Isodeoxyelephantopin, a Novel Sesquiterpene Lactone, Potentiates Apoptosis, Inhibits Invasion, and Abolishes Osteoclastogenesis through Suppression of Nuclear Factor-κB (NF-κB) Activation and NF-κB-Regulated Gene Expression

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-κB (NF-κB), we postulated that ESD and ESI mediate their activities through modulation of the NF-κB activation pathway. Experimental Design: We investigated the effect of ESI and ESD on NF-κB activation by electrophoretic mobility shift assay and NF-κB-regulated gene expression by Western blot analysis. Results: We found that ESI suppressed NF-κB activation induced by a wide variety of inflammatory agents, including tumor necrosis factor (TNF), interleukin-1β, phorbol 12-myristate 13-acetate, and lipopolysaccharide. The suppression was not cell type specific, and both inducible and constitutive NF-κB activation was blocked. ESI did not interfere with the binding of NF-κB to DNA but rather inhibited IκBα kinase, IκBα phosphorylation, IκBα degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. ESI also suppressed the expression of TNF-induced NF-κB-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-κB ligand-induced osteoclastogenesis. Conclusion: Our results indicate that ESI inhibits NF-κB activation and NF-κB-regulated gene expression, which may explain the ability of ESI to enhance apoptosis and inhibit invasion and osteoclastogenesis.