title: Inhibition of type I interferon-mediated antiviral action in human glioma cells by the IKK inhibitors BMS-345541 and TPCA-1.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Ziyun
authors.initials: Z
authors.lastname: Du
authors.forename: Michael A
authors.initials: MA
authors.lastname: Whitt
authors.forename: Jessica
authors.initials: J
authors.lastname: Baumann
authors.forename: Jo Meagan
authors.initials: JM
authors.lastname: Garner
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morton
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Pfeffer
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004686:Encephalomyocarditis virus / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D007370:Interferon Type I / Q000276:immunology / Q000494:pharmacology*; D016209:Interleukin-8 / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects / Q000502:physiology
chemical_list: C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D000577:Amides; D000998:Antiviral Agents; D007093:Imidazoles; D007370:Interferon Type I; D016209:Interleukin-8; D016328:NF-kappa B; D011810:Quinoxalines; D013876:Thiophenes; C499326:2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide; D051550:I-kappa B Kinase