Thiocolchicoside suppresses osteoclastogenesis induced by RANKL and cancer cells through inhibition of inflammatory pathways: a new use for an old drug.
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-kappaB 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-kappaB 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-kappaB pathway was responsible for this effect since the colchicoside inhibited RANKL-induced NF-kappaB activation, activation of IkappaB kinase (IKK) and suppressed inhibitor of NF-kappaBalpha (IkappaBalpha) phosphorylation and degradation, an inhibitor of NF-kappaB. Furthermore, an inhibitor of the IkappaBalpha kinase gamma or NF-kappaB essential modulator, the regulatory component of the IKK complex, demonstrated that the NF-kappaB 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-kappaB 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.
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NF-kappaB IkappaB kinase IKK NF-kappaBalpha IkappaBalpha NF-kappaB IkappaBalpha kinase NF-kappaB IKK colchicoside NF-kappaB RANKL RANKL NF-kappaB receptor activator of NF-kappaB ligand RANKL RANKL NF-kappaB RANKL NF-kappaB thiocolchicoside RANKL thiocolchicoside thiocolchicoside colchicoside thiocolchicoside Thiocolchicoside Thiocolchicoside RANKL