Doxorubicin and aclarubicin showed distinct cytotoxicity in hiPSC-derived cardiac microtissues, with higher doxorubicin sensitivity in cells from patients who developed clinical cardiotoxicity.
Does doxorubicin or aclarubicin cause differential cardiotoxicity in hiPSC-derived cardiac microtissues from patients with or without prior anthracycline-induced cardiotoxicity?
Patient-specific hiPSC-derived 3D cardiac microtissues demonstrate distinct cell type- and drug-specific effects of anthracyclines, offering a promising model for studying individual susceptibility to cardiotoxicity.
Abstract Background Anthracyclines are powerful drugs for treating cancer and have increased survival in patients with different malignancies, including children. Nevertheless, they are widely recognized for causing dose-dependent cardiotoxicity, which displays substantial variability among patients and is challenging to predict. Purpose Here, we aimed to unravel anthracycline-induced cardiotoxicity (AIC) at the cellular level by comparing different anthracycline analogues on multiple cardiac cell types, derived from different patients. Methods We used human induced pluripotent stem cells (hiPSCs) to generate different cardiac cell types with the same patient-specific genetic background. To investigate individual susceptibility, hiPSCs were derived from age- and sex-matched lymphoma patients who either developed AIC (Cardiotox) or did not (No-tox). HiPSC-derived cardiomyocytes (CMs), -cardiac fibroblasts (CFs) and -endothelial cells (ECs) were cultured separately, or assembled in three-dimensional (3D) cardiac microtissues (MTs). Cells and MTs were treated with two anthracycline molecules, doxorubicin (Doxo) or its analogue aclarubicin (Acla), monitored over time by imaging and analyzed 72h after treatment for cell viability and gene expression. Results Doxo and Acla showed different dose-dependent cytotoxicity in all the tested cardiac cell types, and different timing of expression of the DNA damage marker H2AX-γ. In MTs, the treatment caused reduction in cell viability in a cell-type specific manner, reflecting data from 2D mono-cultures, and this overall resulted in altered contractility properties. Methylation analysis and RNA-sequencing revealed distinct epigenetic and gene expression profiles in MTs treated with Doxo or Acla, suggesting drug-specific mechanisms of action. Preliminary data indicate higher sensitivity to Doxo in Cardiotox hiPSC-CMs and -ECs, warranting further study. Conclusions In summary, our findings reveal distinct cell type- and drug-specific effects underlying AIC, highlighting the utility of hiPSC-based cardiac models for studying mechanisms underlying susceptibility to cardiotoxic drugs. We expect that our work will contribute to better understand these effects for guiding future safer chemotherapy strategies.
Campostrini et al. (Fri,) conducted a other in Anthracycline-induced cardiotoxicity. Doxorubicin and aclarubicin was evaluated on Cell viability and gene expression. Doxorubicin and aclarubicin showed distinct cytotoxicity in hiPSC-derived cardiac microtissues, with higher doxorubicin sensitivity in cells from patients who developed clinical cardiotoxicity.