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.

• MeSH
• buněčné linie MeSH
• doxorubicin farmakologie   toxicita   MeSH
• indukované pluripotentní kmenové buňky cytologie   účinky léků   MeSH
• kardiomyocyty cytologie   účinky léků   metabolismus   MeSH
• kardiotoxicita MeSH
• lidé MeSH
• protinádorové látky farmakologie   toxicita   MeSH
• troponin metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

(1) the mechanisms and outcomes of doxorubicin (DOX)-dependent toxicity upon changed intracellular zinc (Zn) concentrations in the cardiomyocytes obtained from human-induced pluripotent stem cells (hiPCS-CMs) were investigated; (2) cells exposed to the DOX were pretreated or cotreated with zinc pyrythione (ZnPyr) and various cellular endpoints and mechanisms were analyzed via cytometric methods; (3) both DOX concentrations (0.3 and 1 μM) induced a concentration-dependent loss of viability, an activation of autophagy, cell death, and the appearance of senescence. These phenotypes were preceded by an oxidative burst, DNA damage, and a loss of mitochondrial and lysosomal integrity. Furthermore, in DOX-treated cells, proinflammatory and stress kinase signaling (in particular, JNK and ERK) were upregulated upon the loss of free intracellular Zn pools. Increased free Zn concentrations proved to have both inhibitory and stimulatory effects on the investigated DOX-related molecular mechanisms, as well as on signaling pathways on the resulting cell fates; and (4) free intracellular Zn pools, their status, and their elevation might have, in a specific context, a pleiotropic impact upon DOX-dependent cardiotoxicity.

• MeSH
• buněčná smrt MeSH
• doxorubicin farmakologie   MeSH
• indukované pluripotentní kmenové buňky * MeSH
• kardiomyocyty metabolismus   MeSH
• lidé MeSH
• zinek * metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH