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Thymoquinone inhibits proliferation, induces apoptosis and chemosensitizes human multiple myeloma cells through suppression of signal transducer and activator of transcription 3 activation pathway.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2010 Oct; Vol. 161 (3), pp. 541-54. - Publication Year :
- 2010
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Abstract
- Background and Purpose: Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) pathway is frequently encountered in several human cancers including multiple myeloma (MM). Thus, agents that suppress STAT3 phosphorylation have a potential for treatment of MM. In the present report, we investigated whether thymoquinone (TQ), the main component isolated from the medicinal plant Nigella sativa, modulated the STAT3 signalling pathway in MM cells.<br />Experimental Approach: The effect of TQ on both constitutive and IL-6-induced STAT3 activation, associated protein kinases, STAT3-regulated gene products involved in proliferation, survival and angiogenesis, cellular proliferation and apoptosis in MM cells, was investigated.<br />Key Results: We found that TQ inhibited both constitutive and IL-6-inducible STAT3 phosphorylation which correlated with the inhibition of c-Src and JAK2 activation. Vanadate reversed the TQ-induced down-regulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that TQ can induce the expression of Src homology-2 phosphatase 2 that correlated with suppression of STAT3 activation. TQ also down-regulated the expression of STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1 and vascular endothelial growth factor. Finally, TQ induced the accumulation of cells in sub-G1 phase, inhibited proliferation and induced apoptosis, as indicated by poly ADP ribose polymerase cleavage. TQ also significantly potentiated the apoptotic effects of thalidomide and bortezomib in MM cells.<br />Conclusions and Implications: Our study has identified STAT3 signalling as a target of TQ and has thus raised its potential application in the prevention and treatment of MM and other cancers.
- Subjects :
- Antineoplastic Agents pharmacology
Benzoquinones antagonists & inhibitors
Boronic Acids pharmacology
Bortezomib
Cell Line, Tumor
Down-Regulation drug effects
Humans
Inositol Polyphosphate 5-Phosphatases
Interleukin-6 pharmacology
Janus Kinase 2 metabolism
Phosphoric Monoester Hydrolases metabolism
Phosphorylation drug effects
Pyrazines pharmacology
STAT3 Transcription Factor antagonists & inhibitors
Thalidomide pharmacology
Vanadates pharmacology
Apoptosis drug effects
Benzoquinones pharmacology
Cell Proliferation drug effects
Multiple Myeloma metabolism
STAT3 Transcription Factor metabolism
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5381
- Volume :
- 161
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 20880395
- Full Text :
- https://doi.org/10.1111/j.1476-5381.2010.00874.x