Casiopeinas are a group of copper-based antineoplastic molecules designed as a less toxic and more therapeutic alternative to\ncisplatin or Doxorubicin; however, there is scarce evidence about their toxic effects on the whole heart and cardiomyocytes.\nGiven this, rat hearts were perfused with Casiopeinas or Doxorubicin and the effects on mechanical performance, energetics,\nand mitochondrial function were measured. As well, the effects of Casiopeinas-triggered cell death were explored in isolated\ncardiomyocytes. Casiopeinas III-Ea, II-gly, and III-ia induced a progressive and sustained inhibition of heart contractile function\nthat was dose- and time-dependent with an IC50 of 1.3 �± 0.2, 5.5 �± 0.5, and 10 �± 0.7 �¼M, correspondingly. Myocardial oxygen\nconsumption was not modified at their respective IC50, although ATP levels were significantly reduced, indicating energy\nimpairment. Isolated mitochondria from Casiopeinas-treated hearts showed a significant loss of membrane potential and\nreduction of mitochondrial Ca2+ retention capacity. Interestingly, Cyclosporine A inhibited Casiopeinas-induced mitochondrial\nCa2+ release, which suggests the involvement of the mitochondrial permeability transition pore opening. In addition,\nCasiopeinas reduced the viability of cardiomyocytes and stimulated the activation of caspases 3, 7, and 9, demonstrating a cell\ndeath mitochondrial-dependent mechanism. Finally, the early perfusion of Cyclosporine A in isolated hearts decreased\nCasiopeinas-induced dysfunction with reduction of their toxic effect. Our results suggest that heart cardiotoxicity of Casiopeinas\nis similar to that of Doxorubicin, involving heart mitochondrial dysfunction, loss of membrane potential, changes in energetic\nmetabolites, and apoptosis triggered by mitochondrial permeability.
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