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Antineoplastic copper coordinated complexes (Casiopeinas) uncouple oxidative phosphorylation and induce mitochondrial permeability transition in cardiac mitochondria and cardiomyocytes

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Abstract

Copper-based drugs, Casiopeinas (Cas), exhibit antiproliferative and antineoplastic activities in vitro and in vivo, respectively. Unfortunately, the clinical use of these novel chemotherapeutics could be limited by the development of dose-dependent cardiotoxicity. In addition, the molecular mechanisms underlying Cas cardiotoxicity and anticancer activity are not completely understood. Here, we explore the potential impact of Cas on the cardiac mitochondria energetics as the molecular mechanisms underlying Cas-induced cardiotoxicity. To explore the properties on mitochondrial metabolism, we determined Cas effects on respiration, membrane potential, membrane permeability, and redox state in isolated cardiac mitochondria. The effect of Cas on the mitochondrial membrane potential (Δψm) was also evaluated in isolated cardiomyocytes by confocal microscopy and flow cytometry. Cas IIIEa, IIgly, and IIIia predominately inhibited maximal NADH- and succinate-linked mitochondrial respiration, increased the state-4 respiration rate and reduced membrane potential, suggesting that Cas also act as mitochondrial uncouplers. Interestingly, cyclosporine A inhibited Cas-induced mitochondrial depolarization, suggesting the involvement of mitochondrial permeability transition pore (mPTP). Similarly to isolated mitochondria, in isolated cardiomyocytes, Cas treatment decreased the Δψm and cyclosporine A treatment prevented mitochondrial depolarization. The production of H2O2 increased in Cas-treated mitochondria, which might also increase the oxidation of mitochondrial proteins such as adenine nucleotide translocase. In accordance, an antioxidant scavenger (Tiron) significantly diminished Cas IIIia mitochondrial depolarization. Cas induces a prominent loss of membrane potential, associated with alterations in redox state, which increases mPTP opening, potentially due to thiol-dependent modifications of the pore, suggesting that direct or indirect inhibition of mPTP opening might reduce Cas-induced cardiotoxicity.

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Acknowledgments

We thank, Tecnológico de Monterrey as well as CONACYT for the Founding Sources gave: this work was partially supported by Endowed Chair in Cardiology- Tec de Monterrey 0020CAT131 as well as CONACYT-México grant 151136 (G. García-Rivas). Casiopeinas synthesis was supported by CONACYT-México grant 179119 8 (L.Ruíz-Azuara). We acknowledge Valeria Oropeza for the figures designs.

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    Authors and Affiliations

    1. Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, Mexico

      Christian Silva-Platas, Carlos Enrique Guerrero-Beltrán, Mariana Carrancá, Elena Cristina Castillo, Judith Bernal-Ramírez, Yuriana Oropeza-Almazán, Lorena N. González, Rocío Rojo, Luis Enrique Martínez, Noemí García & Gerardo García-Rivas

    2. Escuela de Ingeniería y Ciencias, Tecnológico de Monterrey, Monterrey, Mexico

      Juan Valiente-Banuet

    3. Departamento de Química Inorgánica y Nuclear, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, México

      Lena Ruiz-Azuara

    4. Departamento de Toxicología. Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, México

      María Elena Bravo-Gómez

    5. Centro de Investigación Biomédica. Hospital Zambrano Hellion, Tecnológico de Monterrey, San Pedro Garza-García, Mexico

      Noemí García & Gerardo García-Rivas

    6. Laboratorio Nutrición Experimental, Instituto Nacional de Pediatría, Mexico City, México

      Karla Carvajal

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    1. Christian Silva-Platas
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    Correspondence to Gerardo García-Rivas.

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    Christian Silva-Platas, Carlos Enrique Guerrero-Beltrán and Mariana Carrancá contributed equally to this work.

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    Silva-Platas, C., Guerrero-Beltrán, C.E., Carrancá, M. et al. Antineoplastic copper coordinated complexes (Casiopeinas) uncouple oxidative phosphorylation and induce mitochondrial permeability transition in cardiac mitochondria and cardiomyocytes. J Bioenerg Biomembr 48, 43–54 (2016). https://doi.org/10.1007/s10863-015-9640-x

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