Abstract
Tyrosine kinase inhibitors (TKIs) have revolutionized the prognosis of chronic myeloid leukemia. With the advent of highly efficacious therapy, the focus has shifted toward managing TKI adverse effects, such as vascular adverse events (VAEs). We used an in vitro angiogenesis model to investigate the TKI-associated VAEs. Our data show that imatinib, nilotinib, and ponatinib reduce human umbilical vein endothelial cells (HUVECs) viability. Pharmacological concentrations of ponatinib induced apoptosis, reduced migration, inhibited tube formation of HUVECs, and had a negative effect on endothelial progenitor cell (EPC) function. Furthermore, in HUVECs transfected with VEGF receptor 2 (VEGFR2), the effect of ponatinib on tube formation and on all parameters representing normal endothelial cell function was less prominent than in control cells. This is the first report regarding the pathogenesis of ponatinib-associated VAEs. The antiangiogenic effect of ponatinib, possibly mediated by VEGFR2 inhibition, as shown in our study, is another piece in the intricate puzzle of TKI-associated VAEs.
Keywords:
Myeloid leukemias and dysplasias; cell lines and animal models; myeloproliferative disorders.
MeSH terms
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects
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Biomarkers
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Cell Movement / drug effects
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Cell Survival / drug effects
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Colony-Forming Units Assay
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Endothelial Cells / drug effects*
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Endothelial Cells / metabolism*
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Gene Expression
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Human Umbilical Vein Endothelial Cells
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Humans
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Imidazoles / adverse effects
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Imidazoles / pharmacology*
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Imidazoles / therapeutic use
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Immunophenotyping
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Macrophages / drug effects
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Macrophages / metabolism
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Phenotype
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Protein Kinase Inhibitors / adverse effects
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Pyridazines / adverse effects
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Pyridazines / pharmacology*
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Pyridazines / therapeutic use
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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Antineoplastic Agents
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Biomarkers
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Imidazoles
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Protein Kinase Inhibitors
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Pyridazines
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ponatinib
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Vascular Endothelial Growth Factor Receptor-2