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Inhibition of related JAK/STAT pathways with molecular targeted drugs shows strong synergy with ruxolitinib in chronic myeloproliferative neoplasm.
- Source :
-
British journal of haematology [Br J Haematol] 2013 Jun; Vol. 161 (5), pp. 667-676. Date of Electronic Publication: 2013 Apr 05. - Publication Year :
- 2013
-
Abstract
- This study aimed to assess the antitumour effects, molecular mechanisms of action, and potential synergy of ruxolitinib with sorafenib, KNK437, dasatinib, and perifosine, in Philadelphia-negative chronic myeloproliferative neoplasms (MPN). Cytotoxic and cytostatic effects of the different compounds were determined in the JAK2 V617F-positive cell lines, HEL and Ba/F3 (JAK2V617F EPOR) , and in primary mononuclear and bone marrow CD34-positive cells from 19 MPN patients. Ruxolitinib [50% inhibitory concentration (IC50 )(PV)  = 15 nmol/l], as well as sorafenib (IC50 PV=8μmol/l), KNK437 (IC50 PV=100μmol/l ), and perifosine (IC50 PV=15μmol/l ), were able to inhibit proliferation in cell line models and in primary cells from MPN patients. Dasatinib, KNK437, and sorafenib showed a strong synergistic effect in combination with ruxolitinib [combination index (CI)(PV)  < 0·3]. Western blot confirmed that ruxolitinib blocked ERK, and consequently STAT5 activation, sorafenib inhibited ERK, P38 and STAT5, dasatinib blocked SRC and STAT5, and KNK437 decreased the stability of the JAK2 protein, reducing its expression. Inhibiting JAK2-related proliferative pathways has the potential to inhibit cell proliferation in MPNs. Furthermore, the combination of ruxolitinib with inhibitors that target these pathways has a strong synergistic effect, which may be due to decreased activation of the common effector, STAT5.<br /> (© 2013 John Wiley & Sons Ltd.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Benzhydryl Compounds pharmacology
Cell Proliferation drug effects
Cells, Cultured
Chronic Disease
Dasatinib
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical methods
Drug Synergism
Female
Humans
Janus Kinase 2 genetics
Janus Kinase 2 metabolism
Male
Middle Aged
Myeloproliferative Disorders enzymology
Myeloproliferative Disorders pathology
Niacinamide administration & dosage
Niacinamide analogs & derivatives
Niacinamide pharmacology
Nitriles
Phenylurea Compounds administration & dosage
Phenylurea Compounds pharmacology
Phosphorylcholine analogs & derivatives
Phosphorylcholine pharmacology
Polycythemia Vera drug therapy
Polycythemia Vera enzymology
Polycythemia Vera pathology
Pyrazoles administration & dosage
Pyrimidines pharmacology
Pyrrolidinones pharmacology
STAT5 Transcription Factor antagonists & inhibitors
STAT5 Transcription Factor metabolism
Signal Transduction drug effects
Sorafenib
Thiazoles pharmacology
Thrombocythemia, Essential drug therapy
Thrombocythemia, Essential enzymology
Thrombocythemia, Essential pathology
Tumor Cells, Cultured drug effects
Janus Kinases antagonists & inhibitors
Myeloproliferative Disorders drug therapy
Protein Kinase Inhibitors pharmacology
Pyrazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2141
- Volume :
- 161
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- British journal of haematology
- Publication Type :
- Academic Journal
- Accession number :
- 23560534
- Full Text :
- https://doi.org/10.1111/bjh.12308