Embelin suppresses osteoclastogenesis induced by receptor activator of NF-κB ligand and tumor cells in vitro through inhibition of the NF-κB cell signaling pathway.
Most patients with cancer die not because of the tumor in the primary site, but because it has spread to other sites. Common tumors, such as breast, multiple myeloma, and prostate tumors, frequently metastasize to the bone. It is now well recognized that osteoclasts are responsible for the osteolysis observed in bone metastases of the tumor. Receptor activator of NF-κB ligand (RANKL), a member of the tumor necrosis factor superfamily and an activator of the NF-κB signaling pathway, has emerged as a major mediator of bone loss, commonly associated with cancer and other chronic inflammatory diseases. Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone), derived from the Ayurvedic medicinal plant Embelia ribes, has been shown to bind and inhibit X-linked inhibitor of apoptosis protein and inhibit inflammatory pathways. We investigated whether embelin could inhibit osteoclastogenesis-associated bone loss induced by RANKL and by tumor cells in vitro. We found that embelin suppressed the RANKL-induced differentiation of monocytes into osteoclasts. This benzoquinone also suppressed the osteoclastogenesis induced by multiple myeloma and by breast cancer cells. This effect of embelin correlated with the suppression of NF-κB activation and inhibition of IκBα phosphorylation and IκBα degradation. Inhibition of IκBα phosphorylation was due to the inhibition of IκBα kinase (IKK) activation. Furthermore, by using an inhibitor of the IKKγ or NF-κB essential modulator (NEMO), the regulatory component of the IKK complex, we showed that the NF-κB signaling pathway is mandatory for RAW 264.7 cell differentiation into osteoclasts. Thus, embelin, an inhibitor of RANKL-induced NF-κB activation has great potential as a therapeutic agent for osteoporosis and cancer-linked bone loss.
Reuter
Simone
S
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Prasad
Sahdeo
S
Phromnoi
Kanokkarn
K
Kannappan
Ramaswamy
R
Yadav
Vivek R
VR
Aggarwal
Bharat B
BB
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D010024:Osteoporosis / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D053245:RANK Ligand / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D016227:Benzoquinones; D050071:Bone Density Conservation Agents; D016328:NF-kappa B; D053245:RANK Ligand; C505688:TNFSF11 protein, human; C010945:embelin
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