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Eriocalyxin B inhibits nuclear factor-kappaB activation by interfering with the binding of both p65 and p50 to the response element in a noncompetitive manner.
- Source :
-
Molecular pharmacology [Mol Pharmacol] 2006 Dec; Vol. 70 (6), pp. 1946-55. Date of Electronic Publication: 2006 Aug 29. - Publication Year :
- 2006
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Abstract
- Nuclear factor-kappaB (NF-kappaB) has been recognized to play a critical role in cell survival and inflammatory processes. It has become a target for intense drug development for the treatment of cancer, inflammatory, and autoimmune diseases. Here, we describe a potent NF-kappaB inhibitor, eriocalyxin B (Eri-B), an ent-kauranoid isolated from Isodon eriocalyx, an anti-inflammatory remedy. The presence of two alpha,beta-unsaturated ketones give this compound the uniqueness among the ent-kauranoids tested. Eri-B inhibited the NF-kappaB transcriptional activity but not that of cAMP response element-binding protein. It suppressed the transcription of NF-kappaB downstream gene products including cyclooxygenase-2 and inducible nitric-oxide synthase induced by tumor necrosis factor-alpha or lipopolysaccharide in macrophages and hepatocarcinoma cells. Chromatin immunoprecipitation assay indicated that Eri-B selectively blocked the binding between NF-kappaB and the response elements in vivo without affecting the nuclear translocation of the transcription factor. Down-regulation of the endogenous p65 protein sensitized the cells toward the action of the compound. Furthermore, in vitro binding assays suggested that Eri-B reversibly interfered with the binding of p65 and p50 subunits to the DNA in a noncompetitive manner. In summary, this study reveals the novel action of a potent NF-kappaB inhibitor that could be potentially used for the treatment of a variety of NF-kappaB-associated diseases. Modification of the structure of this class of compounds becomes the key to the control of the behavior of the compound against different cellular signaling pathways.
- Subjects :
- Base Sequence
Cell Line, Tumor
Chromatin Immunoprecipitation
Cyclooxygenase 2 metabolism
DNA Primers
Electrophoretic Mobility Shift Assay
Humans
NF-kappa B metabolism
Nitric Oxide Synthase Type II metabolism
Protein Binding
Protein Transport
Reverse Transcriptase Polymerase Chain Reaction
Tumor Necrosis Factor-alpha pharmacology
Diterpenes pharmacology
NF-kappa B antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0026-895X
- Volume :
- 70
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Molecular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 16940413
- Full Text :
- https://doi.org/10.1124/mol.106.028480