Mechanisms of Myocyte Cytotoxicity Induced by the Multiple Receptor Tyrosine Kinase Inhibitor Sunitinib

摘要: The anticancer tyrosine kinase inhibitor sunitinib has been shown recently to be cardiotoxic. Using a neonatal rat myocyte model, we investigated various mechanisms that might responsible for its cardiotoxicity. Sunitinib potently inhibited the enzyme activity of both AMP-activated protein (AMPK) and ribosomal S6 RSK1 at therapeutically relevant concentrations. Heart tissue with high energy needs particularly sensitive inhibition AMPK because role as an sensor regulating ATP levels. As measured by lactate dehydrogenase release, treatment myocytes caused dose-dependent damage therapeutic also reduction in levels phosphorylated α β isoforms phosphorylation target acetyl-Coenzyme A carboxylase. However, were not protected from pretreating them AMPK-activating antidiabetic drug metformin. did affect cellular Together, these last two results do suggest major sunitinib-induced damage. Dexrazoxane, which is clinically approved doxorubicin cardioprotective agent, protect damage, suggests induce oxidative In conclusion, even though inhibits RSK1, given extreme lack selectivity exhibits, it likely other kinases or combinations are cardiotoxic effects sunitinib.