Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a potent inhibitor of nuclear transcription factor-kappa B activation by diverse agents.
Viral replication, immune regulation, and induction of various inflammatory and growth-regulatory genes require activation of a nuclear transcription factor (NF)-kappa B. Agents that can block NF-kappa B activation have potential to block downstream responses mediated through this transcription factor. Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a quinone that has been shown to regulate a wide variety of activities that require NF-kappa B activation. In the present study, we examined the effect of capsaicin and its analogue, resiniferatoxin, on the activation of NF-kappa B induced by different agents including TNF. The pretreatment of human myeloid ML-1a cells with capsaicin blocked TNF-mediated activation of NF-kappa B in a dose- and time-dependent manner. Resiniferatoxin was at least eight times as potent as capsaicin in inhibiting NF-kappa B activation. Neither agent by itself activated NF-kappa B or affected the DNA-binding ability of NF-kappa B. Capsaicin also blocked phorbol ester-mediated NF-kappa B activation, but that mediated through okadaic acid was less effective, suggesting there is a difference in the mechanism of activation of NF-kappa B by different agents. Capsaicin treatment of cells also blocked the degradation of I kappa B alpha, and thus the nuclear translocation of the p65 subunit of NF-kappa B, which is essential for NF-kappa B activation. TNF-dependent promoter activity of I kappa B alpha, which contains NF-kappa B binding sites, was also inhibited by capsaicin. Overall our results indicate that capsaicin and its analogue inhibit NF-kappa B activation, and thus could be used as a potential target for drug development.
Department of Molecular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
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Aggarwal
D002211:Capsaicin / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins; D015479:Leukemia, Myelomonocytic, Acute; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects* / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D004268:DNA-Binding Proteins; D004224:Diterpenes; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009498:Neurotoxins; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C024353:resiniferatoxin; D013755:Tetradecanoylphorbol Acetate; D002211:Capsaicin