Sorafenib, a multi-
kinase inhibitor, is recommended as a new standard
therapy for advanced
hepatocellular carcinoma (HCC); however, it also exhibits severe
cardiotoxicity and the toxicity mechanisms are not completely elucidated. Recent studies suggested that
sorafenib-enhanced ROS may partially contribute to its anti-HCC effect, which implies that redox mechanism might also be involved in
sorafenib's
cardiotoxicity. In this study, we aimed to investigate if
sorafenib is able to induce oxidative stress and how this may impair cellular functions in cardiomyocyte, ultimately accounting for its
cardiotoxicity. Our results showed that in isolated rat hearts,
sorafenib caused ventricular arrhythmias and
left ventricular dysfunction, which were alleviated by the
antioxidant N-(2-mercaptopropionyl)-glycine (MPG). In isolated ventricular myocytes,
sorafenib increased diastolic intracellular Ca2+ levels, decreased Ca transients and the occurrence of Ca2+ waves. These changes were eliminated by MPG,
CaMKII inhibitor
KN-93 and the
mitochondrial permeability transition pore (mPTP)inhibitor
cyclosporin A (CsA). Moreover, the levels of oxidized and phosphorylated
CaMKII were significantly increased.
Sorafenib elevated ROS levels, which was reversed by CsA and MPG; additionally,
sorafenib reduced the activity of mitochondrial
complex III and augmented mitochondrial ROS production. In vivo rats treated with
sorafenib exhibited a reduction of
antioxidant defence and abnormal histological alterations including
hypertrophy, increased
fibrosis, disordered myofibrils and damaged mitochondria, which were protected by MPG. We conclude that
sorafenib induces the disruption of Ca2+ homoeostasis and cardiac injury via enhanced ROS potentially through inhibiting mitochondrial
complex III, the opening of
mPTP and overactivating
CaMKII. These results provide a potential strategy for preventing or reducing
cardiotoxicity of
sorafenib.