciences, Mizuho-Ku, Nagoya, Japan
4Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
Eiji Kubota, email: [email protected]
Keywords: reovirus; gastrointestinal stromal tumor (GIST); imatinib; fas; apoptosis
Received: August 09, 2017 Accepted: December 03, 2017 Published: December 18, 2017
Imatinib, a multitargeted receptor tyrosine kinase inhibitor, is used as the standard initial therapy against inoperable gastrointestinal stromal tumor (GIST). However, GIST can acquire resistance to imatinib within several years of therapy. The development of oncolytic reovirus as an anticancer agent has expanded to many clinical trials for various tumors. Here, we investigated whether reovirus has antitumor activity against GIST cells in the setting of imatinib sensitivity in vitro and in vivo. Cell proliferation and apoptosis assays were performed using a human GIST cell line, GIST-T1, and imatinib-resistant GIST (GIST-IR) cells that we established. The molecular pathways responsible for cell damage by reovirus were explored using PCR-arrays and Western blots. Reovirus significantly induced apoptotic cell death in GIST-T1 and GIST-IR cells in vitro, despite differences in the activation of receptor tyrosine kinase pathways between GIST-T1 and GIST-IR. Molecular assays indicated the possibility that reovirus induces apoptotic cell death via Fas signaling. Furthermore, in vivo mouse tumor xenograft models demonstrated a significant anti-tumor effect of reovirus on both GIST-T1 and GIST-IR cells. Our results demonstrate the therapeutic potential of reovirus against GIST.
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