Abstract
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-κB (NF-κB) is associated with inflammation, carcinogenesis, hyperproliferation, invasion, and angiogenesis, we hypothesized that gossypin mediates its effects through modulation of NF-κB activation. In the present study, we demonstrate that gossypin (and not gossypetin, an aglycone analog) inhibited NF-κB activation induced by inflammatory stimuli and carcinogens. Constitutive NF-κB activation in tumor cells was also inhibited by this flavone. Inhibition of IκBα kinase by gossypin led to the suppression of IκBα phosphorylation and degradation, p65 nuclear translocation, and NF-κB-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-1β–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-κB 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-κB activation pathway, which may explain its role in the suppression of inflammation, carcinogenesis, and angiogenesis.
Serum biomarker profiles of interleukin-6, tumor necrosis factor alpha, matrix-metalloproteinase-2, and vascular endothelial growth factor in endometriosis staging
