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

Authors:
Open Access
Publisher website
Google Scholar
Abstract
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-κB (NF-κB), we hypothesized that the activity of withanolides is mediated through modulation of NF-κB activation. For this report, we investigated the effect of the withanolide on NF-κB and NF-κB-regulated gene expression activated by various carcinogens. We found that withanolides suppressed NF-κB activation induced by a variety of inflammatory and carcinogenic agents, including tumor necrosis factor (TNF), interleukin-1β, doxorubicin, and cigarette smoke condensate. Suppression was not cell type specific, as both inducible and constitutive NF-κB activation was blocked by withanolides. The suppression occurred through the inhibition of inhibitory subunit of IκBα kinase activation, IκBα phosphorylation, IκBα degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. NF-κB-dependent reporter gene expression activated by TNF, TNF receptor (TNFR) 1, TNFR-associated death domain, TNFR-associated factor 2, and IκBα kinase was also suppressed. Consequently, withanolide suppressed the expression of TNF-induced NF-κB-regulated antiapoptotic (inhibitor of apoptosis protein 1, Bfl-1/A1, and FADD-like interleukin-1β-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-κB ligand-induced osteoclastogenesis. Overall, our results indicate that withanolides inhibit activation of NF-κB and NF-κB-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]

This publication has 64 references indexed in Scilit: