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

Agents that can suppress the activation of nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1) may be able to block tumorigenesis and i nflammation. Oleandrin, a polyphenolic cardiac glycoside derived from the l eaves of Nerium oleander, is a candidate NF-kappa B and AP-1 modulator. We investigated the effect of oleandrin on NF-kappa B activation induced by in flammatory agents. Oleandrin blocked tumor necrosis factor (TNF)-induced ac tivation of NF-kappa B in a concentration- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation o f I kappa B alpha, an inhibitor of NF-kappa B. A proprietary hot mater extr act of oleander (Anvirzel) also blocked TNF-induced NF-kappa B activation; subsequent fractionation of the extract revealed that this activity was att ributable to oleandrin. The effects of oleandrin were not cell type specifi c, because it blocked TNF-induced NF-kappa B activation in a variety of cel ls. NF-kappa B-dependent reporter gene transcription activated by TNF was a lso suppressed by oleandrin. The TNF-induced NF-kappa B activation cascade involving TNF receptor 1/TNF receptor-associated death domain/TNF receptor- associated factor 2/NF-kappa B-inducing kinase/I kappa B alpha kinase was i nterrupted at the TNF receptor-associated factor 2 and NF-kappa B-inducing kinase sites by oleandrin, thus suppressing NF-kappa B reporter gene expres sion. Oleandrin blocked NF-kappa B activation induced by phorbol ester and lipopolysaccharide. Oleandrin also blocked AP-1 activation induced by TNF a nd other agents and inhibited the TNF-induced activation of c-Jun NH2-termi nal kinase. Overall, our results indicate that oleandrin inhibits activatio n of NF-kappa B and AP-1 and their associated kinases. This may provide a m olecular basis for the ability of oleandrin to suppress inflammation and pe rhaps tumorigenesis.