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Sci Rep. 2018 Mar 28;8(1):5295. doi: 10.1038/s41598-018-23630-w.

The Anti-Cancer Multikinase Inhibitor Sorafenib Impairs Cardiac Contractility by Reducing Phospholamban Phosphorylation and Sarcoplasmic Calcium Transients.

Author information

1
Division of Cardiology, Medical University of Graz, Graz, Austria.
2
Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
3
Division of Cardiac Surgery, Medical University of Graz, Graz, Austria.
4
Division of Oncology, Medical University of Graz, Graz, Austria.
5
Department of Experimental Therapeutics, UT MD Anderson Cancer Center, Houston, TX, USA.
6
BioTechMed Graz, Graz, Austria.
7
Division of Cardiology, Medical University of Graz, Graz, Austria. herzforschung@gmail.com.
8
Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. herzforschung@gmail.com.

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.

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