Inhibition of type i interferon-mediated antiviral action in human glioma cells by the IKK inhibitors BMS-345541 and TPCA-1

Ziyun Du, Michael Whitt, Jessica Baumann, Jo Meagan Garner, Christopher L. Morton, Andrew M. Davidoff, Lawrence Pfeffer

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The nuclear factor-kappa B (NFκB) signal transduction pathway plays an important role in immunity, inflammation, cell growth, and survival. Since dysregulation of this pathway results in high, constitutive NFκB activation in various cancers and immune disorders, the development of specific drugs to target this pathway has become a focus for treating these diseases. NFκB regulates various aspects of the cellular response to interferon (IFN). However, the role of the upstream regulator of the NFκB signaling pathway, the inhibitor of κB kinase (IKK) complex, on IFN function has not been examined. In the present study, we examined the effects of 2 IKK inhibitors, N-(1,8-Dimethylimidazo[1,2-a]quinoxalin-4-yl)-1,2-ethanediamine hydrochloride (BMS-345541) and 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3- thiophenecarboxamide (TPCA-1), on IFN action in several human glioma cell lines. IKK inhibitors inhibit glioma cell proliferation, as well as TNF-induced RelA (p65) nuclear translocation and NFκB-dependent IL8 gene expression. Importantly, BMS-345541 and TPCA-1 differentially inhibit IFN-induced gene expression, completely suppressing MX1 and GBP1 gene expression, while having only a minor effect on ISG15 expression. Furthermore, these IKK inhibitors displayed marked differences in blocking IFN-induced antiviral action against cytopathic effects and replication of vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV). Our results show that the IKK complex plays an important function in IFN-induced gene expression and antiviral activity. Since VSV and EMCV are oncolytic viruses used in cancer therapy, our results indicate the potential synergy in combining IKK inhibitors with oncolytic viruses.

Original languageEnglish (US)
Pages (from-to)368-377
Number of pages10
JournalJournal of Interferon and Cytokine Research
Volume32
Issue number8
DOIs
StatePublished - Aug 1 2012

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Glioma
NF-kappa B
Interferons
Antiviral Agents
Oncolytic Viruses
Encephalomyocarditis virus
Gene Expression
Vesicular Stomatitis
ethylenediamine
Viruses
Quinoxalines
Immune System Diseases
Interleukin-8
4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline
2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide
Immunity
Signal Transduction
Neoplasms
Cell Survival
Phosphotransferases

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cell Biology
  • Virology

Cite this

Inhibition of type i interferon-mediated antiviral action in human glioma cells by the IKK inhibitors BMS-345541 and TPCA-1. / Du, Ziyun; Whitt, Michael; Baumann, Jessica; Garner, Jo Meagan; Morton, Christopher L.; Davidoff, Andrew M.; Pfeffer, Lawrence.

In: Journal of Interferon and Cytokine Research, Vol. 32, No. 8, 01.08.2012, p. 368-377.

Research output: Contribution to journalArticle

Du, Ziyun ; Whitt, Michael ; Baumann, Jessica ; Garner, Jo Meagan ; Morton, Christopher L. ; Davidoff, Andrew M. ; Pfeffer, Lawrence. / Inhibition of type i interferon-mediated antiviral action in human glioma cells by the IKK inhibitors BMS-345541 and TPCA-1. In: Journal of Interferon and Cytokine Research. 2012 ; Vol. 32, No. 8. pp. 368-377.
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