Carfilzomib Treatment Causes Molecular and Functional Alterations of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

卷:10

Ronghu Wu¹  Aysha Rashid²  Chunhui Xu²  Anant Mandawat³  Rui Liu⁴  Hyun Hwang⁴  Dong Li⁴  Megan R. Lee⁴  Joshua T. Maxwell⁴  Parvin Forghani⁴  Fangxu Sun⁵  Khalid Salaita⁵ 

[1] Winship Cancer Institute Emory University School of Medicine Atlanta GA;

[2] Biomolecular Chemistry Department of Chemistry Emory University Atlanta GA;

[3] Department of Medicine &

[4] Division of Pediatric Cardiology Department of Pediatrics Emory University School of Medicine and Children’s Healthcare of Atlanta Atlanta GA;

[5] School of Chemistry and Biochemistry and the Petit Institute for Bioengineering and Bioscience Georgia Institute of Technology Atlanta GA;

关键词: cardiomyocyte;    cardiotoxicity;    drug research;    gene expression;    stem cell;   

DOI  :  10.1161/JAHA.121.022247

来源: DOAJ

【 摘 要 】

Background Anticancer therapies have significantly improved patient outcomes; however, cardiac side effects from cancer therapies remain a significant challenge. Cardiotoxicity following treatment with proteasome inhibitors such as carfilzomib is known in clinical settings, but the underlying mechanisms have not been fully elucidated. Methods and Results Using human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) as a cell model for drug‐induced cytotoxicity in combination with traction force microscopy, functional assessments, high‐throughput imaging, and comprehensive omic analyses, we examined the molecular mechanisms involved in structural and functional alterations induced by carfilzomib in hiPSC‐CMs. Following the treatment of hiPSC‐CMs with carfilzomib at 0.01 to 10 µmol/L, we observed a concentration‐dependent increase in carfilzomib‐induced toxicity and corresponding morphological, structural, and functional changes. Carfilzomib treatment reduced mitochondrial membrane potential, ATP production, and mitochondrial oxidative respiration and increased mitochondrial oxidative stress. In addition, carfilzomib treatment affected contractility of hiPSC‐CMs in 3‐dimensional microtissues. At a single cell level, carfilzomib treatment impaired Ca2+ transients and reduced integrin‐mediated traction forces as detected by piconewton tension sensors. Transcriptomic and proteomic analyses revealed that carfilzomib treatment downregulated the expression of genes involved in extracellular matrices, integrin complex, and cardiac contraction, and upregulated stress responsive proteins including heat shock proteins. Conclusions Carfilzomib treatment causes deleterious changes in cellular and functional characteristics of hiPSC‐CMs. Insights into these changes could be gained from the changes in the expression of genes and proteins identified from our omic analyses.

【 授权许可】

Unknown