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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.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2006 Oct 01; Vol. 12 (19), pp. 5910-8. - Publication Year :
- 2006
-
Abstract
- Purpose: 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.<br />Experimental Design: 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.<br />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.<br />Conclusion: 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.
- Subjects :
- Blotting, Western
Cell Differentiation
Electrophoretic Mobility Shift Assay
Enzyme Activation drug effects
Humans
I-kappa B Kinase metabolism
I-kappa B Proteins metabolism
Immunoprecipitation
Interleukin-1 pharmacology
Lipopolysaccharides pharmacology
NF-KappaB Inhibitor alpha
NF-kappa B genetics
NF-kappa B metabolism
Osteoclasts cytology
Osteoclasts drug effects
Osteoclasts metabolism
Phosphorylation drug effects
Tetradecanoylphorbol Acetate pharmacology
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha metabolism
Tumor Necrosis Factor-alpha pharmacology
Apoptosis drug effects
Cell Movement drug effects
Lactones pharmacology
NF-kappa B antagonists & inhibitors
Neoplasms drug therapy
Neoplasms metabolism
Sesquiterpenes pharmacology
Terpenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1078-0432
- Volume :
- 12
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 17021000
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-06-0916