Melphalan induces cardiotoxicity through oxidative stress in cardiomyocytes derived from human induced pluripotent stem
- PDF / 5,257,975 Bytes
- 17 Pages / 595.276 x 790.866 pts Page_size
- 88 Downloads / 164 Views
RESEARCH
Open Access
Melphalan induces cardiotoxicity through oxidative stress in cardiomyocytes derived from human induced pluripotent stem cells Rui Liu1,2, Dong Li1, Fangxu Sun3, Antonio Rampoldi1, Joshua T. Maxwell1, Ronghu Wu3, Peter Fischbach1, Sharon M. Castellino1, Yuhong Du4, Haian Fu4, Anant Mandawat5,6,7 and Chunhui Xu1,8*
Abstract Background: Treatment-induced cardiotoxicity is a leading noncancer-related cause of acute and late onset morbidity and mortality in cancer patients on antineoplastic drugs such as melphalan—increasing clinical case reports have documented that it could induce cardiotoxicity including severe arrhythmias and heart failure. As the mechanism by which melphalan impairs cardiac cells remains poorly understood, here, we aimed to use cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) to investigate the cellular and molecular mechanisms of melphalan-induced cardiotoxicity. Methods: hiPSC-CMs were generated and treated with clinically relevant doses of melphalan. To characterize melphalan-induced cardiotoxicity, cell viability and apoptosis were quantified at various treatment durations. Ca2+ transient and contractility analyses were used to examine the alterations of hiPSC-CM function. Proteomic analysis, reactive oxygen species detection, and RNA-Sequencing were conducted to investigate underlying mechanisms. Results: Melphalan treatment of hiPSC-CMs induced oxidative stress, caused Ca2+ handling defects and dysfunctional contractility, altered global transcriptomic and proteomic profiles, and resulted in apoptosis and cell death. The antioxidant N-acetyl-L-cysteine attenuated these genomic, cellular, and functional alterations. In addition, several other signaling pathways including the p53 and transforming growth factor-β signaling pathways were also implicated in melphalan-induced cardiotoxicity according to the proteomic and transcriptomic analyses. Conclusions: Melphalan induces cardiotoxicity through the oxidative stress pathway. This study provides a unique resource of the global transcriptomic and proteomic datasets for melphalan-induced cardiotoxicity and can potentially open up new clinical mechanism-based targets to prevent and treat melphalan-induced cardiotoxicity. Keywords: Cardiotoxicity, Chemotherapy, Contractility, Oxidative stress, Stem cells
* Correspondence: [email protected] 1 Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 2015 Uppergate Drive, Atlanta, GA 30322, USA 8 Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link
Data Loading...
