Oleandrin suppresses activation of nuclear transcription factor-κB, activator protein-1, and c-jun NH2-Terminal kinase

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Titre du document / Document title

Oleandrin suppresses activation of nuclear transcription factor-κB, activator protein-1, and c-jun NH₂-Terminal kinase

Auteur(s) / Author(s)

MANNA S. K.⁽¹⁾ ; SAH N. K.⁽¹⁾ ; NEWMAN R. A.⁽²⁾ ; CISNEROS A.⁽²⁾ ; AGGARWAL B. B.⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾Cytokine Research Laboratory, Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, ETATS-UNIS
⁽²⁾Pharmaceutical Development Center, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, ETATS-UNIS

Résumé / Abstract

Agents that can suppress the activation of nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) may be able to block tumorigenesis and inflammation. Oleandrin, a polyphenolic cardiac glycoside derived from the leaves of Nerium oleander, is a candidate NF-κB and AP-1 modulator. We investigated the effect of oleandrin on NF-KB activation induced by inflammatory agents. Oleandrin blocked tumor necrosis factor (TNF)-induced activation of NF-KB in a concentration- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of IκBα, an inhibitor of NF-κB. A proprietary hot water extract of oleander (Anvirzel) also blocked TNF-induced NF-κB activation; subsequent fractionation of the extract revealed that this activity was attributable to oleandrin. The effects of oleandrin were not cell type specific, because it blocked TNF-induced NF-KB activation in a variety of cells. NF-KB-dependent reporter gene transcription activated by TNF was also suppressed by oleandrin. The TNF-induced NF-KB activation cascade involving TNF receptor 1/TNF receptor-associated death domain/TNF receptor-associated factor 2/NF-κB-inducing kinase/IκBα kinase was interrupted at the TNF receptor-associated factor 2 and NF-KB-inducing kinase sites by oleandrin, thus suppressing NF-κB reporter gene expression. Oleandrin blocked NF-KB activation induced by phorbol ester and lipopolysaccharide. Oleandrin also blocked AP-1 activation induced by TNF and other agents and inhibited the TNF-induced activation of c-Jun NH₂-terminal kinase. Overall, our results indicate that oleandrin inhibits activation of NF-κB and AP-1 and their associated kinases. This may provide a molecular basis for the ability of oleandrin to suppress inflammation and perhaps tumorigenesis.

Revue / Journal Title

Cancer research ISSN 0008-5472 CODEN CNREA8

Source / Source

2000, vol. 60, n^o14, pp. 3838-3847 (58 ref.)

Langue / Language

Anglais

Editeur / Publisher

American Association for Cancer Research, Philadelphia, PA, ETATS-UNIS (1941) (Revue)

Localisation / Location

INIST-CNRS, Cote INIST : 5088, 35400009037137.0260

Nº notice refdoc (ud4) : 1472360