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

Authors' Affiliations: ¹ Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas and ² Organic Chemistry Division, Regional Research Laboratory; ³ Department of Zoology, University of Kerala, Thiruvananthapuram, India

Requests for reprints: Bharat B. Aggarwal, Department of Experimental Therapeutics, Unit 143, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-794-1817; Fax: 713-794-1613; E-mail: aggarwal{at}mdanderson.org.

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-B (NF-B), we postulated that ESD and ESI mediate their activities through modulation of the NF-B activation pathway.

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

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

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

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