Thiocolchicoside suppresses osteoclastogenesis induced by RANKL and cancer cells through inhibition of inflammatory pathways: a new use for an old drug.

Thiocolchicoside suppresses osteoclastogenesis induced by RANKL and cancer cells through inhibition of inflammatory pathways: a new use for an old drug.

MedLine Citation:	PMID: 21955206 Owner: NLM Status: MEDLINE
Abstract/OtherAbstract:	BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY 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 AND IMPLICATIONS: 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:	Simone Reuter; Subash C Gupta; Kanokkarn Phromnoi; Bharat B Aggarwal
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Publication Detail:	Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Journal Detail:	Title: British journal of pharmacology Volume: 165 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2012 Apr
Date Detail:	Created Date: 2012-03-12 Completed Date: 2012-07-23 Revised Date: 2013-05-23
Medline Journal Info:	Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England
Other Details:	Languages: eng Pagination: 2127-39 Citation Subset: IM
Copyright Information:	© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Affiliation:	Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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MeSH Terms
Descriptor/Qualifier:	Animals Bone Neoplasms / drug therapy, secondary Bone Resorption / drug therapy, pathology, physiopathology Cell Line Colchicine / analogs & derivatives, isolation & purification, pharmacology Enzyme Activation / drug effects Female Humans I-kappa B Kinase / metabolism Inflammation / prevention & control Liliaceae / chemistry Male Mice NF-kappa B / metabolism Osteoclasts / drug effects*, pathology, physiology Phytotherapy RANK Ligand / physiology Signal Transduction / drug effects
Grant Support
ID/Acronym/Agency:	CA-124787-01A2/CA/NCI NIH HHS; CA-16 672/CA/NCI NIH HHS; P01 CA124787/CA/NCI NIH HHS
Chemical
Reg. No./Substance:	0/NF-kappa B; 0/RANK Ligand; 0/Tnfsf11 protein, mouse; 602-41-5/thiocolchicoside; 64-86-8/Colchicine; EC 2.7.11.10/I-kappa B Kinase
Comments/Corrections
Comment In:	Br J Pharmacol. 2012 Apr;165(7):2124-6 [PMID: 22122264 ]

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