Apotex Centre, University of Manitoba, Winnipeg, Canada.
Cardiovasc Toxicol. 2010 Mar;10(1):1-8. doi: 10.1007/s12012-009-9056-0.
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.
多激酶抑制剂索拉非尼的应用与心脏缺血或梗死以及高血压的增加有关。我们在新生大鼠心肌细胞模型中研究了可能导致其心脏毒性的各种机制。乳酸脱氢酶释放的测量结果表明，索拉非尼在治疗相关浓度下对心肌细胞造成了剂量依赖性的损伤。有人假设 RAF1 和 BRAF 激酶的抑制可能是索拉非尼诱导的心脏毒性的原因。然而，由于索拉非尼治疗并没有抑制 ERK（细胞外信号调节激酶）的磷酸化，因此可以得出结论，索拉非尼不是通过 RAF 抑制 RAF/MEK/ERK 激酶级联来发挥其损伤作用。临床上批准的蒽环类心脏保护剂右雷佐生不能保护心肌细胞免受损伤。至少在较低的索拉非尼浓度下，这些结果表明索拉非尼不能诱导明显的氧化损伤。总之，鉴于索拉非尼表现出的极端缺乏激酶选择性，抑制 RAF 以外的其他激酶或激酶组合可能导致索拉非尼的心脏毒性作用。
