| Autor: |
Nancy H. Colburn, Matthew R. Young, Alyson R. Baker, James B. McMahon, Kirk R. Gustafson, Heidi R. Bokesch, Curtis J. Henrich, Moon-Il Kang |
| Rok vydání: |
2023 |
| DOI: |
10.1158/1535-7163.c.6531798.v1 |
| Popis: |
NSC 676914 has been identified as a selective nuclear factor-κB (NF-κB) inhibitor that does not inhibit cell proliferation. This compound was originally identified in a high-throughput cell-based assay for activator protein-1 (AP-1) inhibitors using synthetic compound libraries and the National Cancer Institute natural product repository. NSC 676914 shows activity against NF-κB in luciferase reporter assays at concentrations much less than the IC50 for AP-1. A serum response element reporter used as a specificity control and indicator of cell proliferation was relatively insensitive to the compound. Pretreatment with NSC 676914 is here shown to repress 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced IκB-α phosphorylation and translocation of p65/50 to the nucleus but not the processing of p52 from p100, suggesting the inhibition of NF-κB regulator IKKβ rather than IKKα. Inhibition of NF-κB activation occurred as a consequence of blocking phosphorylation of IKK. Induction of IκB-α phosphorylation by TPA was diminished by pretreatment of NSC 676914 even at 1.1 μmol/L. In contrast, kinases c-Jun-NH2-kinase and extracellular signal-regulated kinases 1 and 2, important for AP-1 activation, showed no significant repression by this compound. Furthermore, a Matrigel invasion assay with breast cancer cell lines and a transformation assay in mouse JB6 cells revealed that TPA-induced invasion and transformation responses were completely repressed by this compound. These results suggest that NSC 676914 could be a novel inhibitor having potential therapeutic activity to target NF-κB for cancer treatment or prevention. [Mol Cancer Ther 2009;8(3):571–81] |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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