Sacubitril/Valsartan Ameliorates Crizotinib-Induced Cardiotoxicity in Mice.

BACKGROUND

Lung cancer is one of the major cause of death globally. Crizotinib is a first-line drug used in treating non-small-cell lung cancer (NSCLC). However, the pathophysiological mechanisms underlying its cardiotoxicity are unknown. This study investigated the mechanisms of crizotinib-induced cardiotoxicity and explored whether this toxicity can be prevented by the angiotensin receptor/neprilysin inhibitor sacubitril/valsartan.

METHODS

Male C57BL/6 mice were randomly divided into three groups: control, crizotinib (40 mg for four weeks), and crizotinib + sacubitril/valsartan (40 mg /60 mg for four weeks). Expression of genes in myocardial tissue were detected by transcriptomic sequencing, with verification of the differentially expressed genes (DEGs) using Real time-polymerase chain reaction (RT-PCR). Blood pressure (BP) and cardiac function of animals were measured using non-invasive monitoring and echocardiography approaches. Ventricular refractory period (RP), as well as the induction rate and score of ventricular arrhythmias (VAs) were detected by electrophysiology. Epicardial conductance was measured by mapping. Expression of in myocardium was detected by western blot and RT-PCR.

RESULTS

DEGs detected using transcriptomic sequencing included 10 up-regulated and 20 down-regulated genes. The first 5 DEGs identified were , , , and . Kyoto Encyclopedia of Genes and Genomes (KEGG) result indicated that is involved in myocarditis, cardiomyopathy, and cardiac muscle contraction. Crizotinib treatment increased blood pressure, prolonged QTc interval, shortened ventricular RP, increased the incidence and score of right VAs, and increased expression. Most of these responses were limited by sacubitril/valsartan.

CONCLUSIONS

Crizotinib induced a range of cardiotoxic side effects in a mouse model and increased expression represents a biomarker for this response. These cardiovascular toxic responses can be largely prevented by sacubitril/valsartan.