Eriocalyxin B Inhibits Nuclear Factor-κB Activation by Interfering with the Binding of Both p65 and p50 to the Response Element in a Noncompetitive Manner
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| Title: | Eriocalyxin B Inhibits Nuclear Factor-κB Activation by Interfering with the Binding of Both p65 and p50 to the Response Element in a Noncompetitive Manner |
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| Authors: | Cheng, YC, Leung, CH, Grill, SP, Lam, W, Gao, W, Sun, HD |
| Source: | Molecular Pharmacology. 70:1946-1955 |
| Publisher Information: | Elsevier BV, 2006. |
| Publication Year: | 2006 |
| Subject Terms: | 0301 basic medicine, Chromatin Immunoprecipitation, Dna Primers, Nitric Oxide Synthase Type II, Electrophoretic Mobility Shift Assay, Diterpenes - Pharmacology, Cell Line, 03 medical and health sciences, Cell Line, Tumor, Humans, Cyclooxygenase 2 - Metabolism, DNA Primers, 0303 health sciences, Tumor, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, Tumor Necrosis Factor-alpha, NF-kappa B, 3. Good health, Protein Transport, Cyclooxygenase 2, Nitric Oxide Synthase Type Ii - Metabolism, Tumor Necrosis Factor-Alpha - Pharmacology, Diterpenes, Nf-Kappa B - Antagonists & Inhibitors - Metabolism, Protein Binding |
| Description: | 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. |
| Document Type: | Article |
| Language: | English |
| ISSN: | 0026-895X |
| DOI: | 10.1124/mol.106.028480 |
| Access URL: | https://pubmed.ncbi.nlm.nih.gov/16940413 http://www.irgrid.ac.cn/handle/1471x/1000651 https://molpharm.aspetjournals.org/content/70/6/1946 https://molpharm.aspetjournals.org/content/molpharm/early/2006/08/29/mol.106.028480.full.pdf http://molpharm.aspetjournals.org/lookup/doi/10.1124/mol.106.028480 https://www.ncbi.nlm.nih.gov/pubmed/16940413 http://hub.hku.hk/handle/10722/168067 http://hdl.handle.net/10722/168067 |
| Rights: | Elsevier TDM |
| Accession Number: | edsair.doi.dedup.....3e6b9ea8e5655a06424a8c74b74caa5c |
| Database: | OpenAIRE |
Nájsť tento článok vo Web of Science | 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. |
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| ISSN: | 0026895X |
| DOI: | 10.1124/mol.106.028480 |