Withaferin a strongly elicits IkappaB kinase beta hyperphosphorylation concomitant with potent inhibition of its kinase activity.

摘要: The transcription factor NFkappaB plays a critical role in normal and pathophysiological immune responses. Therefore, the signaling pathways that regulate its activation have become major focus of drug development programs. Withania somnifera (WS) is medicinal plant widely used Palestine for treatment various inflammatory disorders. In this study we show leave extract WS, as well constituent withaferin A (WA), potently inhibits by preventing tumor necrosis factor-induced IkappaB kinase beta via thioalkylation-sensitive redox mechanism, whereas other WS-derived steroidal lactones, such withanolide 12-deoxywithastramonolide, are far less effective. To our knowledge, first communication inhibition plant-derived inhibitor, coinciding with MEK1/ERK-dependent Ser-181 hyperphosphorylation. This prevents phosphorylation degradation, which subsequently blocks translocation, NFkappaB/DNA binding, gene transcription. Taken together, results indicate pure WA or WA-enriched WS extracts can be considered novel class inhibitors, hold promise anti-inflammatory agents disorders and/or cancer.