Background: Some BCR-ABL TKIs (dasatinib, nilotinib and ponatinib) increase the risk of arterial thromboembolism in CML patients compared to the first generation TKI, imatinib. The pathophysiology of these events remains poorly understood but clinical data suggest that these treatments might induce atherosclerotic plaque rupture. The stability of atherosclerotic plaque correlates to the thickness of its fibrous cap. A major mechanism inducing fibrous cap thickening is the production of matrix metalloproteinases (MMPs) by macrophages that degrade fibrous cap components.
Aims: This research aims to determine the effect of BCR-ABL TKIs on the production of two MMPs highly involved in atherosclerotic plaque rupture (MMP-2 and MMP-9).
Methods: The THP-1 cell line differentiated to macrophages using PMA at 100ng/mL during 24h was used to assess the effect of TKIs on human macrophages. The THP-1 cells were treated with the 5 BCR-ABL TKIs at 3 clinically relevant concentrations during 24h and 48h. Macrophage viability was assessed using MTS and LDH assays and the production and activity of MMP-2 and MMP-9 were evaluated by gelatin zymography.
Results: The 5 BCR-ABL TKIs possess few impact on THP-1 viability. MTS and LDH assays demonstrate decreased macrophage viability with nilotinib at high concentration (2µM).
Gelatin zymography demonstrates no impact of TKI on MMP-2 and MMP-9 production after 24h of treatment. After 48h, imatinib at the highest dosage (5µM) increases production of activated MMP-9. Treatment with nilotinib at 2µM decreases the production of activated MMP-9, which might be the consequence of decreased macrophage viability. Other BCR-ABL TKIs do not affect the production and activity of MMP-2 and MMP-9 by THP-1.
Conclusions: BCR-ABL TKIs have little impact on macrophage survival as well as on MMP production and activity and suggest that vascular occlusive events are probably not mediated by impact on macrophages.
To cite this abstract in AMA style:Haguet H, Mullier F, Graux C, Dogné J-, Douxfils J. In vitro Evaluation of the Impact of BCR-ABL Tyrosine Kinase Inhibitors on Atherosclerosis Plaque Rupture [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/in-vitro-evaluation-of-the-impact-of-bcr-abl-tyrosine-kinase-inhibitors-on-atherosclerosis-plaque-rupture/. Accessed October 26, 2020.
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