Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6117051 | Immunology Letters | 2015 | 6 Pages |
Abstract
Activation of the NF-κB pathway is causally linked to initiation and progression of diverse cancers. Therefore, IKKβ, the key regulatory kinase of the canonical NF-κB pathway, should be a logical target for cancer treatment. However, existing IKKβ inhibitors are known to induce paradoxical immune activation, which limits their clinical usefulness. Recently, we identified a quinoxaline urea analog 13-197 as a novel IKKβ inhibitor that delays tumor growth without significant adverse effects in xenograft tumor models. In the present study, we found that 13-197 had little effect on LPS-induced NF-κB target gene induction by primary mouse macrophages while maintaining considerable anti-proliferative activities. These characteristics may explain absence of inflammatory side effects in animals treated with 13-197. Our data also demonstrate that the inflammation and proliferation-related functions of IKKβ can be uncoupled, and highlight the utility of 13-197 to dissect these downstream pathways.
Keywords
IκB3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromideS6KIKKβM-CSFDulbecco’s modified essential medium4E-BP1BMDMGSK3TLRNF-κBTSCHRPEGTAPI3KTNFαLPSDMEMFBSDMSOIκB kinase βMTTEDTAethyleneglycoltetraacetic acidEthylenediaminetetraacetic acidinterleukintuberous sclerosistumor necrosis factor αToll-like receptorstandard error of the meanDimethyl sulfoxidefetal bovine serumInflammatory cytokinesConditioned mediumphosphoinositide 3-kinaselipopolysaccharidebone marrow-derived macrophagemacrophage colony-stimulating factorBone marrow-derived macrophagesSEMinhibitor of NF-κBHorseradish peroxidaseribosomal protein S6 kinaseglycogen synthase kinase 3
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Authors
Dulce Maroni, Sandeep Rana, Chandrani Mukhopadhyay, Amarnath Natarajan, Mayumi Naramura,