Isodeoxyelephantopin, a novel sesquiterpene lactone, potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis through suppression of nuclear factor-kappaB (nf-kappaB) activation and nf-kappaB-regulated gene expression.
OBJECTIVE
Deoxyelephantopin (ESD) and isodeoxyelephantopin (ESI) are two sesquiterpene lactones derived from the medicinal plant Elephantopus scaber Linn. (Asteraceae). Although they are used for the treatment of a wide variety of proinflammatory diseases, very little is known about their mechanism of action. Because most genes that control inflammation are regulated by activation of the transcription factor nuclear factor-kappaB (NF-kappaB), we postulated that ESD and ESI mediate their activities through modulation of the NF-kappaB activation pathway.


METHODS
We investigated the effect of ESI and ESD on NF-kappaB activation by electrophoretic mobility shift assay and NF-kappaB-regulated gene expression by Western blot analysis.


RESULTS
We found that ESI suppressed NF-kappaB activation induced by a wide variety of inflammatory agents, including tumor necrosis factor (TNF), interleukin-1beta, phorbol 12-myristate 13-acetate, and lipopolysaccharide. The suppression was not cell type specific, and both inducible and constitutive NF-kappaB activation was blocked. ESI did not interfere with the binding of NF-kappaB to DNA but rather inhibited IkappaBalpha kinase, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. ESI also suppressed the expression of TNF-induced NF-kappaB-regulated, proliferative, antiapoptotic, and metastatic gene products. These effects correlated with enhancement of apoptosis induced by TNF and suppression of TNF-induced invasion and receptor activator of NF-kappaB ligand-induced osteoclastogenesis.


CONCLUSIONS
Our results indicate that ESI inhibits NF-kappaB activation and NF-kappaB-regulated gene expression, which may explain the ability of ESI to enhance apoptosis and inhibit invasion and osteoclastogenesis.
Ichikawa
Haruyo
H
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Nair
Mangalam S
MS
Takada
Yasunari
Y
Sheeja
D B Alan
DB
Kumar
M A Suresh
MA
Oommen
Oommen V
OV
Aggarwal
Bharat B
BB
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects*; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D047468:Immunoprecipitation; D007375:Interleukin-1 / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012717:Sesquiterpenes / Q000494:pharmacology*; D013729:Terpenes / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
D020672:I-kappa B Proteins; D007375:Interleukin-1; D007783:Lactones; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012717:Sesquiterpenes; C439524:TNF protein, human; D013729:Terpenes; D014409:Tumor Necrosis Factor-alpha; C045728:elephantopin; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase; D013755:Tetradecanoylphorbol Acetate