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Leukemia. 2017 Nov;31(11):2388-2397. doi: 10.1038/leu.2017.245. Epub 2017 Jul 31.

Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target site.

Author information

1
Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
2
Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
3
Department/Clinic for Companion Animals and Horses, Clinic for Small Animals, Clinical Unit of Internal Medicine, University of Veterinary Medicine Vienna, Vienna, Austria.
4
Department of Internal Medicine III, Cardiology and Angiology, Medical University of Innsbruck, Innsbruck, Austria.
5
Department for Pharmacology and Genetics, Division of Translational Cell Genetics, Medical University of Innsbruck, Innsbruck, Austria.
6
Research Center for Molecular Medicine (CeMM), Vienna, Austria.
7
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
8
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
9
Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.
10
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
11
Department of Internal Medicine II, Division of Angiology, Medical University of Vienna, Vienna, Austria.
12
Medical Clinic 3, Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB), Bonn, Germany.

Abstract

The BCR/ABL1 inhibitor Nilotinib is increasingly used to treat patients with chronic myeloid leukemia (CML). Although otherwise well-tolerated, Nilotinib has been associated with the occurrence of progressive arterial occlusive disease (AOD). Our objective was to determine the exact frequency of AOD and examine in vitro and in vivo effects of Nilotinib and Imatinib on endothelial cells to explain AOD-development. In contrast to Imatinib, Nilotinib was found to upregulate pro-atherogenic adhesion-proteins (ICAM-1, E-selectin, VCAM-1) on human endothelial cells. Nilotinib also suppressed endothelial cell proliferation, migration and tube-formation and bound to a distinct set of target-kinases, relevant to angiogenesis and atherosclerosis, including angiopoietin receptor-1 TEK, ABL-2, JAK1 and MAP-kinases. Nilotinib and siRNA against ABL-2 also suppressed KDR expression. In addition, Nilotinib augmented atherosclerosis in ApoE-/- mice and blocked reperfusion and angiogenesis in a hindlimb-ischemia model of arterial occlusion, whereas Imatinib showed no comparable effects. Clinically overt AOD-events were found to accumulate over time in Nilotinib-treated patients. After a median observation-time of 2.0 years, the AOD-frequency was higher in these patients (29.4%) compared to risk factor- and age-matched controls (<5%). Together, Nilotinib exerts direct pro-atherogenic and anti-angiogenic effects on vascular endothelial cells, which may contribute to development of AOD in patients with CML.

PMID:
28757617
PMCID:
PMC5669463
DOI:
10.1038/leu.2017.245
[Indexed for MEDLINE]
Free PMC Article

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