title: Ponatinib reduces viability, migration, and functionality of human endothelial cells.
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.
authors.affiliation: a Felsenstein Medical Research Center , Tel Aviv , Israel.
authors.forename: Ayala
authors.initials: A
authors.lastname: Gover-Proaktor
authors.affiliation: a Felsenstein Medical Research Center , Tel Aviv , Israel.
authors.forename: Galit
authors.initials: G
authors.lastname: Granot
authors.affiliation: a Felsenstein Medical Research Center , Tel Aviv , Israel.|b The Sackler School of Medicine , Tel Aviv University , Tel Aviv , Israel.
authors.forename: Saar
authors.initials: S
authors.lastname: Shapira
authors.affiliation: a Felsenstein Medical Research Center , Tel Aviv , Israel.
authors.forename: Oshrat
authors.initials: O
authors.lastname: Raz
authors.affiliation: b The Sackler School of Medicine , Tel Aviv University , Tel Aviv , Israel.|c Division of Hematology, Davidoff Cancer Center , Beilinson Hospital, Rabin Medical Center , Petah- Tikva , Israel.
authors.forename: Oren
authors.initials: O
authors.lastname: Pasvolsky
authors.affiliation: b The Sackler School of Medicine , Tel Aviv University , Tel Aviv , Israel.|d Division of Hematology , Chaim Sheba Medical Center , Tel Aviv , Israel.
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.affiliation: a Felsenstein Medical Research Center , Tel Aviv , Israel.
authors.forename: Dorit L
authors.initials: DL
authors.lastname: Lev
authors.affiliation: c Division of Hematology, Davidoff Cancer Center , Beilinson Hospital, Rabin Medical Center , Petah- Tikva , Israel.
authors.forename: Aida
authors.initials: A
authors.lastname: Inbal
authors.affiliation: a Felsenstein Medical Research Center , Tel Aviv , Israel.|b The Sackler School of Medicine , Tel Aviv University , Tel Aviv , Israel.
authors.forename: Ido
authors.initials: I
authors.lastname: Lubin
authors.affiliation: b The Sackler School of Medicine , Tel Aviv University , Tel Aviv , Israel.|c Division of Hematology, Davidoff Cancer Center , Beilinson Hospital, Rabin Medical Center , Petah- Tikva , Israel.
authors.forename: Pia
authors.initials: P
authors.lastname: Raanani
authors.affiliation: b The Sackler School of Medicine , Tel Aviv University , Tel Aviv , Israel.|c Division of Hematology, Davidoff Cancer Center , Beilinson Hospital, Rabin Medical Center , Petah- Tikva , Israel.
authors.forename: Avi
authors.initials: A
authors.lastname: Leader
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D015870:Gene Expression; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D016130:Immunophenotyping; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D011724:Pyridazines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C545373:ponatinib; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Myeloid leukemias and dysplasias; cell lines and animal models; myeloproliferative disorders