Background: New-generation BCR-ABL tyrosine kinase inhibitors (TKIs) used in chronic myeloid leukemia (CML) induce cardiovascular events. However, the mechanism(s) by which these treatments induce these events is currently not clear. First in vitro investigations indicate that they influence the viability of endothelial cells, potentially explaining the occurrence of cardiovascular events.
Aims: This research aims to specify the mechanism(s) by which BCR-ABL TKIs affect endothelial cell viability.
Methods: Three concentration of the five BCR-ABL TKIs have been tested on Human Umbilical Venous Endothelial Cells (HUVECs). All experiments have been performed in media with 10% dialyzed FBS in order to minimize the effect of plasma protein binding. MTS and LDH assays were performed to assess the effect of TKI on cell viability. Rate of apoptotic and necrotic cells have been measured using Annexin V staining, and BrdU assay assessed the effect on cell proliferation. Generation of reactive oxygen species (ROS) was evaluated using a specific fluorescent probe (CM-H2DCFDA) by flow cytometry.
Results: All BCR-ABL TKIs affect endothelial cell viability after 72h of treatment. However, their impact on HUVECs are different according to the TKI. Ponatinib induces apoptosis and necrosis of endothelial cells (Figure). Nilotinib induces necrosis but at high dose only (2µM). Dasatinib increases the generation of ROS by HUVEC. Finally, all BCR-ABL TKIs dose-dependently influence HUVEC proliferation as early as 24h of treatment (decrease of number of cells in S-phase and increase of HUVEC in G0-G1 phase). However, this impact is significant only at the highest concentration for imatinib, nilotinib and bosutinib.
Conclusions: Cell death within the arterial wall has already been recognized in atherosclerosis, and it appears plausible that dasatinib, nilotinib and ponatinib facilitate atherosclerosis development through alteration of endothelial cell viability.
To cite this abstract in AMA style:Haguet H, Mullier F, Graux C, Dogné J-, Douxfils J. In vitro Investigation of the Impact of BCR-ABL Tyrosine Kinase Inhibitors on Endothelial Cells [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/in-vitro-investigation-of-the-impact-of-bcr-abl-tyrosine-kinase-inhibitors-on-endothelial-cells/. Accessed October 26, 2020.
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