Double-edged sword effect of biochanin to inhibit nuclear factor kappaB: Suppression of serine/threonine and tyrosine kinases

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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-κB) 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-κB activation induced by PMA, LPS, pervanadate (PV), or H2O2, but only partially that induced by TNFα. Genistein was unable to inhibit IL-8-induced IKK activity, but it blocked PV-induced IKK activity. Biochanin inhibited activation of NF-κB 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-κB activation not only by blocking the upstream IKK, but also PTK that phosphorylate tyrosine residues of IκBα. Thus, the double-edged sword effect of inhibition of NF-κB 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.

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