The Impact of Statin on Chemotherapy‐Induced Cardiotoxicity

Abstract

Tyrosine Kinase Inhibitors (TKIs) are chemotherapy agents that can damage cardiomyocytes resulting in cardiotoxicity and heart failure. TKIs target enzymes that control diverse biological pathways such as cell metabolism and apoptosis. Autophagy is a self‐degradative process involving the translocation of light chain 3 (LC3) proteins onto the autophagosome membrane, followed by fusion with lysosome for degradation. In cardiomyocytes, autophagy activation has been shown to be either protective or detrimental. We previously demonstrated autophagy to be cardioprotective of ischemia‐reperfusion injuries, presumably through maintaining cell homeostasis by removing damaged organelles such as mitochondria. Recent studies have shown that statins, HMG‐CoA reductase inhibitors commonly used to lower cholesterol levels, enhance cardiomyocyte autophagy. We hypothesize that TKIs disrupts cardiomyocyte autophagy, and autophagy activation protects cardiomyocytes from TKI‐induced toxicity. As a proof of concept, we chose the well‐established TKI dasatinib due to its high risk for heart failure in patients. We treated H9c2 rat myoblast cells with dasatinib either alone or in combination with commonly used statins: simvastatin, atorvastatin, pravastatin, and rosuvastatin. We performed MTT colorimetric assays on 96‐well plates to quantify H9c2 viability, and dual‐channel flow cytometry to assess autophagy levels with an autophagy detection nanoparticle (ADN) developed in‐house, and cell membrane integrity with propidium. We further confirmed autophagy protein, LC3, expression by western blot. After 24‐hour exposure, dasatinib significantly reduced H9c2 myocyte cell survival and ADN fluorescence. Atorvastatin and dasatinib co‐treatment significantly enhanced H9c2 survival. Interestingly, the reduction in cell death was associated with the restoration of H9c2 autophagy homeostasis, detected by ADN fluorescence. The autophagy increase was confirmed by western blot. Statin treatment thus causes a robust cytoprotective effect in H9c2 myocytes against dasatinib, presumably through autophagy activation.Support or Funding InformationFunding: R25‐HL007785, R00‐HL121152.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.