Withanolides potentiate apoptosis, inhibit invasion, and abolish osteoclastogenesis through suppression of nuclear factor-kappaB (NF-kappaB) activation and NF-kappaB-regulated gene expression
Language: 
English
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-kappaB (NF-kappaB), we hypothesized that the activity of withanolides is mediated through modulation of NF-kappaB activation. For this report, we investigated the effect of the withanolide on NF-kappaB and NF-kappaB-regulated gene expression activated by various carcinogens. We found that withanolides suppressed NF-kappaB activation induced by a variety of inflammatory and carcinogenic agents, including tumor necrosis factor (TNF), interleukin-1beta, doxorubicin, and cigarette smoke condensate. Suppression was not cell type specific, as both inducible and constitutive NF-kappaB activation was blocked by withanolides. The suppression occurred through the inhibition of inhibitory subunit of IkappaB alpha kinase activation, IkappaB alpha phosphorylation, IkappaB alpha degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. NF-kappaB-dependent reporter gene expression activated by TNF, TNF receptor (TNFR) 1, TNFR-associated death domain, TNFR-associated factor 2, and IkappaB alpha kinase was also suppressed. Consequently, withanolide suppressed the expression of TNF-induced NF-kappaB-regulated antiapoptotic (inhibitor of apoptosis protein 1, Bfl-1/A1, and FADD-like interleukin-1beta-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-kappaB ligand-induced osteoclastogenesis. Overall, our results indicate that withanolides inhibit activation of NF-kappaB and NF-kappaB-regulated gene expression, which may explain the ability of withanolides to enhance apoptosis and inhibit invasion and osteoclastogenesis.

Author(s): 
Ichikawa, Haruyo
Takada, Yasunari
Shishodia, Shishir
Jayaprakasam, Bolleddula
Nair, Muraleedharan G.
Aggarwal, Bharat B.
Item Type: 
Journal Article
Publication Title: 
Molecular Cancer Therapeutics
Journal Abbreviation: 
Mol. Cancer Ther.
Publication Date: 
Jun 2006
Publication Year: 
2006
Pages: 
1434-1445
Volume: 
5
Issue: 
6
ISSN: 
1535-7163
DOI: 
10.1158/1535-7163.MCT-06-0096
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 16818501

Turabian/Chicago Citation

Haruyo Ichikawa, Yasunari Takada, Shishir Shishodia, Bolleddula Jayaprakasam, Muraleedharan G. Nair and Bharat B. Aggarwal. Jun 2006. "Withanolides potentiate apoptosis, inhibit invasion, and abolish osteoclastogenesis through suppression of nuclear factor-kappaB (NF-kappaB) activation and NF-kappaB-regulated gene expression." Molecular Cancer Therapeutics 5: 6: 1434-1445. 10.1158/1535-7163.MCT-06-0096.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1158/1535-7163.MCT-06-0096 | issn = 1535-7163 | volume = 5 | pages = 1434-1445 | last = Ichikawa | first = Haruyo | coauthors = Takada, Yasunari, Shishodia, Shishir, Jayaprakasam, Bolleddula, Nair, Muraleedharan G., Aggarwal, Bharat B. | title = Withanolides potentiate apoptosis, inhibit invasion, and abolish osteoclastogenesis through suppression of nuclear factor-kappaB (NF-kappaB) activation and NF-kappaB-regulated gene expression | journal = Molecular Cancer Therapeutics | date = Jun 2006 | pmid = | pmc = }} </ref>