Isodeoxyelephantopin, a novel sesquiterpene lactone, potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis through suppression of nuclear factor-kappa B (NF-kappa B) activation and NF-kappa B-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-kappa B (NF-kappa B), we postulated that ESD and ESI mediate their activities through modulation of the NF-kappa B activation pathway.

Experimental Design: We investigated the effect of ESI and ESD on NF-kappa B activation by electrophoretic mobility shift assay and NF-kappa B-regulated gene expression by Western blot analysis.

Results: We found that ESI suppressed NF-kappa B activation induced by a wide variety of inflammatory agents, including tumor necrosis factor (TNF), interleukin-1 beta phorbol 12-myristate 13-acetate, and lipopolysaccharide. The suppression was not cell type specific, and both inducible and constitutive NF-kappa B activation was blocked. ESI did not interfere with the binding of NF-kappa B to DNA but rather inhibited I kappa B alpha kinase, I kappa B alpha phosphorylation, I kappa B alpha degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. ESI also suppressed the expression of TNF-induced NF-kappa B-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-kappa B ligand-induced osteoclastogenesis.

Conclusion: Our results indicate that ESI inhibits NF-kappa B activation and NF-kappa B-regulated gene expression, which may explain the ability of ESI to enhance apoptosis and inhibit invasion and osteoclastogenesis.