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: Sunil Kumar Manna
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 83 Issue 10 Pg. 1383-92 (May 15 2012) ISSN: 1873-2968 [Electronic] England
• PMID: 22387535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• NF-kappa B
• Protein Kinase Inhibitors
• Genistein
• Protein-Tyrosine Kinases
• Protein Serine-Threonine Kinases
• biochanin A

Topics

• Base Sequence
• Genistein (pharmacology)
• Humans
• Jurkat Cells
• NF-kappa B (antagonists & inhibitors)
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Protein-Tyrosine Kinases (antagonists & inhibitors)