Double-edged sword effect of biochanin to inhibit nuclear factor kappaB: Suppression of serine/threonine and tyrosine kinases
- 作者：Sunil Kumar Manna ; manna@cdfd.org.in
- 关键词：AP-1 ; activator protein 1 ; C3-toxin ; Clostridium botulinum C3 transferase ; CE ; cytoplasmic extracts ; Cox2 ; cyclooxygenase 2 ; ICAM ; intercellular adhesion molecule ; NF-魏B ; nuclear transcription factor kappaB ; IL ; interleukin ; I魏B ; inhibitory subunit of N
- 刊名：Biochemical Pharmacology
- 出版年：2012
- 期刊代码：2_00062952
- 类别：pha
- 出版时间：15 May, 2012
- 卷：83
- 期：10
- 页码：1383-1392
- 文件大小：1668 K
摘要
Several protein tyrosine kinase (PTK) inhibitors predominantly isoflavones, such as genistein, erbstatin, quercetin, daidzein, present in red clover, cabbage and alfalfa, show apoptotic effect against cancer cells. In this study I found that biochanin, a methoxy form of genistein, inhibits IL-8-mediated activation of nuclear transcription factor kappaB (NF-魏B) and activator protein 1 (AP-1) more potently than genistein as shown in Jurkat T-cell line. Both biochanin and genistein potently inhibited activity of Lck and Syk, but biochanin specifically inhibited activity of IKK. Biochanin inhibited completely NF-魏B activation induced by PMA, LPS, pervanadate (PV), or H2O2, but only partially that induced by TNF伪. Genistein was unable to inhibit IL-8-induced IKK activity, but it blocked PV-induced IKK activity. Biochanin inhibited activation of NF-魏B by TRAF6 completely, but by TRAF2 partially. In silico data suggested that biochanin interacted strongly with serine/threonine kinase than genistein, though both equally interacted with PTK. The data show that both biochanin and genistein are potent inhibitors of PTK, but biochanin is a potent inhibitor of serine/threonine kinase too. Formononetin, having hydroxyl methoxy group is less potent to inhibit IKK than biochanin. Biochanin inhibits NF-魏B activation not only by blocking the upstream IKK, but also PTK that phosphorylate tyrosine residues of I魏B伪. Thus, the double-edged sword effect of inhibition of NF-魏B via inhibition of both serine/threonine kinase and PTK by biochanin might show useful therapeutic value against activities of cells that lead to tumorigenesis and inflammation.