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.

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-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.

• Authors: Ajaikumar B Kunnumakkara, Asha S Nair, Kwang Seok Ahn, Manoj K Pandey, Zhengfang Yi, Mingyao Liu, Bharat B Aggarwal
• Journal: Blood (Blood) Vol. 109 Issue 12 Pg. 5112-21 (Jun 15 2007) ISSN: 0006-4971 [Print] United States
• PMID: 17332240 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Anti-Inflammatory Agents
• Anticarcinogenic Agents
• Flavones
• Flavonoids
• NF-kappa B
• Transforming Growth Factor beta1
• Tumor Necrosis Factor-alpha
• gossypin
• I-kappa B Kinase

Topics

• Angiogenesis Inhibitors (pharmacology)
• Anti-Inflammatory Agents (pharmacology)
• Anticarcinogenic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cells, Cultured
• Down-Regulation (genetics)
• Endothelium, Vascular (cytology)
• Enzyme Activation (drug effects)
• Flavones
• Flavonoids (pharmacology)
• Humans
• I-kappa B Kinase (antagonists & inhibitors)
• NF-kappa B (antagonists & inhibitors, metabolism)
• Osteoclasts (drug effects)
• Transforming Growth Factor beta1 (pharmacology)
• Tumor Necrosis Factor-alpha (pharmacology)