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Kaileh M, Vanden Berghe W, Heyerick A, Horion J, Piette J, Libert C, De
Keukeleire D, Essawi T, Haegeman G.
J Biol Chem. 2007 Feb 16;282(7):4253-64
Withaferin a strongly
elicits IkappaB kinase beta hyperphosphorylation concomitant with potent
inhibition of its kinase activity.
Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST),
Department of Molecular Biology, Ghent University-UGent, K. L. Ledeganckstraat
35, B-9000 Gent, Belgium.
The transcription factor NFkappaB plays a critical role in normal and
pathophysiological immune responses. Therefore, NFkappaB 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 NFkappaB activation by
preventing the tumor necrosis factor-induced activation of IkappaB kinase beta
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 IkappaB
kinase beta inhibition by a plant-derived inhibitor, coinciding with
MEK1/ERK-dependent Ser-181 hyperphosphorylation. This prevents IkappaB
phosphorylation and degradation, which subsequently blocks NFkappaB
translocation, NFkappaB/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 NFkappaB inhibitors, which hold promise as novel
anti-inflammatory agents for treatment of various inflammatory disorders and/or
cancer.
PMID: 17150968
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