Bouitbir 2019 Toxicology
| Bouitbir J, Alshaikhali A, Panajatovic MV, Abegg VF, Paech F, KrΓ€henbΓΌhl S (2019) Mitochondrial oxidative stress plays a critical role in the cardiotoxicity of sunitinib. Toxicology 426:152281. |
Bouitbir J, Alshaikhali A, Panajatovic MV, Abegg VF, Paech F, Kraehenbuehl S (2019) Toxicology
Abstract: Sunitinib is cardiotoxic, but the mechanisms are not entirely clear. We aimed to enlarge our knowledge about the role of mitochondria in cardiac toxicity of sunitinib in vitro and in vivo. For this reason, we studied the toxicity of sunitinib on cardiac H9c2 cells exposed for 24βh, permeabilized rat cardiac fibers exposed for 15βminutes and in mice treated orally with sunitinib for 2 weeks (7.5βmg/kg/day). In H9c2 cells exposed for 24βh, sunitinib was more cytotoxic under galactose (favoring mitochondrial metabolism) compared to glucose conditions (favoring glycolysis). Sunitinib dissipated the mitochondrial membrane potential starting at 10βΞΌM under glucose and at 5βΞΌM under galactose conditions. Sunitinib reduced activities of mitochondrial enzyme complexes of the electron transport chain (ETC), increased mitochondrial ROS accumulation and decreased the cellular GSH pool. Electron microscopy revealed swollen mitochondria with loss of cristae. Accordingly, sunitinib caused caspase 3 activation and DNA fragmentation in H9c2 cells. Co-exposure with mito-TEMPO (mitochondrial-specific ROS scavenger) for 24βh prevented ATP and GSH depletion, as well as the increases in H2O2 and caspase 3/7 activity observed with sunitinib. In mice, treatment with sunitinib for two weeks increased plasma concentrations of troponin I and creatine kinase MB, indicating cardiomyocyte damage. The activity of enzyme complexes of the ETC was decreased, mitochondrial ROS were increased and cleavage of caspase 3 was increased, suggesting cardiomyocyte apoptosis. In conclusion, mitochondrial damage with ROS accumulation appears to be an important mechanism of cardiotoxicity associated with sunitinib, eventually leading to apoptotic cell death.
Copyright Β© 2019. Published by Elsevier B.V. β’ Keywords: Sunitinib, Apoptosis, Cardiac toxicity, Electron transport chain, Reactive oxygen species β’ Bioblast editor: Plangger M β’ O2k-Network Lab: CH Basel Kraehenbuehl S
Labels: MiParea: Respiration, Pharmacology;toxicology
Organism: Mouse, Rat
Tissue;cell: Heart
Preparation: Permeabilized cells, Permeabilized tissue
Coupling state: LEAK, OXPHOS
Pathway: N, S, CIV, NS, ROX
HRR: Oxygraph-2k
Labels, 2019-08
