Ponatinib reduces viability, migration, and functionality of human endothelial cells
Ayala Gover-Proaktor1, Galit Granot1, Saar Shapira1,2
1a Felsenstein Medical Research Center , Tel Aviv , Israel.
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.
Insights
Tyrosine kinase inhibitors (TKIs) can cause vascular adverse events (VAEs). This study found ponatinib, a TKI, impairs endothelial cell function and may cause VAEs by inhibiting VEGFR2, impacting angiogenesis.
Area of Science:
- Biomedical research
- Molecular biology
- Oncology
Background:
- Tyrosine kinase inhibitors (TKIs) have transformed chronic myeloid leukemia treatment.
- Managing TKI-associated vascular adverse events (VAEs) is now a clinical focus.
- Understanding the mechanisms behind TKI-induced VAEs is crucial for patient safety.
Purpose of the Study:
- To investigate the in vitro effects of TKIs on endothelial cells.
- To elucidate the specific mechanisms of ponatinib-associated vascular adverse events.
- To explore the role of VEGFR2 in ponatinib's effects on angiogenesis.
Main Methods:
- Utilized an in vitro angiogenesis model with human umbilical vein endothelial cells (HUVECs).
- Assessed HUVEC viability, apoptosis, migration, and tube formation.
- Evaluated the impact of ponatinib on endothelial progenitor cell (EPC) function.
- Investigated ponatinib's effects in HUVECs with modified VEGF receptor 2 (VEGFR2) expression.
Main Results:
- Imatinib, nilotinib, and ponatinib reduced HUVEC viability.
- Ponatinib induced apoptosis, inhibited migration, and impaired tube formation in HUVECs at pharmacological concentrations.
- Ponatinib negatively affected endothelial progenitor cell function.
- Ponatinib's detrimental effects on endothelial cell function were less pronounced in VEGFR2-transfected cells.
Conclusions:
- Ponatinib exhibits antiangiogenic properties, potentially through VEGFR2 inhibition.
- This study provides novel insights into the pathogenesis of ponatinib-associated vascular adverse events.
- The findings contribute to understanding the complex mechanisms of TKI-induced VAEs.
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