Sunitinib, a multitargeted oral tyrosine kinase inhibitor, used widely to treat solid tumors, results in hypertension in up to 47% and left ventricular dysfunction in up to 19% of treated individuals. The relative contribution of afterload toward inducing cardiac dysfunction with sunitinib treatment remains unknown. We created a preclinical model of sunitinib cardiotoxicity using engineered microtissues that exhibited cardiomyocyte death, decreases in force generation, and spontaneous beating at clinically relevant doses. Simulated increases in afterload augmented sunitinib cardiotoxicity in both rat and human microtissues, which suggest that antihypertensive therapy may be a strategy to prevent left ventricular dysfunction in patients treated with sunitinib.
Keywords: 2D, 2-dimensional; 3D, 3-dimensional; AICAR, 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside; AMPK, adenosine monophosphate-activated protein kinase; ATP, adenosine triphosphate; CCCP, carbonyl cyanide m-chlorophenyl hydrazine; CMT, cardiac microtissue; DMSO, dimethyl sulfoxide; EDTA, ethylenediamine tetraacetic acid; Hu-iPS-CM, human induced pluripotent stem cell cardiomyocyte; LV, left ventricle; NRVM, neonatal rat ventricular myocyte; PDMS, polydimethylsiloxane; RPMI, Roswell Park Memorial Institute medium; TMRM, tetramethylrhodamine; afterload; apoptosis; cardiotoxicity; huMSC, human mesenchymal stem cell; iPS-CM, induced pluripotent stem cell-derived cardiomyocyte; sunitinib; tissue engineering; toxicology; tyrosine kinase inhibitors.