title: Thiocolchicoside suppresses osteoclastogenesis induced by RANKL and cancer cells through inhibition of inflammatory pathways: a new use for an old drug.
abstract: OBJECTIVE
  Most patients with cancer die not because of the tumour in the primary site, but because it has spread to other sites. Common tumours, such as breast, multiple myeloma, and prostate tumours, frequently metastasize to the bone. To search for an inhibitor of cancer-induced bone loss, we investigated the effect of thiocolchicoside, a semi-synthetic colchicoside derived from the plant Gloriosa superba and clinically used as a muscle relaxant, on osteoclastogenesis induced by receptor activator of NF-κB ligand (RANKL) and tumour cells.
  
  
  METHODS
  We used RAW 264.7 (murine macrophage) cells, a well-established system for osteoclastogenesis, and evaluated the effect of thiocolchicoside on RANKL-induced NF-κB signalling and osteoclastogenesis as well as on osteoclastogenesis induced by tumour cells.
  
  
  RESULTS
  Thiocolchicoside suppressed osteoclastogenesis induced by RANKL, and by breast cancer and multiple myeloma cells. Inhibition of the NF-κB pathway was responsible for this effect since the colchicoside inhibited RANKL-induced NF-κB activation, activation of IκB kinase (IKK) and suppressed inhibitor of NF-κBα (IκBα) phosphorylation and degradation, an inhibitor of NF-κB. Furthermore, an inhibitor of the IκBα kinase γ or NF-κB essential modulator, the regulatory component of the IKK complex, demonstrated that the NF-κB signalling pathway is mandatory for osteoclastogenesis induced by RANKL.
  
  
  CONCLUSIONS
  Together, these data suggest that thiocolchicoside significantly suppressed osteoclastogenesis induced by RANKL and tumour cells via the NF-κB signalling pathway. Thus, thiocolchicoside, a drug that has been used for almost half a century to treat muscle pain, may also be considered as a new treatment for bone loss.
authors.affiliation: Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Reuter
authors.forename: Subash C
authors.initials: SC
authors.lastname: Gupta
authors.forename: Kanokkarn
authors.initials: K
authors.lastname: Phromnoi
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D001862:Bone Resorption / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D003078:Colchicine / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000517:prevention & control; D019668:Liliaceae / Q000737:chemistry; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D008517:Phytotherapy; D053245:RANK Ligand / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D051550:I-kappa B Kinase; D003078:Colchicine; C004280:thiocolchicoside