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Publikationstyp: Zeitschriftenaufsatz
Dokumentart: Originalarbeit

Publikationsjahr: 2017

AutorInnen: Hadzijusufovic, E; Albrecht-Schgoer, K; Huber, K; Hoermann, G; Grebien, F; Eisenwort, G; Schgoer, W; Herndlhofer, S; Kaun, C; Theurl, M; Sperr, WR; Rix, U; Sadovnik, I; Jilma, B; Schernthaner, GH; Wojta, J; Wolf, D; Superti-Furga, G; Kirchmair, R; Valent, P

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

Quelle: Leukemia. 2017; 31(11):2388-2397

Autor/innen der Vetmeduni Vienna:

Grebien Florian,
Hadzijusufovic Emir,

Beteiligte Vetmed-Organisationseinheiten
Klinische Abteilung für Interne Medizin Kleintiere,

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.

Keywords Pubmed: Adult
Aged, 80 and over
Apolipoproteins E/genetics
Atherosclerosis/chemically induced
Endothelium, Vascular/cytology
Endothelium, Vascular/drug effects*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Protein Kinase Inhibitors/adverse effects*
Pyrimidines/adverse effects*
Vascular Diseases/chemically induced*

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