scholarly journals A phosphoproteomic signature in endothelial cells predicts vascular toxicity of tyrosine kinase inhibitors used in CML

2018 ◽  
Vol 2 (14) ◽  
pp. 1680-1684 ◽  
Author(s):  
Srila Gopal ◽  
Qing Lu ◽  
Joshua J. Man ◽  
Wendy Baur ◽  
Sitara P. Rao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Drug Development ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Screening Tool ◽  
Kinase Inhibitors ◽  
Vascular Toxicity ◽  
Key Points

Key Points Newer CML kinase inhibitors increase ischemia risk and are toxic to endothelial cells where they produce a proteomic toxicity signature. This phosphoproteomic EC toxicity signature predicts bosutinib to be safe, providing a potential screening tool for safer drug development.

scholarly journals Oral Bruton tyrosine kinase inhibitors selectively block atherosclerotic plaque–triggered thrombus formation in humans

Blood ◽  
2018 ◽  
Vol 131 (24) ◽  
pp. 2605-2616 ◽  
Author(s):  
Kristina Busygina ◽  
Janina Jamasbi ◽  
Till Seiler ◽  
Hans Deckmyn ◽  
Christian Weber ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Atherosclerotic Plaque ◽  
Kinase Inhibitors ◽  
Thrombus Formation ◽  
Drug Dosing ◽  
Key Points ◽  
Bruton Tyrosine Kinase ◽  
Platelet Thrombus ◽  
Btk Inhibitors

Key Points Btk inhibitors specifically block platelet thrombus formation on atherosclerotic plaque but spare physiologic hemostasis. Irreversible Btk inactivation in platelets incapable of enzyme resynthesis allows low intermittent drug dosing for antiatherothrombosis.

scholarly journals Oral Bruton tyrosine kinase inhibitors block activation of the platelet Fc receptor CD32a (FcγRIIA): a new option in HIT?

2019 ◽  
Vol 3 (23) ◽  
pp. 4021-4033 ◽  
Author(s):  
Luise Goldmann ◽  
Rundan Duan ◽  
Thorsten Kragh ◽  
Georg Wittmann ◽  
Christian Weber ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Platelet Activation ◽  
Kinase Inhibitors ◽  
Fc Receptor ◽  
Cross Linking ◽  
Key Points ◽  
Bruton Tyrosine Kinase

Key Points Six different BTKi’s blocked platelet activation in blood after FcγRIIA stimulation by cross-linking, anti-CD9 antibodies, or HIT serum. Established oral irreversible and novel reversible BTKi’s may offer a new option to treat HIT.

scholarly journals Impact of BCR-ABL transcript type on outcome in patients with chronic-phase CML treated with tyrosine kinase inhibitors

Blood ◽  
2016 ◽  
Vol 127 (10) ◽  
pp. 1269-1275 ◽  
Author(s):  
Preetesh Jain ◽  
Hagop Kantarjian ◽  
Keyur P. Patel ◽  
Graciela Nogueras Gonzalez ◽  
Rajyalakshmi Luthra ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Treatment Modality ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Key Points ◽  
Transcript Type

Key Points Patients with e13a2 transcripts have inferior outcomes with imatinib 400; e14a2 has favorable outcomes regardless of treatment modality. Multivariate analysis showed that the expression of e14a2 or both e14a2 and e13a2 predicts optimal ELN responses and longer EFS and TFS.

scholarly journals MicroRNA-486 regulates normal erythropoiesis and enhances growth and modulates drug response in CML progenitors

Blood ◽  
2015 ◽  
Vol 125 (8) ◽  
pp. 1302-1313 ◽  
Author(s):  
Li-Sheng Wang ◽  
Ling Li ◽  
Liang Li ◽  
Su Chu ◽  
Keh-Dong Shiang ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Drug Response ◽  
Kinase Inhibitors ◽  
Erythroid Progenitors ◽  
Growth And Survival ◽  
Key Points

Key Points miR-486-5p is expressed in megakaryocyte-erythroid progenitors and regulates growth and survival by regulating FOXO1 and AKT. miR-486-5p is overexpressed in CML progenitors and enhances their growth, survival, and response to tyrosine kinase inhibitors.

Role of protein tyrosine phosphorylation in H2O2-induced activation of endothelial cell phospholipase D

1996 ◽  
Vol 271 (3) ◽  
pp. L400-L408 ◽  
Author(s):  
V. Natarajan ◽  
S. Vepa ◽  
R. S. Verma ◽  
W. M. Scribner
Keyword(s):  
Endothelial Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinase Inhibitors ◽  
Phospholipase D ◽  
Kinase Inhibitors ◽  
Tyrosine Phosphatase ◽  
Dependent Manner ◽  
Protein Tyrosine Phosphorylation ◽  
Protein Tyrosine

Oxidant-induced activation of phospholipase D (PLD) in bovine pulmonary artery endothelial cells (BPAEC) is independent of protein kinase C and calcium. In the present study, the effects of tyrosine kinase and protein tyrosine phosphatase (PTPase) inhibitors on hydrogen peroxide (H2O2)-induced PLD activation and protein tyrosine phosphorylation were examined in BPAEC. Pretreatment of BPAEC with putative tyrosine kinase inhibitors genistein, tyrphostin, and herbimycin attenuated H2O2 (1 mM)-induced PLD activation. The inhibitory effect of the tyrosine kinase inhibitors was highly specific for H2O2-induced modulation and showed no effect on PLD activation mediated by 12-O-tetradecanoylphorbol 13-acetate or bradykinin. Furthermore, addition of H2O2 increased in a time-dependent manner tyrosine phosphorylation of several proteins (17-200 kDa), as determined by immunoblot analysis with antiphosphotyrosine antibodies. H2O2-mediated protein tyrosine phosphorylation preceded PLD activation, and a good correlation was observed on the effect of genistein in H2O2-induced PLD activation and protein tyrosine phosphorylation. Addition of vanadate, a phosphotyrosine phosphatase inhibitor, synergistically increased both PLD activation and protein tyrosine phosphorylation mediated by H2O2. Moreover, vanadate by itself had minimal effect on basal PLD activity in BPAEC; however, at 10 microM vanadate, an increase in protein tyrosine phosphorylation was observed. In addition to vanadate, phenylarsine oxide and diamide potentiated H2O2-induced PLD activation. These results suggest that tyrosine kinase activation may be involved in H2O2-induced PLD activation in vascular endothelial cells.

Tyrosine kinase inhibitors impair fibroblast growth factor signaling in coronary endothelial cells

1994 ◽  
Vol 266 (1) ◽  
pp. H107-H120 ◽  
Author(s):  
J. R. Hawker ◽  
H. J. Granger
Keyword(s):  
Endothelial Cells ◽  
Tyrosine Kinase ◽  
Dna Synthesis ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Nuclear Translocation ◽  
Fibroblast Growth ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Dose Dependent

We examined the effect of various tyrosine kinase inhibitors on basic fibroblast growth factor (bFGF)-induced cell signaling and DNA synthesis in coronary venular endothelial cells (CVEC). Two tyrosine kinase inhibitors, genistein and methyl 2,5-dihydroxycinnamate, showed reversible, dose-dependent inhibition of bFGF-stimulated DNA synthesis in CVEC with half-maximal inhibitory concentrations of 12 and 3 microM, respectively. Both compounds exhibited preferential inhibition of bFGF vs. serum-induced DNA synthesis. bFGF stimulated increased tyrosine phosphorylation of CVEC cellular proteins, including the FGF receptor, which were visible within 1 min of treatment. Concomitant with their effect on DNA synthesis, both compounds exhibited dose-dependent inhibition of tyrosine phosphorylation of intracellular substrates induced by bFGF. A 2-h pretreatment of quiescent CVEC with genistein blocked nuclear translocation but not cytoplasmic internalization of bFGF, whereas the same treatment with methyl 2,5-dihydroxycinnamate inhibited both processes. These results suggest that activation of bFGF receptor tyrosine kinase activity plays a role in nuclear translocation of bFGF and initiation of DNA synthesis in endothelial cells.

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