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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5112-5121.
Prepublished online as a Blood First Edition Paper on March 1, 2007; DOI 10.1182/blood-2007-01-067256.


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CHEMOKINES, CYTOKINES, AND INTERLEUKINS

Gossypin, a pentahydroxy glucosyl flavone, inhibits the transforming growth factor beta-activated kinase-1-mediated NF-{kappa}B activation pathway, leading to potentiation of apoptosis, suppression of invasion, and abrogation of osteoclastogenesis

Ajaikumar B. Kunnumakkara1, Asha S. Nair1, Kwang Seok Ahn1, Manoj K. Pandey1, Zhengfang Yi2, Mingyao Liu2, and Bharat B. Aggarwal1

1 Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX; 2 Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University System HSC, Houston, TX.

Gossypin, a flavone originally isolated from Hibiscus vitifolius, has been shown to suppress angiogenesis, inflammation, and carcinogenesis. The mechanisms of these activities, however, are unknown. Because nuclear factor-{kappa}B (NF-{kappa}B) is associated with inflammation, carcinogenesis, hyperproliferation, invasion, and angiogenesis, we hypothesized that gossypin mediates its effects through modulation of NF-{kappa}B activation. In the present study, we demonstrate that gossypin (and not gossypetin, an aglycone analog) inhibited NF-{kappa}B activation induced by inflammatory stimuli and carcinogens. Constitutive NF-{kappa}B activation in tumor cells was also inhibited by this flavone. Inhibition of I{kappa}B{alpha} kinase by gossypin led to the suppression of I{kappa}B{alpha} phosphorylation and degradation, p65 nuclear translocation, and NF-{kappa}B-regulated gene expression. This, in turn, led to the down-regulation of gene products involved in cell survival (IAP2, XIAP, Bcl-2, Bcl-xL, survivin, and antiFas-associated death domain–like interleukin-1ß–converting enzyme-inhibitory protein), proliferation (c-myc, cyclin D1, and cyclooxygenase-2), angiogenesis (vascular endothelial growth factor), and invasion (matrix metalloprotease-9). Suppression of these gene products by gossypin enhanced apoptosis induced by tumor necrosis factor and chemotherapeutic agents, suppressed tumor necrosis factor–induced cellular invasion, abrogated receptor activator of NF-{kappa}B ligand–induced osteoclastogenesis, and vascular endothelial growth factor–induced migration of human umbilical vein endothelial cells. Overall, our results demonstrate that gossypin inhibits the NF-{kappa}B activation pathway, which may explain its role in the suppression of inflammation, carcinogenesis, and angiogenesis.


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