title: Double-edged sword effect of biochanin to inhibit nuclear factor kappaB: suppression of serine/threonine and tyrosine kinases.
abstract: 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.
authors.affiliation: Laboratory of Immunology, Centre for DNA Fingerprinting & Diagnostics, Nampally, Hyderabad 500001, India. manna@cdfd.org.in
authors.forename: Sunil Kumar
authors.initials: SK
authors.lastname: Manna
mesh_terms: D001483:Base Sequence; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C004541:biochanin A