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

Article Details

Citation

Reuter S, Gupta SC, Phromnoi K, Aggarwal BB

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

Br J Pharmacol. 2012 Apr;165(7):2127-2139.

PubMed ID
Not Available
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-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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
(2E)-3-(2,4-DICHLOROPHENYL)-N-HYDROXYACRYLAMIDEBotulinum neurotoxin type AKi (nM)300N/AN/ADetails
(2E)-3-(2,4-DICHLOROPHENYL)-N-HYDROXYACRYLAMIDEBotulinum neurotoxin type AKi (nM)5600N/AN/ADetails
(2R,3R,4R,5S)-2-(HYDROXYMETHYL)-1-NONYLPIPERIDINE-3,4,5-TRIOLGlucosylceramidaseKi (nM)300N/AN/ADetails
(2R,3R,4R,5S)-2-(HYDROXYMETHYL)-1-NONYLPIPERIDINE-3,4,5-TRIOLGlucosylceramidaseIC 50 (nM)300N/AN/ADetails
(2R,3R,4R,5S)-2-(HYDROXYMETHYL)-1-NONYLPIPERIDINE-3,4,5-TRIOLGlucosylceramidaseIC 50 (nM)660N/AN/ADetails
(2R,3R,4R,5S)-2-(HYDROXYMETHYL)-1-NONYLPIPERIDINE-3,4,5-TRIOLGlucosylceramidaseIC 50 (nM)1500N/AN/ADetails
(2R)-N-[(2R)-2-(DIHYDROXYBORYL)-1-L-PROLYLPYRROLIDIN-2-YL]-N-[(5R)-5-(DIHYDROXYBORYL)-1-L-PROLYLPYRROLIDIN-2-YL]-L-PROLINAMIDEDipeptidyl peptidase 4Ki (nM)3N/AN/ADetails
(R)-RolipramcAMP-specific 3',5'-cyclic phosphodiesterase 4BKi (nM)220N/AN/ADetails
2-Amino-3-Methyl-1-Pyrrolidin-1-Yl-Butan-1-OneDipeptidyl peptidase 4Ki (nM)470N/AN/ADetails
3-{[4-([amino(imino)methyl]aminosulfonyl)anilino]methylene}-2-oxo-2,3-dihydro-1H-indoleCyclin-dependent kinase 2Kd (nM)2877.525Details
3-{[4-([amino(imino)methyl]aminosulfonyl)anilino]methylene}-2-oxo-2,3-dihydro-1H-indoleCyclin-dependent kinase 2Kd (nM)17687.525Details
4-[(4-METHYL-1-PIPERAZINYL)METHYL]-N-[3-[[4-(3-PYRIDINYL)-2-PYRIMIDINYL]AMINO]PHENYL]-BENZAMIDEProto-oncogene tyrosine-protein kinase SrcIC 50 (nM)7800N/AN/ADetails
5-METHYL-3-(9-OXO-1,8-DIAZA-TRICYCLO[10.6.1.013,18]NONADECA-12(19),13,15,17-TETRAEN-10-YLCARBAMOYL)-HEXANOIC ACIDMatrilysinKi (nM)850N/AN/ADetails
7-NitroindazoleNitric oxide synthase, endothelialIC 50 (nM)36000N/AN/ADetails
7-NitroindazoleNitric oxide synthase, inducibleIC 50 (nM)24000N/AN/ADetails
9-(5,5-Difluoro-5-Phosphonopentyl)GuaninePurine nucleoside phosphorylaseKi (nM)18N/AN/ADetails
AC-(D)Phe-pro-borolys-OHProthrombinKi (nM)0.24N/AN/ADetails
ApadenosonAdenosine receptor A2aKi (nM)0.5N/AN/ADetails
Arotinoid acidRetinoic acid receptor betaEC 50 (nM)4N/AN/ADetails
Arotinoid acidRetinoic acid receptor betaEC 50 (nM)3N/AN/ADetails
Arotinoid acidRetinoic acid receptor betaKi (nM)0.5N/AN/ADetails
Arotinoid acidRetinoic acid receptor betaKd (nM)5N/AN/ADetails
BrequinarDihydroorotate dehydrogenase (quinone), mitochondrialKi (nM)12N/AN/ADetails
CamptothecinDNA topoisomerase 1IC 50 (nM)700N/AN/ADetails
CanertinibEpidermal growth factor receptorKd (nM)190N/AN/ADetails
CanertinibEpidermal growth factor receptorKd (nM)170N/AN/ADetails
CanertinibEpidermal growth factor receptorKd (nM)260N/AN/ADetails
CanertinibEpidermal growth factor receptorKd (nM)220N/AN/ADetails
CarbenoxoloneCorticosteroid 11-beta-dehydrogenase isozyme 1IC 50 (nM)500N/AN/ADetails
Chenodeoxycholic acidBile acid receptorEC 50 (nM)13000N/AN/ADetails
Cholic AcidBile acid receptorEC 50 (nM)>100000N/AN/ADetails
DapagliflozinSodium/glucose cotransporter 2IC 50 (nM)0.49N/AN/ADetails
DapagliflozinSodium/glucose cotransporter 2EC 50 (nM)3N/AN/ADetails
DexmethylphenidateSodium-dependent dopamine transporterKi (nM)16N/AN/ADetails
DoramapimodMitogen-activated protein kinase 14Kd (nM)370N/AN/ADetails
ElacridarATP-binding cassette sub-family G member 2IC 50 (nM)127N/AN/ADetails
ElacridarP-glycoprotein 1IC 50 (nM)193N/AN/ADetails
Huperzine AAcetylcholinesteraseIC 50 (nM)5N/AN/ADetails
Huperzine AAcetylcholinesteraseIC 50 (nM)150N/AN/ADetails
KelatorphanLeukotriene A-4 hydrolaseIC 50 (nM)5N/AN/ADetails
KelatorphanLeukotriene A-4 hydrolaseKi (nM)18N/AN/ADetails
KelatorphanLeukotriene A-4 hydrolaseKi (nM)10N/AN/ADetails
MaravirocC-C chemokine receptor type 5IC 50 (nM)0.2N/AN/ADetails
MaravirocC-C chemokine receptor type 5Kd (nM)25N/AN/ADetails
METHYL N-({(2S,3S)-3-[(PROPYLAMINO)CARBONYL]OXIRAN-2-YL}CARBONYL)-L-ISOLEUCYL-L-PROLINATECathepsin BIC 50 (nM)80N/AN/ADetails
METHYLAMINO-PHENYLALANYL-LEUCYL-HYDROXAMIC ACIDInterstitial collagenaseKi (nM)7N/AN/ADetails
METHYLAMINO-PHENYLALANYL-LEUCYL-HYDROXAMIC ACIDInterstitial collagenaseKi (nM)6N/AN/ADetails
METHYLAMINO-PHENYLALANYL-LEUCYL-HYDROXAMIC ACIDNeutrophil collagenaseKi (nM)2N/AN/ADetails
N-[3-(N'-HYDROXYCARBOXAMIDO)-2-(2-METHYLPROPYL)-PROPANOYL]-O-TYROSINE-N-METHYLAMIDEInterstitial collagenaseKi (nM)6N/AN/ADetails
N-[3-(N'-HYDROXYCARBOXAMIDO)-2-(2-METHYLPROPYL)-PROPANOYL]-O-TYROSINE-N-METHYLAMIDEInterstitial collagenaseIC 50 (nM)1.9N/AN/ADetails
N(G)-IminoethylornithineNitric oxide synthase, endothelialKi (nM)810N/AN/ADetails
N4-HYDROXY-2-ISOBUTYL-N1-(9-OXO-1,8-DIAZA-TRICYCLO[10.6.1.013,18]NONADECA-12(19),13,15,17-TETRAEN-10-YL)-SUCCINAMIDEMatrilysinKi (nM)3N/AN/ADetails
NeflamapimodMitogen-activated protein kinase 14IC 50 (nM)45N/AN/ADetails
NeflamapimodMitogen-activated protein kinase 14IC 50 (nM)150N/AN/ADetails
NeflamapimodMitogen-activated protein kinase 14IC 50 (nM)180N/AN/ADetails
NeflamapimodMitogen-activated protein kinase 14IC 50 (nM)9N/AN/ADetails
NeflamapimodMitogen-activated protein kinase 14IC 50 (nM)51N/AN/ADetails
NeflamapimodMitogen-activated protein kinase 14Kd (nM)2800N/AN/ADetails
NicotinamideNAD-dependent protein deacylase sirtuin-5, mitochondrialIC 50 (nM)46600N/AN/ADetails
NomifensineSodium-dependent dopamine transporterKi (nM)23.5N/AN/ADetails
NomifensineSodium-dependent dopamine transporterKi (nM)10N/AN/ADetails
NomifensineSodium-dependent dopamine transporterKi (nM)7N/AN/ADetails
NomifensineSodium-dependent dopamine transporterKi (nM)450N/AN/ADetails
NomifensineSodium-dependent noradrenaline transporterKi (nM)5N/AN/ADetails
NomifensineSodium-dependent noradrenaline transporterKi (nM)4N/AN/ADetails
NomifensineSodium-dependent noradrenaline transporterKi (nM)1200N/AN/ADetails
NomifensineSodium-dependent serotonin transporterKi (nM)1400N/AN/ADetails
NomifensineSodium-dependent serotonin transporterKi (nM)1200N/AN/ADetails
NomifensineSodium-dependent serotonin transporterKi (nM)800N/AN/ADetails
OlomoucineCyclin-dependent kinase 2IC 50 (nM)7000N/AN/ADetails
OsanetantNeuromedin-K receptorIC 50 (nM)0.8N/AN/ADetails
OsanetantNeuromedin-K receptorIC 50 (nM)0.21N/AN/ADetails
PazopanibPlatelet-derived growth factor receptor alphaKd (nM)4900N/AN/ADetails
PazopanibPlatelet-derived growth factor receptor betaKd (nM)2000N/AN/ADetails
PazopanibVascular endothelial growth factor receptor 1Kd (nM)140007.425Details
PazopanibVascular endothelial growth factor receptor 2Kd (nM)14000N/AN/ADetails
PD-0325901Dual specificity mitogen-activated protein kinase kinase 1IC 50 (nM)0.6N/AN/ADetails
PhosphoramidonNeprilysinIC 50 (nM)30N/AN/ADetails
PhosphoramidonNeprilysinIC 50 (nM)100N/AN/ADetails
PimagedineNitric oxide synthase, inducibleIC 50 (nM)54000N/AN/ADetails
RimonabantCannabinoid receptor 1Ki (nM)1.6N/AN/ADetails
RimonabantCannabinoid receptor 1Ki (nM)11N/AN/ADetails
RimonabantCannabinoid receptor 1Ki (nM)7.3N/AN/ADetails
RimonabantCannabinoid receptor 1Ki (nM)1.8N/AN/ADetails
RimonabantCannabinoid receptor 1Ki (nM)13N/AN/ADetails
SeliciclibCasein kinase I isoform epsilonKd (nM)320000N/AN/ADetails
SeliciclibCyclin-dependent kinase 2Kd (nM)3400000N/AN/ADetails
SeliciclibCyclin-dependent kinase 7Kd (nM)18000007.423Details
SemaxanibVascular endothelial growth factor receptor 2IC 50 (nM)1000N/AN/ADetails
StanoloneAndrogen receptorKi (nM)10N/AN/ADetails
StanoloneAndrogen receptorEC 50 (nM)0.05N/AN/ADetails
Staurosporine3-phosphoinositide-dependent protein kinase 1Kd (nM)1700N/AN/ADetails
StaurosporineCyclin-dependent kinase 2Kd (nM)7000N/AN/ADetails
StaurosporineMAP kinase-activated protein kinase 2Kd (nM)880000N/AN/ADetails
StaurosporineProtein kinase C theta typeKd (nM)8500N/AN/ADetails
StaurosporineSerine/threonine-protein kinase pim-1Kd (nM)3200N/AN/ADetails
StaurosporineTyrosine-protein kinase CSKKd (nM)330000N/AN/ADetails
StaurosporineTyrosine-protein kinase ITK/TSKKd (nM)19000N/AN/ADetails
StaurosporineTyrosine-protein kinase LckKd (nM)30000N/AN/ADetails
StaurosporineTyrosine-protein kinase SYKKd (nM)14000N/AN/ADetails
SuraminNAD-dependent protein deacylase sirtuin-5, mitochondrialIC 50 (nM)25000N/AN/ADetails
SuraminNAD-dependent protein deacylase sirtuin-5, mitochondrialIC 50 (nM)46600N/AN/ADetails
TapentadolMu-type opioid receptorKi (nM)160N/AN/ADetails
TapentadolMu-type opioid receptorEC 50 (nM)670N/AN/ADetails
ThiorphanNeprilysinIC 50 (nM)5N/AN/ADetails
ThiorphanNeprilysinKi (nM)4.7N/AN/ADetails
ThiorphanNeprilysinIC 50 (nM)7.9N/AN/ADetails
ThiorphanNeprilysinIC 50 (nM)4.8N/AN/ADetails
ThiorphanNeprilysinKi (nM)1.7N/AN/ADetails
ThiorphanNeprilysinKi (nM)2.2N/AN/ADetails
TofacitinibTyrosine-protein kinase JAK3Ki (nM)2200N/AN/ADetails
TorcetrapibCholesteryl ester transfer proteinIC 50 (nM)13N/AN/ADetails
Trichostatin AHistone deacetylase 7IC 50 (nM)22.46N/AN/ADetails
UbenimexLeukotriene A-4 hydrolaseIC 50 (nM)4000N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)9500N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)5900N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)12000N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)7900N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)8900N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)11000N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)4800N/AN/ADetails
VandetanibProtein-tyrosine kinase 6Kd (nM)160000N/AN/ADetails
VandetanibProto-oncogene tyrosine-protein kinase receptor RetKd (nM)34000N/AN/ADetails
VandetanibProto-oncogene tyrosine-protein kinase receptor RetKd (nM)14000N/AN/ADetails
VatalanibVascular endothelial growth factor receptor 1Kd (nM)96007.425Details
VatalanibVascular endothelial growth factor receptor 2Kd (nM)62000N/AN/ADetails
VorinostatHistone deacetylase 1IC 50 (nM)76N/AN/ADetails
VorinostatHistone deacetylase 1IC 50 (nM)258N/AN/ADetails
VorinostatHistone deacetylase 1IC 50 (nM)41N/AN/ADetails
VorinostatHistone deacetylase 1IC 50 (nM)69N/AN/ADetails
VorinostatHistone deacetylase 1IC 50 (nM)196N/AN/ADetails
VorinostatHistone deacetylase 2IC 50 (nM)66N/AN/ADetails
VorinostatHistone deacetylase 2IC 50 (nM)921N/AN/ADetails
VorinostatHistone deacetylase 2IC 50 (nM)180N/AN/ADetails
VorinostatHistone deacetylase 2IC 50 (nM)537N/AN/ADetails
VorinostatHistone deacetylase 2IC 50 (nM)256N/AN/ADetails
VorinostatHistone deacetylase 3IC 50 (nM)350N/AN/ADetails
VorinostatHistone deacetylase 3IC 50 (nM)110N/AN/ADetails
VorinostatHistone deacetylase 3IC 50 (nM)28N/AN/ADetails
VorinostatHistone deacetylase 3IC 50 (nM)41N/AN/ADetails
VorinostatHistone deacetylase 3IC 50 (nM)43N/AN/ADetails
VorinostatHistone deacetylase 6IC 50 (nM)28.6N/AN/ADetails
VorinostatHistone deacetylase 6IC 50 (nM)18N/AN/ADetails
VorinostatHistone deacetylase 6IC 50 (nM)118N/AN/ADetails