Oleandrin suppresses activation of nuclear transcription factor-kappa B and activator protein-1 and potentiates apoptosis induced by ceramide.
Ceramide (N-acetyl-D-sphingosine), a second messenger for cell signaling induces transcription factors, like nuclear factor-kappa B (NF-kappa B), and activator protein-1 (AP-1) and is involved in inflammation and apoptosis. Agents that can suppress these transcription factors may be able to block tumorigenesis and inflammation. Oleandrin (trans-3,4',5-trihydroxystilbene), a polyphenolic cardiac glycoside derived from the leaves of Nerium oleander, has been used in the treatment of cardiac abnormalities in Russia and China for years. We investigated the effect of oleandrin on NF-kappa B and AP-1 activation and apoptosis induced by ceramide. Oleandrin blocked ceramide-induced NF-kappa B activation. Oleandrin-mediated suppression of NF-kappa B was not restricted to human epithelial cells; it was also observed in human lymphoid, insect, and murine macrophage cells. The suppression of NF-kappa B coincided with suppression of AP-1. Ceramide-induced reactive intermediates generation, lipid peroxidation, cytotoxicity, caspase activation, and DNA fragmentation were potentiated by oleandrin. Oleandrin did not show its activity in primary cells. Oleandrin's anticarcinogenic, anti-inflammatory, and growth-modulatory effects may thus be partially ascribed to the inhibition of activation of NF-kappa B and AP-1 and potentiation of apoptosis.
Sreenivasan
Yashin
Y
Laboratory of Immunology, Centre for DNA Fingerprinting & Diagnostics, Nacharam, Hyderabad 500 076, India.
Sarkar
Abira
A
Manna
Sunil Kumar
SK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002298:Cardenolides / Q000494:pharmacology*; D002460:Cell Line; D002518:Ceramides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D002298:Cardenolides; D002518:Ceramides; D016328:NF-kappa B; D018808:Transcription Factor AP-1; C021065:oleandrin