J. Bouitbir1, A. Alshaikhali1, M. Panajatovic1, V. Abegg1, F. Paech1, S. Krähenbühl1 (1Basel)
Purpose: Tyrosine kinases inhibitors (TKI) are known to induce cardiac toxicity in patients, which may be caused by mitochondrial damage. The aim of the current study was to improve our knowledge about the role of mitochondria in cardiac toxicity of TKIs, in particular concerning oxidative stress and cell death.
Design & methods: We exposed cardiac H9c2 cells for 24h with imatinib, sorafenib or sunitinib. In addition, we treated mice with sunitinib (7.5 mg/kg/day) for two weeks.
Results: In H9c2 cells exposed for 24 h, all TKIs investigated showed a higher cytotoxicity profile in the presence of galactose (favoring mitochondrial metabolism) compared to glucose (favoring glycolysis). The TKIs dissipated the mitochondrial membrane potential and reduced activities of mitochondrial enzyme complexes of the electron transport chain (ETC). In addition, the TKIs increased superoxide accumulation and decreased the cellular GSH pool, inducing apoptosis. Electron microscopy showed swollen mitochondria with loss of cristae. In mice, treatment with sunitinib for two weeks increased plasma troponin I and creatine kinase MB, indicating cardiomyocyte damage. The activity of enzyme complexes of the ETC was decreased and the mitochondrial content of reactive oxygen species (ROS) was increased. Cleavage of caspase 3 was increased in hearts of sunitinib-treated mice, suggesting cardiomyocyte apoptosis.
Conclusions: Mitochondrial ROS accumulation appears to be an important mechanism of cardiotoxicity associated with sunitinib and other cardiotoxic TKIs, leading to the activation of apoptosis.