title: 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.
abstract: 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.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Reuter
authors.forename: Sahdeo
authors.initials: S
authors.lastname: Prasad
authors.forename: Kanokkarn
authors.initials: K
authors.lastname: Phromnoi
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Kannappan
authors.forename: Vivek R
authors.initials: VR
authors.lastname: Yadav
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
mesh_terms: 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
chemical_list: D016227:Benzoquinones; D050071:Bone Density Conservation Agents; D016328:NF-kappa B; D053245:RANK Ligand; C505688:TNFSF11 protein, human; C010945:embelin
references.citation: Chem Ber. 1972;105(2):614-24
references.pmid: 4645596
references.citation: J Biol Chem. 2004 Sep 3;279(36):37219-22
references.pmid: 15252035
references.citation: Endocrinology. 2001 Mar;142(3):1290-5
references.pmid: 11181547
references.citation: Cancer Cell. 2004 Sep;6(3):203-8
references.pmid: 15380510
references.citation: Clin Cancer Res. 2006 Feb 15;12(4):1221-8
references.pmid: 16489077
references.citation: Curr Opin Otolaryngol Head Neck Surg. 2008 Aug;16(4):325-30
references.pmid: 18626250
references.citation: Indian J Physiol Pharmacol. 1977 Jan-Mar;21(1):31-9
references.pmid: 873589
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10137-42
references.pmid: 15220474
references.citation: Br J Cancer. 2001 Jul 6;85(1):78-84
references.pmid: 11437406
references.citation: Mol Cancer Ther. 2009 Aug;8(8):2339-47
references.pmid: 19671767
references.citation: Nature. 2003 May 15;423(6937):337-42
references.pmid: 12748652
references.citation: J Mammary Gland Biol Neoplasia. 2005 Apr;10(2):169-80
references.pmid: 16025223
references.citation: Nat Med. 2007 Jan;13(1):62-9
references.pmid: 17159986
references.citation: Mol Pharmacol. 2007 Jan;71(1):209-19
references.pmid: 17028156
references.citation: Yao Xue Xue Bao. 1963 Sep;10:578-80
references.pmid: 14082600
references.citation: J Bone Miner Res. 2008 Jun;23(6):826-36
references.pmid: 18558816
references.citation: J Biol Chem. 2004 Dec 24;279(52):54841-8
references.pmid: 15485831
references.citation: Cancer Res. 2003 Sep 1;63(17):5438-45
references.pmid: 14500379
references.citation: N Engl J Med. 2004 Apr 15;350(16):1655-64
references.pmid: 15084698
references.citation: J Biol Chem. 2006 Jun 9;281(23):15809-20
references.pmid: 16613848
references.citation: Morphologie. 2008 Dec;92(299):162-70
references.pmid: 19019718
references.citation: Int J Cancer. 2005 Aug 20;116(2):253-62
references.pmid: 15800904
references.citation: Clin Cancer Res. 2005 Jan 1;11(1):162-5
references.pmid: 15671541
references.citation: Cancer. 2000 Jun 15;88(12 Suppl):2989-94
references.pmid: 10898342
references.citation: J Immunol. 2003 Nov 15;171(10):5547-53
references.pmid: 14607962
references.citation: Mol Pharmacol. 2007 Jun;71(6):1703-14
references.pmid: 17387141
references.citation: Blood. 2001 Dec 15;98(13):3527-33
references.pmid: 11739153
references.citation: Chemotherapy. 1994 Mar-Apr;40(2):109-13
references.pmid: 7510605
references.citation: Blood. 2002 Dec 15;100(13):4615-21
references.pmid: 12393684
references.citation: Nat Rev Genet. 2003 Aug;4(8):638-49
references.pmid: 12897775
references.citation: Mol Pathol. 1997 Jun;50(3):132-7
references.pmid: 9292147
references.citation: J Am Dent Assoc. 2008 Jan;139(1):23-30
references.pmid: 18167381
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3540-5
references.pmid: 10097072
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11581-6
references.pmid: 11562486
references.citation: Genes Dev. 1997 Dec 15;11(24):3482-96
references.pmid: 9407039
references.citation: J Biol Chem. 2007 Jun 15;282(24):17340-50
references.pmid: 17439942
references.citation: Cancer Treat Rev. 2001 Jun;27(3):165-76
references.pmid: 11417967
references.citation: Apoptosis. 2004 Nov;9(6):677-90
references.pmid: 15505411
references.citation: J Cell Biol. 2000 Jan 24;148(2):333-42
references.pmid: 10648566
references.citation: J Dent Educ. 2008 Aug;72(8):919-29
references.pmid: 18676801
references.citation: Immunol Rev. 2005 Dec;208:30-49
references.pmid: 16313339
references.citation: J Biol Chem. 2001 Aug 10;276(32):30499-503
references.pmid: 11408488
references.citation: J Exp Med. 2005 May 16;201(10):1677-87
references.pmid: 15897281
references.citation: Clin Exp Metastasis. 2008;25(2):119-29
references.pmid: 18064531
references.citation: Clin Cancer Res. 2003 Apr;9(4):1436-40
references.pmid: 12684416
references.citation: Blood. 2004 Apr 15;103(8):3175-84
references.pmid: 15070700
references.citation: J Musculoskelet Neuronal Interact. 2008 Jul-Sep;8(3):204-16
references.pmid: 18799853
references.citation: Nat Med. 2004 Jun;10(6):617-24
references.pmid: 15156202
references.citation: J Bone Miner Res. 1996 Feb;11(2):150-9
references.pmid: 8822338
references.citation: Br J Haematol. 2004 Jul;126(2):192-201
references.pmid: 15238139