Abstract
Tyrosine-kinase inhibitors (TKIs) have revolutionized cancer therapy in recent years. Although more targeted than conventional chemotherapy, TKIs exhibit substantial cardiotoxicity, often manifesting as hypertension or heart failure. Here, we assessed myocyte intrinsic cardiotoxic effects of the TKI sorafenib and investigated underlying alterations of myocyte calcium homeostasis. We found that sorafenib reversibly decreased developed force in auxotonically contracting human myocardia (3 µM: −25 ± 4%, 10 µM: −29 ± 7%, 30 µM: −43 ± 12%, p < 0.01), reduced peak cytosolic calcium concentrations in isolated cardiomyocytes (10 µM: 52 ± 8.1% of baseline, p < 0.001), and slowed cytosolic calcium removal kinetics (RT50, RT10, Tau, p < 0.05). Beta-adrenergic stimulation induced augmentation of calcium transient (CaT) amplitude was attenuated in sorafenib-treated cells (2.7 ± 0.3-fold vs. 3.6 ± 0.2-fold in controls, p < 0.001). Sarcoplasmic reticulum (SR) calcium content was reduced to 67 ± 4% (p < 0.01), and SR calcium re-uptake slowed (p < 0.05). Sorafenib significantly reduced serine 16 phosphorylation of phospholamban (PLN, p < 0.05), while PLN threonine 17 and CaMKII (T286) phosphorylation were not altered. Our data demonstrate that sorafenib acutely impairs cardiac contractility by reducing S16 PLN phosphorylation, leading to reduced SR calcium content, CaT amplitude, and slowed cytosolic calcium removal. These results indicate myocyte intrinsic cardiotoxicity irrespective of effects on the vasculature and chronic cardiac remodeling.
Highlights
Targeted therapies, such as monoclonal antibodies, small molecule protein kinase inhibitors, or immunotherapy revolutionized cancer treatment and substantially improved survival in many types of cancer
These effects on contractility are cardiomyocyte intrinsic and mediated by a reduction of systolic cytoplasmic calcium concentrations associated with reduced sarcoplasmic reticulum (SR) calcium load and phospholamban S16 phosphorylation
Sorafenib causes several cardiac adverse events including hypertension, vascular events leading to ischemia, or congestive heart failure[2,20,21,22]
Summary
Targeted therapies, such as monoclonal antibodies, small molecule protein kinase inhibitors, or immunotherapy revolutionized cancer treatment and substantially improved survival in many types of cancer. Multi-kinase inhibitors blocking vascular endothelial growth factor (VEGF) signal transduction appear to be problematic in respect to cardiovascular toxicity[11]. They often increase blood pressure (22% with sunitinib12, 15% with sorafenib)[13], and increase the risk of vascular events such as endothelial injury, vasospasm, or arterial thrombosis[14,15]. If pre-existing cardiac conditions like hypertrophy or ischemia are present, the adverse effects of multi-kinase inhibition with sorafenib are amplified[16]. Sorafenib is a tyrosine kinase inhibitor with anti-VEGF activity and was first approved by the FDA in 2005 Among other kinases it inhibits VEGF receptor 1–3 tyrosine kinases, platelet derived growth factor (PDGF) family receptors, and the Ras-Raf-MEK-ERK signal transduction pathway[1,6]. It remains unclear if cardiac toxicity is mainly a consequence of vascular effects with secondary myocardial damage, impaired remodeling with chronic treatment, or direct cardiomyocyte toxic effects
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