Journal
STEM CELL RESEARCH & THERAPY
Volume 11, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13287-020-01984-1
Keywords
Cardiotoxicity; Chemotherapy; Contractility; Oxidative stress; Stem cells
Funding
- Children's Heart Research and Outcomes Center at Emory University
- Children's Healthcare of Atlanta
- Center for Pediatric Technology at Emory University
- Georgia Institute of Technology
- Imagine, Innovate and Impact (I3) Funds from the Emory School of Medicine
- Georgia CTSA NIH [UL1-TR002378]
- Center for Advancement of Science in Space [GA-2017-266]
- National Institutes of Health [R21AA025723, R01HL136345]
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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-beta 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.
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