QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.107.034512v1 71/6/1703    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sung, B. Articles by Aggarwal, B. B. Search for Related Content PubMed PubMed Citation Articles by Sung, B. Articles by Aggarwal, B. B.

Fisetin, an Inhibitor of Cyclin-Dependent Kinase 6, Down-Regulates Nuclear Factor-B-Regulated Cell Proliferation, Antiapoptotic and Metastatic Gene Products through the Suppression of TAK-1 and Receptor-Interacting Protein-Regulated IB Kinase Activation

Cytokine Research Laboratory, Department Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Fisetin (3,7,3',4'-tetrahydroxyflavone) exhibits anti-inflammatory and antiproliferative effects through a mechanism that is poorly understood. Although fisetin has been cocrystalized with cyclin-dependent kinase 6 and inhibits its activity, this inhibition is not sufficient to explain various activities assigned to this flavonol. Because of the critical role of the NF-B pathway in regulation of inflammation and proliferation of tumor cells, we postulated that fisetin modulates this pathway. To test this hypothesis, we examined the effect of fisetin on NF-B and NF-B-regulated gene products in vitro. We found that among nine different flavones tested, fisetin was potent in suppressing tumor necrosis factor (TNF)-induced NF-B activation. Fisetin also suppressed the NF-B activation induced by various inflammatory agents and carcinogens, and it blocked the phosphorylation and degradation of IB by inhibiting IB (IKK) activation, which in turn led to suppression of the phosphorylation and nuclear translocation of p65. NF-B-dependent reporter gene expression was also suppressed by fisetin, as was NF-B reporter activity induced by TNFR1, TRADD, TRAF2, NIK, and IKK but not that induced by p65 transfection. Fisetin also inhibited TNF-induced TAK1 and receptor-interacting protein activation, events that lie upstream of IKK activation. The expression of NF-B-regulated gene products involved in antiapoptosis (cIAP-1/2, Bcl-2, Bcl-xL, XIAP, Survivin, and TRAF1), proliferation (cyclin D1, c-Myc, COX-2), invasion (ICAM-1 and MMP-9), and angiogenesis (vascular endothelial growth factor) were also down-regulated by fisetin. This correlated with potentiation of apoptosis induced by TNF, doxorubicin, and cisplatin. Thus, overall, our results indicate that fisetin mediates antitumor and anti-inflammatory effects through modulation of NF-B pathways.

Address correspondence to: Bharat B. Aggarwal, Department of Experimental Therapeutics, Unit 143, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail: aggarwal{at}mdanderson.org

This article has been cited by other articles:

				B. Sung, M. K. Pandey, K. S. Ahn, T. Yi, M. M. Chaturvedi, M. Liu, and B. B. Aggarwal Anacardic acid (6-nonadecyl salicylic acid), an inhibitor of histone acetyltransferase, suppresses expression of nuclear factor-{kappa}B-regulated gene products involved in cell survival, proliferation, invasion, and inflammation through inhibition of the inhibitory subunit of nuclear factor-{kappa}B{alpha} kinase, leading to potentiation of apoptosis Blood, May 15, 2008; 111(10): 4880 - 4891. [Abstract] [Full Text] [PDF]