Rivaroxaban Ameliorates Sunitinib-Induced Injury of Cardiomyocytes via Repressing MAPK Signaling Pathway

Abstract

Background: Sunitinib (SU) is used to treat kidney cancer. However, it can also cause cardiotoxicity. This study is performed to investigate whether rivaroxaban (RIV) attenuates SU-induced cardiotoxicity (SIC).

Methods and Materials: AC16 cells and primary cardiomyocytes of neonatal mouse were treated with different concentrations (2–10 μM) of SU for 24 h or with 6 μM SU and 10 μg/mL RIV for 24 h. The viability of cardiomyocytes was evaluated using the cell counting kit-8 (CCK-8) assay, and the apoptosis rate was evaluated using flow cytometry. The activity of caspase-3 was determined. The levels of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were also measured. The potential targets and downstream pathways of RIV in SIC treatment were investigated using network pharmacology, molecular docking, and molecular dynamics simulation. qPCR and western blotting were used to detect the regulatory effects of SU and RIV on mRNA and protein expression of MAPK pathway-related genes, respectively.

Results: RIV treatment alleviated SU-induced cardiomyocyte injury by promoting viability and inhibiting apoptosis, oxidative stress, and the inflammatory response in AC16 cells and primary cardiomyocytes. Caspase 3 (CASP3), signal transducer and activator of transcription 3 (STAT3), SRC proto-oncogene, nonreceptor tyrosine kinase (SRC), ATP-binding cassette subfamily G member 2 (ABCG2), and ATP-binding cassette subfamily B member 1 (ABCB1) were candidate targets of RIV in SIC. The binding affinities between RIV and CASP3, STAT3, SRC, ABCG2, and ABCB1 were all less than −7.5 kcal/mol, indicating that RIV could bind stably to these targets. Bioinformatics analyses suggested that the mitogen-activated protein kinase (MAPK) pathway was involved in the mechanism by which RIV alleviated SIC. RIV treatment decreased the mRNA expression of CASP3 and increased the mRNA expression of STAT3, SRC, ABCG2, and ABCB1 in AC16 cells and primary cardiomyocytes. RIV also inhibited the SU-induced activation of the MAPK pathway.

Conclusion: RIV exerts a protective effect against SU-induced cardiomyocyte injury by inhibiting the MAPK signaling pathway. RIV therapy may be a promising strategy to inhibit SU’s cardiotoxicity in cancer patients.