Effect of the multitargeted tyrosine kinase inhibitors imatinib, dasatinib, sunitinib, and sorafenib on mitochondrial function in isolated rat heart mitochondria and H9c2 cells.
Cardiovascular disease has recently been suggested to be a significant complication of cancer treatment with several kinase inhibitors. In some cases, the mechanisms leading to cardiotoxicity are postulated to include mitochondrial dysfunction, either as a primary or secondary effect. Detecting direct effects on mitochondrial function, such as uncoupling of oxidative phosphorylation or inhibition of electron transport chain components, as well as identifying targets within the mitochondrial electron transport chain, can be accomplished in vitro. Here, we examined the effects of the tyrosine kinase inhibitor drugs imatinib, dasatinib, sunitinib, and sorafenib on ATP content in H9c2 cells grown under conditions where cells are either glycolytically or aerobically poised. Furthermore, we measured respiratory capacity of isolated rat heart mitochondria in the presence of the four kinase inhibitors and examined their effect on each of the oxidative phosphorylation complexes. Of the four kinase inhibitors examined, only sorafenib directly impaired mitochondrial function at clinically relevant concentrations, potentially contributing to the cytotoxic effect of the drug. For the other three kinase inhibitors lacking direct mitochondrial effects, altered kinase and other signaling pathways, are a more reasonable explanation for potential toxicity.
Will
Yvonne
Y
Exploratory Safety Differentiation, Pfizer, Inc., Groton, Connecticut 06340, USA.
Dykens
James A
JA
Nadanaciva
Sashi
S
Hirakawa
Brad
B
Jamieson
Joseph
J
Marroquin
Lisa D
LD
Hynes
James
J
Patyna
Shem
S
Jessen
Bart A
BA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001549:Benzamides; D001557:Benzenesulfonates / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport / Q000187:drug effects; D005690:Galactose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D000068877:Imatinib Mesylate; D007211:Indoles / Q000633:toxicity*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D009536:Niacinamide / Q000031:analogs & derivatives; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010671:Phenylurea Compounds; D010879:Piperazines / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity*; D011758:Pyrroles / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077157:Sorafenib; D000077210:Sunitinib; D013844:Thiazoles / Q000633:toxicity*
D001549:Benzamides; D001557:Benzenesulfonates; D007211:Indoles; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D013844:Thiazoles; D009536:Niacinamide; D000068877:Imatinib Mesylate; D000255:Adenosine Triphosphate; D000077157:Sorafenib; D011505:Protein-Tyrosine Kinases; D005947:Glucose; D000069439:Dasatinib; D000077210:Sunitinib; D005690:Galactose