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

Abstract

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.

• Authors: Parvin Forghani, Aysha Rashid, Fangxu Sun, Rui Liu, Dong Li, Megan R Lee, Hyun Hwang, Joshua T Maxwell, Anant Mandawat, Ronghu Wu, Khalid Salaita, Chunhui Xu
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 10 Issue 24 Pg. e022247 (12 21 2021) ISSN: 2047-9980 [Electronic] England
• PMID: 34873922 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Oligopeptides
• carfilzomib

Topics

• Humans
• Induced Pluripotent Stem Cells (drug effects)
• Myocytes, Cardiac (drug effects)
• Oligopeptides (adverse effects)