Oleandrin suppresses activation of nuclear transcription factor-kappaB, activator protein-1, and c-Jun NH2-terminal kinase

Cancer Res. 2000 Jul 15;60(14):3838-47.

Abstract

Agents that can suppress the activation of nuclear factor-kappaB (NF-kappaB) 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-kappaB and AP-1 modulator. We investigated the effect of oleandrin on NF-kappaB activation induced by inflammatory agents. Oleandrin blocked tumor necrosis factor (TNF)-induced activation of NF-kappaB in a concentration- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of IkappaBalpha, an inhibitor of NF-kappaB. A proprietary hot water extract of oleander (Anvirzel) also blocked TNF-induced NF-kappaB 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-kappaB activation in a variety of cells. NF-kappaB-dependent reporter gene transcription activated by TNF was also suppressed by oleandrin. The TNF-induced NF-kappaB activation cascade involving TNF receptor 1/TNF receptor-associated death domain/TNF receptor-associated factor 2/NF-kappaB-inducing kinase/IkappaBalpha kinase was interrupted at the TNF receptor-associated factor 2 and NF-kappaB-inducing kinase sites by oleandrin, thus suppressing NF-kappaB reporter gene expression. Oleandrin blocked NF-kappaB 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-kappaB and AP-1 and their associated kinases. This may provide a molecular basis for the ability of oleandrin to suppress inflammation and perhaps tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cardenolides / chemistry
  • Cardenolides / pharmacology*
  • Cell Line
  • Ceramides / pharmacology
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • HeLa Cells
  • Humans
  • Hydrogen Peroxide / pharmacology
  • I-kappa B Proteins*
  • JNK Mitogen-Activated Protein Kinases
  • Lipid Peroxidation / drug effects
  • Lipopolysaccharides / pharmacology
  • MAP Kinase Kinase 4
  • MAP Kinase Kinase Kinase 1*
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Phorbol Esters / pharmacology
  • Plant Extracts / pharmacology
  • Protein-Serine-Threonine Kinases / metabolism
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • Time Factors
  • Transcription Factor AP-1 / metabolism*
  • Transcription, Genetic / drug effects
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / metabolism
  • U937 Cells

Substances

  • Cardenolides
  • Ceramides
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Phorbol Esters
  • Plant Extracts
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Hydrogen Peroxide
  • Protein-Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • Map3k1 protein, mouse
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases
  • Sodium-Potassium-Exchanging ATPase
  • oleandrin