Honokiol Potentiates Apoptosis, Suppresses Osteoclastogenesis, and Inhibits Invasion through Modulation of Nuclear Factor-κB Activation Pathway

Abstract

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-KB (NF-KB) activation. Honokiol suppressed NF-KB activation induced by a 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 IKBA through the inhibition of activation of IKBA kinase and of Akt. This led to suppression of the phosphorylation and nuclear translocation of p65 and NF-KB-dependent reporter gene expression. Magnolol, a honokiol isomer, was equally active. The expression of NF-KB-regulated gene products involved in antiapoptosis (IAP1, IAP2, Bcl-x L , Bcl-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-KB activation in in vivo mouse dorsal skin model. Thus, overall, our results indicate that NF-KB and NF-KB-regulated gene expression inhibited by honokiol enhances apoptosis and suppresses osteoclastogenesis and invasion. (Mol Cancer Res 2006;4(9):621 -33)

Targeting apoptosis pathways in cancer with magnolol and honokiol, bioactive constituents of the bark of <i>Magnolia officinalis </i>

“…Honokiol inhibited TNF-induced NF-κB activation and IkBα phosphorylation and degradation through its inhibition of the activation of IκBα kinase and Akt. Honokiol also inhibited NF-κB-dependent reporter gene expression induced by TNFR1, TRADD, TRAF, NIK, and IKKβ (88). Consistent with honokiol's effect on NF-κB, honokiol decreased levels of NF-κB target genes, including IAP1, IAP2, Bcl-xL, Bcl-2, cFLIP, TRAF1, and survivin (88).…”

“…Honokiol also inhibited NF-κB-dependent reporter gene expression induced by TNFR1, TRADD, TRAF, NIK, and IKKβ (88). Consistent with honokiol's effect on NF-κB, honokiol decreased levels of NF-κB target genes, including IAP1, IAP2, Bcl-xL, Bcl-2, cFLIP, TRAF1, and survivin (88). NF-κB and NF-κB-regulated gene expression inhibited by honokiol can thus enhance apoptosis.…”

“…Honokiol affected NF-κB signaling, but not through a direct effect on NF-κB DNA binding (88). Honokiol inhibited TNF-induced NF-κB activation and IkBα phosphorylation and degradation through its inhibition of the activation of IκBα kinase and Akt.…”

Honokiol causes G0-G1 phase cell cycle arrest in human prostate cancer cells in association with suppression of retinoblastoma protein level/phosphorylation and inhibition of E2F1 transcriptional activity

“…In a separate study, honokiol treatment potentiated apoptosis, suppressed osteoclastogenesis, and inhibited invasion through the modulation of NF-nB (16). The NF-nB is a transcription factor involved in the regulation of various genes, including inflammatory cytokines, chemokines, cell adhesion molecules, growth factors, and IFNs (17).…”

“…Because honokiol treatment suppresses NF-nB activation (15,16), we hypothesized that this phytochemical might inhibit growth of human prostate cancer cells. In the present study, we tested this hypothesis using PC-3 (an androgen-independent cell line lacking functional p53) and LNCaP (an androgen-responsive cell line with wild-type p53) human prostate cancer cell lines as a model.…”