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Article: Novel mechanism of inhibition of nuclear factor-κB DNA-binding activity by diterpenoids isolated from Isodon rubescens

TitleNovel mechanism of inhibition of nuclear factor-κB DNA-binding activity by diterpenoids isolated from Isodon rubescens
Authors
Issue Date2005
PublisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.org
Citation
Molecular Pharmacology, 2005, v. 68 n. 2, p. 286-297 How to Cite?
AbstractThe development of specific inhibitors that can block nuclear factor-κB (NF-κB) activation is an approach for the treatment of cancer, autoimmune, and inflammatory diseases. Several diterpenoids, oridonin, ponicidin, xindongnin A, and xindongnin B were isolated from the herb Isodon rubescens. These compounds were found to be potent inhibitors of NF-κB transcription activity and the expression of its downstream targets, cyclooxygenase-2 and inducible nitric-oxide synthase. The mechanisms of action of the diterpenoids against NF-κB are similar, but significant differences were also identified. All of the diterpenoids directly interfere with the DNA-binding activity of NF-κB to its response DNA sequence. Oridonin and ponicidin have an additional impact on the translocation of NF-κB from the cytoplasm to nuclei without affecting IκB-α phosphorylation and degradation. The effect of these compounds on the interaction of NF-κB with consensus DNA sequences is unique. Different inhibitory effects were observed when NF-κB bound to various DNA sequences. Both p65/p65 and p50/p50 homodimers, as well as p65/p50 heterodimer association with their responsive DNA, were inhibited. Kinetic studies on NF-κB-DNA interaction indicate that the diterpenoids decrease the Bmax app but have no effect on Kd app. This suggests that this class of compounds interacts with both p65 and p50 subunits at a site other than the DNA binding site and subsequently modulates the binding affinity of the transcription factor toward DNA with different NF-κB binding sequences. The diterpenoid structure could therefore serve as a scaffold for the development of more potent and selective NF-κB inhibitors that target regulated gene transcription. Copyright © 2005 The American Society for Pharmacology and Experimental Therapeutics.
Persistent Identifierhttp://hdl.handle.net/10722/167944
ISSN
2015 Impact Factor: 3.931
2015 SCImago Journal Rankings: 2.047
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLeung, CHen_US
dc.contributor.authorGrill, SPen_US
dc.contributor.authorLam, Wen_US
dc.contributor.authorHan, QBen_US
dc.contributor.authorSun, HDen_US
dc.contributor.authorCheng, YCen_US
dc.date.accessioned2012-10-08T03:13:14Z-
dc.date.available2012-10-08T03:13:14Z-
dc.date.issued2005en_US
dc.identifier.citationMolecular Pharmacology, 2005, v. 68 n. 2, p. 286-297en_US
dc.identifier.issn0026-895Xen_US
dc.identifier.urihttp://hdl.handle.net/10722/167944-
dc.description.abstractThe development of specific inhibitors that can block nuclear factor-κB (NF-κB) activation is an approach for the treatment of cancer, autoimmune, and inflammatory diseases. Several diterpenoids, oridonin, ponicidin, xindongnin A, and xindongnin B were isolated from the herb Isodon rubescens. These compounds were found to be potent inhibitors of NF-κB transcription activity and the expression of its downstream targets, cyclooxygenase-2 and inducible nitric-oxide synthase. The mechanisms of action of the diterpenoids against NF-κB are similar, but significant differences were also identified. All of the diterpenoids directly interfere with the DNA-binding activity of NF-κB to its response DNA sequence. Oridonin and ponicidin have an additional impact on the translocation of NF-κB from the cytoplasm to nuclei without affecting IκB-α phosphorylation and degradation. The effect of these compounds on the interaction of NF-κB with consensus DNA sequences is unique. Different inhibitory effects were observed when NF-κB bound to various DNA sequences. Both p65/p65 and p50/p50 homodimers, as well as p65/p50 heterodimer association with their responsive DNA, were inhibited. Kinetic studies on NF-κB-DNA interaction indicate that the diterpenoids decrease the Bmax app but have no effect on Kd app. This suggests that this class of compounds interacts with both p65 and p50 subunits at a site other than the DNA binding site and subsequently modulates the binding affinity of the transcription factor toward DNA with different NF-κB binding sequences. The diterpenoid structure could therefore serve as a scaffold for the development of more potent and selective NF-κB inhibitors that target regulated gene transcription. Copyright © 2005 The American Society for Pharmacology and Experimental Therapeutics.en_US
dc.languageengen_US
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.orgen_US
dc.relation.ispartofMolecular Pharmacologyen_US
dc.subject.meshAnimalsen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshDna - Antagonists & Inhibitors - Genetics - Metabolismen_US
dc.subject.meshDiterpenes - Chemistry - Isolation & Purification - Pharmacologyen_US
dc.subject.meshHumansen_US
dc.subject.meshIsodonen_US
dc.subject.meshMiceen_US
dc.subject.meshNf-Kappa B - Antagonists & Inhibitors - Genetics - Metabolismen_US
dc.subject.meshProtein Binding - Drug Effects - Physiologyen_US
dc.titleNovel mechanism of inhibition of nuclear factor-κB DNA-binding activity by diterpenoids isolated from Isodon rubescensen_US
dc.typeArticleen_US
dc.identifier.emailLeung, CH:duncanl@hkucc.hku.hken_US
dc.identifier.authorityLeung, CH=rp00730en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1124/mol.105.012765en_US
dc.identifier.pmid15872117-
dc.identifier.scopuseid_2-s2.0-23044504665en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-23044504665&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume68en_US
dc.identifier.issue2en_US
dc.identifier.spage286en_US
dc.identifier.epage297en_US
dc.identifier.isiWOS:000230549900005-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridLeung, CH=7402612570en_US
dc.identifier.scopusauthoridGrill, SP=7004975986en_US
dc.identifier.scopusauthoridLam, W=7203021943en_US
dc.identifier.scopusauthoridHan, QB=7202485341en_US
dc.identifier.scopusauthoridSun, HD=7404828012en_US
dc.identifier.scopusauthoridCheng, YC=36041844200en_US

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