Doxorubicin exposure in human induced pluripotent stem cell-derived cardiomyocytes significantly dysregulated 1290 genes, identifying p53 as a key regulator of death receptor-mediated apoptosis.
Transcriptomic profiling identifies p53 and increased death receptor expression as key early indicators and potential predictive biomarkers for doxorubicin-induced cardiotoxicity.
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.
McSweeney et al. (Wed,) conducted a other in Doxorubicin-induced cardiotoxicity. Doxorubicin vs. Vehicle (0.0015% DMSO) was evaluated on Significantly dysregulated genes after 48 h exposure. Doxorubicin exposure in human induced pluripotent stem cell-derived cardiomyocytes significantly dysregulated 1290 genes, identifying p53 as a key regulator of death receptor-mediated apoptosis.