Preclinical evaluation of potential nilotinib cardiotoxicity

Abstract In vitro , concentrations ≥10 μM of nilotinib were needed to induce markers of cytotoxicity, apoptosis, and endoplasmic reticulum stress in both neonatal rat ventricular myocytes, a putative target tissue, and non-target heart fibroblasts, indicating a lack of cardiomyocyte-specific nilotin...

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Bibliographic Details
Published in:Leukemia research 2011-05, Vol.35 (5), p.631-637
Main Authors: Wolf, Armin, Couttet, Philippe, Dong, Min, Grenet, Olivier, Heron, Marcia, Junker, Ursula, Ledieu, David, Mahl, Andreas, Marrer, Estelle, Persohn, Elke, Pognan, Francois, Zhou, Wei, Tsao, Jeffrey, Roman, Danielle
Format: Article
Language:English
Subjects:
ABL1
Animals
Animals, Newborn
Cardiotoxicity
Cardiotoxins - adverse effects
Cardiotoxins - pharmacology
Cells, Cultured
Chronic myeloid leukemia
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Heart - drug effects
Heart - physiology
Heart Ventricles - anatomy & histology
Heart Ventricles - drug effects
Heart Ventricles - ultrastructure
Hematology, Oncology and Palliative Medicine
Left ventricular function
Male
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - physiology
Nilotinib
Pyrimidines - adverse effects
Pyrimidines - pharmacology
Random Allocation
Rats
Rats, Sprague-Dawley
Rats, Wistar
Tyrosine kinase inhibitor
Ventricular Function - drug effects
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Summary:Abstract In vitro , concentrations ≥10 μM of nilotinib were needed to induce markers of cytotoxicity, apoptosis, and endoplasmic reticulum stress in both neonatal rat ventricular myocytes, a putative target tissue, and non-target heart fibroblasts, indicating a lack of cardiomyocyte-specific nilotinib toxicity in vitro . In rats, oral nilotinib treatment at 80 mg/kg for 4 weeks induced increased heart weight; however, this was not associated with relevant histopathological changes or effects on heart function. Thus, nilotinib at and above clinically relevant concentrations (4.27 μM) did not induce overt cardiovascular pathologies or heart failure in vitro or in vivo under study conditions.
ISSN:0145-2126
1873-5835
DOI:10.1016/j.leukres.2010.11.001