Gossypin, a pentahydroxy glucosyl flavone, inhibits the transforming growth factor beta-activated kinase-1-mediated NF-kappaB activation pathway, leading to potentiation of apoptosis, suppression of invasion, and abrogation of osteoclastogenesis.
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-kappaB (NF-kappaB) is associated with inflammation, carcinogenesis, hyperproliferation, invasion, and angiogenesis, we hypothesized that gossypin mediates its effects through modulation of NF-kappaB activation. In the present study, we demonstrate that gossypin (and not gossypetin, an aglycone analog) inhibited NF-kappaB activation induced by inflammatory stimuli and carcinogens. Constitutive NF-kappaB 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-kappaB-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-1 beta-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-kappaB 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-kappaB activation pathway, which may explain its role in the suppression of inflammation, carcinogenesis, and angiogenesis.
Kunnumakkara
Ajaikumar B
AB
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Nair
Asha S
AS
Ahn
Kwang Seok
KS
Pandey
Manoj K
MK
Yi
Zhengfang
Z
Liu
Mingyao
M
Aggarwal
Bharat B
BB
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D047309:Flavones; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D000893:Anti-Inflammatory Agents; D016588:Anticarcinogenic Agents; D047309:Flavones; D005419:Flavonoids; D016328:NF-kappa B; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C022944:gossypin; D051550:I-kappa B Kinase