Preclinical evaluation of potential nilotinib cardiotoxicity.
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.
Preclinical Safety, Novartis Institutes for Biomedical Research, CH-4009 Basel, Switzerland.
Armin
A
Wolf
Philippe
P
Couttet
Min
M
Dong
Olivier
O
Grenet
Marcia
M
Heron
Ursula
U
Junker
David
D
Ledieu
Andreas
A
Mahl
Estelle
E
Marrer
Elke
E
Persohn
Francois
F
Pognan
Wei
W
Zhou
Jeffrey
J
Tsao
Danielle
D
Roman
D000818:Animals; D000831:Animals, Newborn; D054715:Cardiotoxins / Q000009:adverse effects / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000033:anatomy & histology / Q000187:drug effects / Q000648:ultrastructure; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000009:adverse effects* / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D016276:Ventricular Function / Q000187:drug effects
D054715:Cardiotoxins; D011743:Pyrimidines; C498826:nilotinib