Abstract
Doxorubicin is an important anticancer drug in the clinic. Unfortunately, it causes cumulative and dose-dependent cardiotoxic side effects. As the population of cancer survivors who have been exposed to treatment continues to grow, there is increased interest in assessing the long-term cardiac effects of doxorubicin and understanding the underlying mechanisms at play. In this study, we investigated doxorubicin-induced transcriptomic changes using RNA-sequencing (RNAseq) and a cellular model comprised of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Analyses of predicted upstream regulators identified the p53 protein as a key regulator of transcriptomic changes induced by doxorubicin. Clustering and pathway analyses showed that increased death receptor (DR) expression and enrichment of the extrinsic apoptotic pathway are significantly associated with doxorubicin-induced cardiotoxicity. Increased expression of p53 and DRs were confirmed via immunoblotting. Our data pinpoints increased DR expression as an early transcriptomic indicator of cardiotoxicity, suggesting that DR expression might function as a predictive biomarker for cardiac damage.
Highlights
Doxorubicin is the most commonly used member of the anthracycline family, which is widely prescribed for the treatment of various cancer types
Flow cytometry analyses of cardiomyocytes stained for cardiac troponin-T demonstrated a >99% pure population[18]
Doxorubicin is an effective chemotherapeutic drug that is prescribed for the treatment of numerous cancer types
Summary
Doxorubicin is the most commonly used member of the anthracycline family, which is widely prescribed for the treatment of various cancer types. Given the accumulating population of cancer survivors that have been exposed to treatment as children or adults, the potential long-term cardiac risk has become an interdisciplinary point of interest. While it remains unclear how exactly anthracyclines cause cardiotoxicity, several mechanisms have been shown to contribute to the development of cardiac damage, including. CMs functionally express most of the ion channels and sarcomeric proteins found in adult human cardiomyocytes and can spontaneously contract, serving as a species-specific complimentary platform to existing animal models Using this model, we recently identified the upregulation of death receptor (DR) expression and Official journal of the Cell Death Differentiation Association
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