Abstract
Modern diagnostic strategies for early recognition of cancer therapeutics-related cardiac dysfunction involve cardiac troponins measurement. Still, the role of other markers of cardiotoxicity is still unclear. The present study was designed to investigate dynamics of response of human cardiomyocytes derived from induced pluripotent stem cells (hiPCS-CMs) to doxorubicin with the special emphasis on their morphological changes in relation to expression and organization of troponins. The hiPCS-CMs were treated with doxorubicin concentrations (1 and 0.3 µM) for 48 h and followed for next up to 6 days. Exposure of hiPCS-CMs to 1 µM doxorubicininduced suppression of both cardiac troponin T (cTnT) and cardiac troponin I (cTnI) gene expression. Conversely, lower 0.3 µM doxorubicin concentration produced no significant changes in the expression of aforementioned genes. However, the intracellular topography, arrangement, and abundance of cardiac troponin proteins markedly changed after both doxorubicin concentrations. In particular, at 48 h of treatment, both cTnT and cTnI bundles started to reorganize, with some of them forming compacted shapes extending outwards and protruding outside the cells. At later intervals (72 h and onwards), the whole troponin network collapsed and became highly disorganized following, to some degree, overall changes in the cellular shape. Moreover, membrane permeability of cardiomyocytes was increased, and intracellular mitochondrial network rearranged and hypofunctional. Together, our results demonstrate complex effects of clinically relevant doxorubicin concentrations on hiPCS-CM cells including changes in cTnT and cTnI, but also in other cellular compartments contributing to the overall cytotoxicity of this class of cytostatics.
Highlights
Chemotherapy-related cardiotoxicity continues to be one of the limiting factors in the antineoplastic treatment regimens leading to a significant damage of the heart with consequent cardiac failure in treated patients [1]
The first studies of Herman and Adamcova [4,5] in the nineties describe a significant elevation of cardiac troponin T in experimental models of chronic ANT cardiotoxicity
Numerous experimental papers have demonstrated that ANT-induced cardiac damage is associated with a relatively prolonged release of cardiac troponins related to the cumulative dose of ANT and that cTns are very important biochemical markers for evaluation of cardiotoxic or potentially cardioprotective effect of new agents [6,7,8,9,10,11]
Summary
Chemotherapy-related cardiotoxicity continues to be one of the limiting factors in the antineoplastic treatment regimens leading to a significant damage of the heart with consequent cardiac failure in treated patients [1]. The ANT (DOX)-induced cardiotoxicity and resulting chronic heart failure have been related to iron-catalyzed oxidative damage to the heart [2]. The first studies of Herman and Adamcova [4,5] in the nineties describe a significant elevation of cardiac troponin T (cTnT) in experimental models of chronic ANT cardiotoxicity. Numerous experimental papers have demonstrated that ANT-induced cardiac damage is associated with a relatively prolonged release of cardiac troponins (cTns) related to the cumulative dose of ANT and that cTns are very important biochemical markers for evaluation of cardiotoxic or potentially cardioprotective effect of new agents [6,7,8,9,10,11]
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