Melphalan induces cardiotoxicity through oxidative stress in cardiomyocytes derived from human induced pluripotent stem cells

Stem Cell Research & Therapy

Anant Mandawat¹  Dong Li²  Joshua T. Maxwell²  Antonio Rampoldi²  Peter Fischbach²  Sharon M. Castellino²  Rui Liu³  Chunhui Xu⁴  Haian Fu⁵  Yuhong Du⁵  Fangxu Sun⁶  Ronghu Wu⁶ 

[1] Department of Medicine, Emory University School of Medicine, 30322, Atlanta, GA, USA;Department of Hematology and Medical Oncology, Emory University School of Medicine, 30322, Atlanta, GA, USA;Cardio-Oncology Program, Winship Cancer Institute of Emory University, 30322, Atlanta, GA, USA;Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 2015 Uppergate Drive, 30322, Atlanta, GA, USA;Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 2015 Uppergate Drive, 30322, Atlanta, GA, USA;Department of Pediatrics, The Third Xiangya Hospital of Central South University, 410013, Changsha, Hunan, China;Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 2015 Uppergate Drive, 30322, Atlanta, GA, USA;Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 30322, Atlanta, GA, USA;Emory Chemical Biology Discovery Center and the Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 30322, Atlanta, GA, USA;School of Chemistry and Biochemistry and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 30332, Atlanta, GA, USA;

关键词: Cardiotoxicity;    Chemotherapy;    Contractility;    Oxidative stress;    Stem cells;   

DOI  :  10.1186/s13287-020-01984-1

来源: Springer

【 摘 要 】

BackgroundTreatment-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.MethodshiPSC-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.ResultsMelphalan 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.ConclusionsMelphalan 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.

【 授权许可】

CC BY