Inhibition of the inflammatory cytokine TNF-α increases adenovirus activity in ovarian cancer via modulation of cIAP1/2 expression

Mol Ther. 2011 Mar;19(3):490-9. doi: 10.1038/mt.2010.247. Epub 2010 Nov 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae* / drug effects
  • Adenoviridae* / immunology
  • Adenoviridae* / metabolism
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Knockdown Techniques
  • Humans
  • Infliximab
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Oncolytic Virotherapy
  • Oncolytic Viruses* / drug effects
  • Oncolytic Viruses* / immunology
  • Oncolytic Viruses* / metabolism
  • Ovarian Neoplasms* / metabolism
  • Ovarian Neoplasms* / pathology
  • Ovarian Neoplasms* / therapy
  • Ovarian Neoplasms* / virology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Survival Analysis
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Virus Replication / drug effects
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal
  • Inhibitor of Apoptosis Proteins
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • Infliximab