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

• Published in: Clinical cancer research 2006-10, Vol.12 (19), p.5910
• Main Authors: Ichikawa, Haruyo, Nair, Mangalam S, Takada, Yasunari, Sheeja, D B Alan, Kumar, M A Suresh, Oommen, Oommen V, Aggarwal, Bharat B
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Blotting, Western; Cell Differentiation; Cell Movement - drug effects; Electrophoretic Mobility Shift Assay; Enzyme Activation - drug effects; Humans; I-kappa B Kinase - metabolism; I-kappa B Proteins - metabolism; Immunoprecipitation; Interleukin-1 - pharmacology; Lactones - pharmacology; Lipopolysaccharides - pharmacology; Neoplasms - drug therapy; Neoplasms - metabolism; NF-kappa B - antagonists & inhibitors; NF-kappa B - genetics; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; Osteoclasts - cytology; Osteoclasts - drug effects; Osteoclasts - metabolism; Phosphorylation - drug effects; Sesquiterpenes - pharmacology; Terpenes - pharmacology; Tetradecanoylphorbol Acetate - pharmacology; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 1078-0432

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. 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. 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. 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.