title: Inhibition of the inflammatory cytokine TNF-α increases adenovirus activity in ovarian cancer via modulation of cIAP1/2 expression.
abstract: Oncolytic adenoviruses show promise as a cancer treatment. However, they generate acute inflammatory responses with production of cytokines, including tumor necrosis factor-α (TNF-α). We investigated whether inhibition of TNF-α augments efficacy of the E1A CR2-deleted adenovirus dl922-947 in ovarian cancer. dl922-947 induced transcription of TNF-α and its downstream signaling targets interleukin-6 and -8 (IL-6 and IL-8) in ovarian cancer cells. In vitro, RNAi-mediated knockdown of TNF-α reduced production of multiple inflammatory cytokines after infection and increased ovarian cancer cell sensitivity to virus cytotoxicity, as did treatment with the anti-TNF-α antibody infliximab. In vivo, stable knockdown of TNF-α in IGROV-1 xenografts increased the anticancer activity of dl922-947. In addition, inhibition of TNF-α using monoclonal antibodies also improved dl922-947 efficacy. This increased efficacy resulted from suppression of cellular inhibitor of apoptosis-1 and -2 (cIAP1 and cIAP2) transcription in malignant cells and a consequent increase in caspase-mediated apoptosis. These findings suggest that TNF-α acts as a survival factor in adenovirus-infected cells. Combining TNF-α inhibition with oncolytic adenoviruses could improve antitumor activity in clinical trials.
authors.affiliation: Centres for Molecular Oncology and Imaging, Institute of Cancer, Barts and The London School of Medicine and Dentistry, London, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Salako
authors.forename: Hagen
authors.initials: H
authors.lastname: Kulbe
authors.forename: Carin K
authors.initials: CK
authors.lastname: Ingemarsdotter
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Pirlo
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Williams
authors.forename: Michelle
authors.initials: M
authors.lastname: Lockley
authors.forename: Frances R
authors.initials: FR
authors.lastname: Balkwill
authors.forename: Iain A
authors.initials: IA
authors.lastname: McNeish
mesh_terms: D000256:Adenoviridae / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D000069285:Infliximab; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy / Q000821:virology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab