Preclinical evaluation of potential nilotinib cardiotoxicity

Area of Science:

• Cardiovascular Science
• Pharmacology
• Toxicology

Background:

• Nilotinib is a tyrosine kinase inhibitor used to treat chronic myeloid leukemia.
• Potential cardiovascular side effects of tyrosine kinase inhibitors warrant investigation.
• Understanding nilotinib's specific effects on cardiac tissue is crucial for patient safety.

Purpose of the Study:

• To evaluate the in vitro and in vivo cardiotoxicity of nilotinib.
• To determine if nilotinib exhibits specific toxicity towards cardiomyocytes.
• To assess the impact of nilotinib on cardiac function and pathology in a preclinical model.

Main Methods:

• In vitro assessment of nilotinib cytotoxicity, apoptosis, and endoplasmic reticulum stress in neonatal rat ventricular myocytes and cardiac fibroblasts.
• In vivo study involving oral administration of nilotinib to rats for 4 weeks at 80 mg/kg.
• Evaluation of heart weight, histopathology, and cardiac function in treated rats.

Main Results:

• In vitro, concentrations of nilotinib ≥ 10 μM were required to induce cytotoxicity, apoptosis, and endoplasmic reticulum stress in both cardiomyocytes and fibroblasts.
• In vivo, nilotinib treatment at 80 mg/kg resulted in increased heart weight but no significant histopathological changes or functional deficits.
• Clinically relevant concentrations of nilotinib (≥ 4.27 μM) did not induce overt cardiovascular pathologies or heart failure in vitro or in vivo.

Conclusions:

• Nilotinib does not demonstrate cardiomyocyte-specific toxicity in vitro.
• Nilotinib treatment in rats at a high dose did not lead to adverse cardiovascular effects.
• Nilotinib appears to be safe concerning cardiovascular pathologies and heart failure under the studied conditions.