Abstract |
NSC 676914 has been identified as a selective nuclear factor-kappaB ( NF-kappaB) 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-kappaB 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 IkappaB-alpha phosphorylation and translocation of p65/50 to the nucleus but not the processing of p52 from p100, suggesting the inhibition of NF-kappaB regulator IKKbeta rather than IKKalpha. Inhibition of NF-kappaB activation occurred as a consequence of blocking phosphorylation of IKK. Induction of IkappaB-alpha phosphorylation by TPA was diminished by pretreatment of NSC 676914 even at 1.1 mumol/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-kappaB for cancer treatment or prevention.
|
Authors | Moon-Il Kang, Curtis J Henrich, Heidi R Bokesch, Kirk R Gustafson, James B McMahon, Alyson R Baker, Matthew R Young, Nancy H Colburn |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 8
Issue 3
Pg. 571-81
(Mar 2009)
ISSN: 1535-7163 [Print] United States |
PMID | 19258426
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
|
Chemical References |
- 2-(4-((4-amino-2-methylphenyl)diazenyl)phenylsulfonyl)ethanesulfonoperoxoic acid
- Antineoplastic Agents
- Azo Compounds
- I-kappa B Proteins
- NF-kappa B
- Small Molecule Libraries
- Sulfonic Acids
- Transcription Factor AP-1
|
Topics |
- Antineoplastic Agents
(isolation & purification, pharmacology, therapeutic use)
- Azo Compounds
(pharmacology, therapeutic use)
- Breast Neoplasms
(drug therapy, genetics, pathology)
- Cell Nucleus
(drug effects, metabolism)
- Cell Proliferation
(drug effects)
- Cells, Cultured
- Drug Screening Assays, Antitumor
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- I-kappa B Proteins
(metabolism)
- Models, Biological
- NF-kappa B
(antagonists & inhibitors, genetics)
- Phosphorylation
(drug effects)
- Small Molecule Libraries
(analysis)
- Substrate Specificity
- Sulfonic Acids
(pharmacology, therapeutic use)
- Transcription Factor AP-1
(antagonists & inhibitors, genetics)
- Transfection
|