Honokiol potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through modulation of nuclear factor-κB activation pathway

Recent reports have indicated that honokiol can induce apoptosis, suppress tumor growth, and inhibit angiogenesis. In this report, we found that honokiol potentiated the apoptosis induced by tumor necrosis factor (TNF) and chemotherapeutic agents, suppressed TNF-induced tumor cell invasion, and inhibited RANKL-induced osteoclastogenesis, all of which are known to require nuclear factor-kappa B (NF-kappa B) activation. Honokiol suppressed NF-kappa B activation induced by variety of inflammatory stimuli, and this suppression was not cell type specific. Further studies showed that honokiol blocked TNF-induced phosphorylation, ubiquitination, and degradation of I kappa B alpha through the inhibition of activation of I kappa B alpha kinase and of Akt. This led to suppression of the phosphorylation and nuclear translocation of p65 and NF-kappa B-dependent reporter gene expression. Magnolol, a honokiol isomer, was equally active. The expression of NF-kappa B-regulated gene products involved in antiapoptosis (IAP1, IAP2, Bcl-X-L, 136-2, cFLIP, TRAF1, and survivin), proliferation (cyclin D1, cyclooxygenase-2, and c-myc), invasion (matrix metalloproteinase-9 and intercellular adhesion molecule-1), and angiogenesis (vascular endothelial growth factor) were also down-regulated by honokiol. Honokiol also down-regulated NF-kappa B activation in in vivo mouse dorsal skin model. Thus, overall, our results indicate that NF-kappa B and NF-kappa B-regulated gene expression inhibited by honokiol enhances apoptosis and suppresses osteoclastogenesis and invasion.