Ex Vivo Cardiotoxicity of Antineoplastic Casiopeinas Is Mediated through Energetic Dysfunction and Triggered Mitochondrial‐Dependent Apoptosis

Abstract

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

Amorphous SiO2 nanoparticles promote cardiac dysfunction via the opening of the mitochondrial permeability transition pore in rat heart and human cardiomyocytes

“…The amount of nanoSiO 2 that reduced the relaxation of ex vivo hearts down to IC 50 was estimated on average as 93 μg/mL, very close to the reported average of 99 μg/mL IC 50 viability of adult rat cardiomyocytes [24]. Compared to other mitochondrial prooxidant molecules exposed under similar conditions to ex vivo hearts, the t 50 present a similar value of 30 min [60]. Metabolic inhibition, either by depravation of substrates or reduction of the PO 2 in the extracellular fluid, reduce the oxidative phosphorylation and the ATP availability.…”

“…Animals were heparinized and anesthetized with pentobarbital sodium (1000 U/kg and 100 mg/kg i.p, respectively) before removal and hanging the heart. Following a gold standard technique [38,60], hearts were mounted on a Langendorff apparatus and then perfused with Tyrode medium (TM) in mM: 128 NaCl, 0.4 NaH 2 PO 4 , 6 glucose, 5.4 KCl, 0.5 MgCl-6H 2 O, 5 creatinine, 5 taurine, and 25 HEPES, pH 7.4 at 37°C for 5 min and digested by 0.1% collagenase type II (Worthington Biochemical, Lakewood, NJ) dissolved in TM for 15 min. Ventricles were dissected and cells mechanically disaggregated.…”

Anticancer activity, DNA binding and cell mechanistic studies of estrogen-functionalised Cu(II) complexes

“…In addition, the altered copper metabolism displayed by many cancer cells as well as the differential response between normal and tumour cells to copper, laid down the rationale for the development of copper complexes as anticancer agents. Casiopeinas is the generic name of a group of copper complexes designed to be used as antineoplastics and have recently shown promising results as chemotherapeutic agents in animal models and clinical trials [3,4]. Copper is involved in fundamental biological processes such as respiration, detoxification of ROS (reactive oxygen species) and copper-based drugs show a wide spectrum of action [5][6][7][8][9][10][11][12].…”

Contribution of membrane transporters to chemotherapy‐induced cardiotoxicity

“…Alternatively, ex vivo evaluation of rodent cardiomyocytes directly obtained from animals of a desired genetic constitution (e.g., deletion of a specific SLC with or without transgenic expression of human transporters) has been proven useful in demonstrating transporter‐dependence of particular drug phenotypes in advance of in vivo testing 57 . These procedures allow adverse effects of drugs on the heart to be detected by measuring drug uptake, mechanical performance, energetics, mitochondrial function, glucose uptake, and/or cell viability, depending on the specific drug or drug combinations being tested 58 . In advance of clinical testing, selection of a proper, predictive nonclinical in vivo model and an optimal technique for imaging‐based cardiac assessment is required to arrive at a strategy that could be clinically beneficial.…”