Abstract 13783: Disease Modeling Doxorubicin-induced Cardiotoxicity Using Human Induced Pluripotent Stem Cells-derived Cardiomyocytes From Healthy and Type 2 Diabetic Patients

Abstract

Introduction: Doxorubicin-Induced Cardiotoxicity (DIC) is one of the most common clinical complications in cancer patients. Patients with diabetes have a higher incidence of breast cancer, and their risks of developing DIC is also higher as compared to healthy patients. The human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) have the unique potential to recapitulate the genetic background and have emerged as a powerful tool for disease modeling and drug screening. Hypothesis: We hypothesized that cardiomyocytes derived from T2 diabetic patients will recapitulate greater sensitivity to DIC as compared to CMs derived from non-diabetic individuals. Methods: The patient specific iPSCs were differentiated into CMs with modifications to enhance cardiomyocyte purity (Fig. 1A, n=4 cell lines in each group). After 30 days from the initial differentiation, CMs were exposed to different concentrations of doxorubicin (DOX) based on the pharmacokinetic characteristics of doxorubicin in humans. The DOX-induced stress on the CMs after 24h and 48h was investigated via the analysis of 1) Cellular LDH release 2) Cellular viability using Alamar Blue assay and 3) CM-markers using real-time PCR. Results: Following the treatment with DOX the (iPSC)-derived cardiomyocytes (CMs) from the diabetic patients were more sensitive as compared to control CMs by: 1) An increase in the LDH release, Fig. 1B, 2) Decrease in the cellular viability, Fig. 1C, and 3) Greater downregulation of cardiac specific structural genes including Troponin T and Troponin I mRNA expression. Conclusions: For the first time, we demonstrate the ability of hiPSC-CMs derived from diabetic individuals to recapitulate greater sensitivity to DOX in vitro , validating this platform for predicting DIC severity in vivo .