Hepatocellular Toxicity Associated with Tyrosine Kinase Inhibitors: Mitochondrial Damage and Inhibition of Glycolysis
Tyrosine kinase inhibitors (TKIs) are anticancer drugs with a lesser toxicity than classical chemotherapeutic agents but still with a narrow therapeutic window. While hepatotoxicity is known for most TKIs, underlying mechanisms remain mostly unclear. We therefore aimed at investigating mechanisms of...
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doaj-0b10a7289b494c778ece0d1ba486b8052020-11-24T22:47:14ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122017-06-01810.3389/fphar.2017.00367239357Hepatocellular Toxicity Associated with Tyrosine Kinase Inhibitors: Mitochondrial Damage and Inhibition of GlycolysisFranziska Paech0Franziska Paech1Jamal Bouitbir2Jamal Bouitbir3Jamal Bouitbir4Stephan Krähenbühl5Stephan Krähenbühl6Stephan Krähenbühl7Division of Clinical Pharmacology and Toxicology, University Hospital BaselBasel, SwitzerlandDepartment of Biomedicine, University of BaselBasel, SwitzerlandDivision of Clinical Pharmacology and Toxicology, University Hospital BaselBasel, SwitzerlandDepartment of Biomedicine, University of BaselBasel, SwitzerlandSwiss Centre of Applied Human ToxicologyBasel, SwitzerlandDivision of Clinical Pharmacology and Toxicology, University Hospital BaselBasel, SwitzerlandDepartment of Biomedicine, University of BaselBasel, SwitzerlandSwiss Centre of Applied Human ToxicologyBasel, SwitzerlandTyrosine kinase inhibitors (TKIs) are anticancer drugs with a lesser toxicity than classical chemotherapeutic agents but still with a narrow therapeutic window. While hepatotoxicity is known for most TKIs, underlying mechanisms remain mostly unclear. We therefore aimed at investigating mechanisms of hepatotoxicity for imatinib, sunitinib, lapatinib and erlotinib in vitro. We treated HepG2 cells, HepaRG cells and mouse liver mitochondria with TKIs (concentrations 1–100 μM) for different periods of time and assessed toxicity. In HepG2 cells maintained with glucose (favoring glycolysis), all TKIs showed a time- and concentration-dependent cytotoxicity and, except erlotinib, a drop in intracellular ATP. In the presence of galactose (favoring mitochondrial metabolism), imatinib, sunitinib and erlotinib showed a similar toxicity profile as for glucose whereas lapatinib was less toxic. For imatinib, lapatinib and sunitinib, cytotoxicity increased in HepaRG cells induced with rifampicin, suggesting formation of toxic metabolites. In contrast, erlotinib was more toxic in HepaRG cells under basal than CYP-induced conditions. Imatinib, sunitinib and lapatinib reduced the mitochondrial membrane potential in HepG2 cells and in mouse liver mitochondria. In HepG2 cells, these compounds increased reactive oxygen species production, impaired glycolysis, and induced apoptosis. In addition, imatinib and sunitinib impaired oxygen consumption and activities of complex I and III (only imatinib), and reduced the cellular GSH pool. In conclusion, imatinib and sunitinib are mitochondrial toxicants after acute and long-term exposure and inhibit glycolysis. Lapatinib affected mitochondria only weakly and inhibited glycolysis, whereas the cytotoxicity of erlotinib could not be explained by a mitochondrial mechanism.http://journal.frontiersin.org/article/10.3389/fphar.2017.00367/fulltyrosine kinase inhibitorhepatotoxicitymitochondrial toxicityglycolysisROSapoptosis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Franziska Paech Franziska Paech Jamal Bouitbir Jamal Bouitbir Jamal Bouitbir Stephan Krähenbühl Stephan Krähenbühl Stephan Krähenbühl |
spellingShingle |
Franziska Paech Franziska Paech Jamal Bouitbir Jamal Bouitbir Jamal Bouitbir Stephan Krähenbühl Stephan Krähenbühl Stephan Krähenbühl Hepatocellular Toxicity Associated with Tyrosine Kinase Inhibitors: Mitochondrial Damage and Inhibition of Glycolysis Frontiers in Pharmacology tyrosine kinase inhibitor hepatotoxicity mitochondrial toxicity glycolysis ROS apoptosis |
author_facet |
Franziska Paech Franziska Paech Jamal Bouitbir Jamal Bouitbir Jamal Bouitbir Stephan Krähenbühl Stephan Krähenbühl Stephan Krähenbühl |
author_sort |
Franziska Paech |
title |
Hepatocellular Toxicity Associated with Tyrosine Kinase Inhibitors: Mitochondrial Damage and Inhibition of Glycolysis |
title_short |
Hepatocellular Toxicity Associated with Tyrosine Kinase Inhibitors: Mitochondrial Damage and Inhibition of Glycolysis |
title_full |
Hepatocellular Toxicity Associated with Tyrosine Kinase Inhibitors: Mitochondrial Damage and Inhibition of Glycolysis |
title_fullStr |
Hepatocellular Toxicity Associated with Tyrosine Kinase Inhibitors: Mitochondrial Damage and Inhibition of Glycolysis |
title_full_unstemmed |
Hepatocellular Toxicity Associated with Tyrosine Kinase Inhibitors: Mitochondrial Damage and Inhibition of Glycolysis |
title_sort |
hepatocellular toxicity associated with tyrosine kinase inhibitors: mitochondrial damage and inhibition of glycolysis |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2017-06-01 |
description |
Tyrosine kinase inhibitors (TKIs) are anticancer drugs with a lesser toxicity than classical chemotherapeutic agents but still with a narrow therapeutic window. While hepatotoxicity is known for most TKIs, underlying mechanisms remain mostly unclear. We therefore aimed at investigating mechanisms of hepatotoxicity for imatinib, sunitinib, lapatinib and erlotinib in vitro. We treated HepG2 cells, HepaRG cells and mouse liver mitochondria with TKIs (concentrations 1–100 μM) for different periods of time and assessed toxicity. In HepG2 cells maintained with glucose (favoring glycolysis), all TKIs showed a time- and concentration-dependent cytotoxicity and, except erlotinib, a drop in intracellular ATP. In the presence of galactose (favoring mitochondrial metabolism), imatinib, sunitinib and erlotinib showed a similar toxicity profile as for glucose whereas lapatinib was less toxic. For imatinib, lapatinib and sunitinib, cytotoxicity increased in HepaRG cells induced with rifampicin, suggesting formation of toxic metabolites. In contrast, erlotinib was more toxic in HepaRG cells under basal than CYP-induced conditions. Imatinib, sunitinib and lapatinib reduced the mitochondrial membrane potential in HepG2 cells and in mouse liver mitochondria. In HepG2 cells, these compounds increased reactive oxygen species production, impaired glycolysis, and induced apoptosis. In addition, imatinib and sunitinib impaired oxygen consumption and activities of complex I and III (only imatinib), and reduced the cellular GSH pool. In conclusion, imatinib and sunitinib are mitochondrial toxicants after acute and long-term exposure and inhibit glycolysis. Lapatinib affected mitochondria only weakly and inhibited glycolysis, whereas the cytotoxicity of erlotinib could not be explained by a mitochondrial mechanism. |
topic |
tyrosine kinase inhibitor hepatotoxicity mitochondrial toxicity glycolysis ROS apoptosis |
url |
http://journal.frontiersin.org/article/10.3389/fphar.2017.00367/full |
work_keys_str_mv |
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