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Title: Withaferin a strongly elicits I B kinase hyperphosphorylation concomitant with potent inhibition of its kinase activity
Authors: Kaileh, Mary 
Berghe, Wim Vanden 
Heyerick, Arne 
Horion, Julie 
Piette, Jacques 
Libert, Claude 
De Keukeleire, Denis 
Essawi, Tamer 
Haegeman, Guy 
Keywords: Antineoplastic agents - Development;Botany, Medical;Protein-protein interactions;Materia Medica - Palestine;Medicine, Traditional - Palestine;Cancer - Treatment - Palestine
Issue Date: 2006
Abstract: The transcription factor NF B plays a critical role in normal and pathophysiological immune responses. Therefore, NF B and the signaling pathways that regulate its activation have become a major focus of drug development programs. Withania somnifera (WS) is a medicinal plant that is widely used in Palestine for the treatment of various inflammatory disorders. In this study we show that the leave extract of WS, as well as its major constituent withaferin A (WA), potently inhibits NF B activation by preventing the tumor necrosis factor-induced activation of I B kinase via a thioalkylation-sensitive redox mechanism, whereas other WS-derived steroidal lactones, such as withanolide A and 12-deoxywithastramonolide, are far less effective. To our knowledge, this is the first communication of I B kinase inhibition by a plant-derived inhibitor, coinciding with MEK1/ ERK-dependent Ser-181 hyperphosphorylation. This prevents I B phosphorylation and degradation, which subsequently blocks NF B translocation, NF B/DNA binding, and gene transcription. Taken together, our results indicate that pure WA or WA-enriched WS extracts can be considered as a novel class of NF B inhibitors, which hold promise as novel anti-inflammatory agents for treatment of various inflammatory disorders and/or cancer.
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