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Research Articles: Targets

Withanolides potentiate apoptosis, inhibit invasion, and abolish osteoclastogenesis through suppression of nuclear factor-B (NF-B) activation and NF-B–regulated gene expression

¹ Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas and ² Bioactive Natural Products and Phytoceuticals, Department of Horticulture and National Food Safety and Toxicology Center, Michigan State University, East Lansing, Michigan

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

The plant Withania somnifera Dunal (Ashwagandha), also known as Indian ginseng, is widely used in the Ayurvedic system of medicine to treat tumors, inflammation, arthritis, asthma, and hypertension. Chemical investigation of the roots and leaves of this plant has yielded bioactive withanolides. Earlier studies showed that withanolides inhibit cyclooxygenase enzymes, lipid peroxidation, and proliferation of tumor cells. Because several genes that regulate cellular proliferation, carcinogenesis, metastasis, and inflammation are regulated by activation of nuclear factor-B (NF-B), we hypothesized that the activity of withanolides is mediated through modulation of NF-B activation. For this report, we investigated the effect of the withanolide on NF-B and NF-B-regulated gene expression activated by various carcinogens. We found that withanolides suppressed NF-B activation induced by a variety of inflammatory and carcinogenic agents, including tumor necrosis factor (TNF), interleukin-1ß, doxorubicin, and cigarette smoke condensate. Suppression was not cell type specific, as both inducible and constitutive NF-B activation was blocked by withanolides. The suppression occurred through the inhibition of inhibitory subunit of IB kinase activation, IB phosphorylation, IB degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. NF-B-dependent reporter gene expression activated by TNF, TNF receptor (TNFR) 1, TNFR-associated death domain, TNFR-associated factor 2, and IB kinase was also suppressed. Consequently, withanolide suppressed the expression of TNF-induced NF-B-regulated antiapoptotic (inhibitor of apoptosis protein 1, Bfl-1/A1, and FADD-like interleukin-1ß-converting enzyme–inhibitory protein) and metastatic (cyclooxygenase-2 and intercellular adhesion molecule-1) gene products, enhanced the apoptosis induced by TNF and chemotherapeutic agents, and suppressed cellular TNF-induced invasion and receptor activator of NF-B ligand-induced osteoclastogenesis. Overall, our results indicate that withanolides inhibit activation of NF-B and NF-B-regulated gene expression, which may explain the ability of withanolides to enhance apoptosis and inhibit invasion and osteoclastogenesis. [Mol Cancer Ther 2006;5(6):1434–45]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: B.B. Aggarwal is a Ransom Horne, Jr., professor of cancer research.

Received 2/21/06; revised 4/ 1/06; accepted 4/27/06.