Mechanisms of myocyte cytotoxicity induced by the multikinase inhibitor sorafenib.
The use of the anticancer multikinase inhibitor sorafenib is associated with cardiac ischemia or infarction and an increase in hypertension. We investigated various mechanisms that might be responsible for its cardiotoxicity in a neonatal rat myocyte model. As measured by lactate dehydrogenase release, sorafenib treatment of myocytes caused dose-dependent damage at therapeutically relevant concentrations. It had been hypothesized that inhibition of RAF1 and BRAF kinases may be responsible for sorafenib induced cardiotoxicity. However, because sorafenib treatment did not inhibit phosphorylation of ERK (extracellular signal-regulated kinase), it was concluded that sorafenib did not exert its damaging effects through RAF inhibition of the RAF/MEK/ERK kinase cascade. The clinically approved doxorubicin cardioprotective agent dexrazoxane did not protect myocytes from damage. At lower sorafenib concentrations, at least, these results are consistent with sorafenib not being able to induce significant oxidative damage. In conclusion, given the extreme lack of kinase selectivity that sorafenib exhibits, it is likely that inhibition of kinases other than RAF, or combinations of kinases, contributes to the cardiotoxic effects of sorafenib.
Hasinoff
Brian B
BB
Apotex Centre, University of Manitoba, Winnipeg, Canada. B_Hasinoff@UManitoba.ca
Patel
Daywin
D
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000037:antagonists & inhibitors / Q000633:toxicity*; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002469:Cell Separation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D066298:In Vitro Techniques; D007502:Iron Chelating Agents / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008856:Microscopy, Fluorescence; D032383:Myocytes, Cardiac / Q000473:pathology*; D009536:Niacinamide / Q000031:analogs & derivatives; D010084:Oxidation-Reduction; D010671:Phenylurea Compounds; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011929:Razoxane / Q000494:pharmacology; D000077157:Sorafenib
D001557:Benzenesulfonates; D002316:Cardiotonic Agents; D007502:Iron Chelating Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D011929:Razoxane; D000255:Adenosine Triphosphate; D000077157:Sorafenib; D007770:L-Lactate Dehydrogenase; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D053179:Caspase 7