Mechanisms of Myocyte Cytotoxicity Induced by the Multikinase Inhibitor Sorafenib

Abstract

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.

Structural and functional screening in human induced-pluripotent stem cell-derived cardiomyocytes accurately identifies cardiotoxicity of multiple drug types

“…Interestingly, the majority of compounds that induced structural cardiac toxicity in our studies were oncology therapeutics that are known to induce direct cardiac damaging effects (Doherty et al, 2013;Kerkela et al, 2006Kerkela et al, , 2009Wolf et al, 2011;Hasinoff and Patel, 2010;Arola et al, 2000). The most toxic of the oncology drugs was the anthracycline daunorubicin, which tested significantly positive on all of our structural toxicity endpoints, reflecting the known effects of anthracyclines on oxidative stress and cell death (Minotti et al, 2004;Sawyer et al, 2010).…”

Sudden cardiac death in a patient with advanced hepatocellular carcinoma with good response to sorafenib treatment: A case report with literature analysis

“…For Ederhy et al (47) and Force et al (48), heart damage occurs as the direct consequence of the inhibition of cardiomyocyte survival through the interruption of the extracellular-signal-regulated kinase (ERK) kinase cascade mediated by the blockade of RAF kinase-1 and BRAF. However, studies on rat pups' myocytes have not supported this hypothesis (49).…”

Cardiovascular Toxicity and Monitoring Methods in Oncologic Patients

“…In a neonatal rat myocyte model, it was demonstrated that therapeutically relevant concentrations of sorafenib caused dose-dependent damage, probably due to its lack of selectivity (Hasinoff and Patel 2010). In a phase 3 trial for renal cell carcinoma, this drug caused cardiac ischemia and infarction in 3 % of patients (Yeh et al 2004).…”