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

Abstract

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
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 165 Issue 7 Pg. 2127-39 (Apr 2012) ISSN: 1476-5381 [Electronic] England
• PMID: 21955206 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• NF-kappa B
• RANK Ligand
• Tnfsf11 protein, mouse
• I-kappa B Kinase
• Colchicine
• thiocolchicoside

Topics

• 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)