title: Oncolytic reovirus combined with trastuzumab enhances antitumor efficacy through TRAIL signaling in human HER2-positive gastric cancer cells.
abstract: The human epidermal growth factor receptor 2 (HER2)-targeting agent, trastuzumab, is effective for HER2-overexpressing gastric cancer therapy. As oncolytic reovirus is currently undergoing clinical trials internationally, we wanted to explore whether combination therapy using trastuzumab and reovirus might provide a novel, more effective therapeutic option for gastric cancer. Cell proliferation and cell apoptosis were examined in vitro, while molecular analysis of pathways responsible for cell damage was examined using polymerase chain reaction array. Activation of the proteins related to apoptosis, cell growth and survival was detected by Western blotting. Mouse tumor xenograft models were used to examine antitumor activity in vivo. Reovirus sensitized HER2-overexpressing gastric cancer cells to undergo apoptosis. Both in vitro and in vivo studies provided evidence that the combination therapy is a more powerful modality against HER2-overexpressing gastric cancer cells than treatment using a single agent. Molecular analysis indicated that combination therapy induced significantly higher levels of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in cancer cells. Antibody against TRAIL strongly inhibited cell toxicity caused by the combined treatment. These data suggest that reovirus may augment trastuzumab-induced cytotoxicity in gastric cancer cells.
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan; Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Hamano
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan. Electronic address: ao.mine@med.nagoya-cu.ac.jp.
authors.forename: Mineyoshi
authors.initials: M
authors.lastname: Aoyama
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kataoka
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Ebi
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kubota
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Mizoshita
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanida
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors.forename: Randal N
authors.initials: RN
authors.lastname: Johnston
authors.affiliation: Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Asai
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Joh
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012087:Reoviridae / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D053221:TNF-Related Apoptosis-Inducing Ligand; D000068878:Trastuzumab; C505653:TNFSF10 protein, human; C508053:ERBB2 protein, human
keywords: Gastric cancer cell; Human epidermal growth factor receptor 2 (HER2); Reovirus; Trastuzumab; Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)