Paech 2018a Toxicology
|Paech F, Mingard C, Grünig D, Abegg VF, Bouitbir J, Krähenbühl S (2018) Mechanisms of mitochondrial toxicity of the kinase inhibitors ponatinib, regorafenib and sorafenib in human hepatic HepG2 cells. Toxicology 395:34-44.|
Abstract: Previous studies have shown that certain kinase inhibitors are mitochondrial toxicants. In the current investigation, we determined the mechanisms of mitochondrial impairment by the kinase inhibitors ponatinib, regorafenib, and sorafenib in more detail. In HepG2 cells cultured in galactose and exposed for 24 h, all three kinase inhibitors investigated depleted the cellular ATP pools at lower concentrations than cytotoxicity occurred, compatible with mitochondrial toxicity. The kinase inhibitors impaired the activity of different complexes of the respiratory chain in HepG2 cells exposed to the toxicants for 24 h and in isolated mouse liver mitochondria exposed acutely. As a consequence, they increased mitochondrial production of ROS in HepG2 cells in a time- and concentration-dependent fashion and decreased the mitochondrial membrane potential concentration-dependently. In HepG2 cells exposed for 24 h, they induced mitochondrial fragmentation, lysosome content and mitophagy as well as mitochondrial release of cytochrome c, leading to apoptosis and/or necrosis. In conclusion, the kinase inhibitors ponatinib, regorafenib, and sorafenib impaired the function of the respiratory chain, which was associated with increased ROS production and a drop in the mitochondrial membrane potential. Despite activation of defense measures such as mitochondrial fission and mitophagy, some cells were liquidated concentration-dependently by apoptosis or necrosis. Mitochondrial dysfunction may represent a toxicological mechanism of hepatotoxicity associated with certain kinase inhibitors.
• Keywords: Apoptosis, Hepatotoxicity, Kinase inhibitor, Mitochondrial fission & mitophagy, Mitochondrial toxicity, Reactive oxygen species (ROS) • Bioblast editor: Kandolf G • O2k-Network Lab: CH Basel Kraehenbuehl S
Labels: MiParea: Respiration, mt-Medicine Pathology: Cancer
Organism: Human, Mouse Tissue;cell: Liver, Other cell lines Preparation: Permeabilized cells, Isolated mitochondria
Coupling state: LEAK, OXPHOS, ET Pathway: N, S, DQ, CIV, ROX HRR: Oxygraph-2k