title: Antineoplastic copper coordinated complexes (Casiopeinas) uncouple oxidative phosphorylation and induce mitochondrial permeability transition in cardiac mitochondria and cardiomyocytes.
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.
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, Mexico.
authors.forename: Christian
authors.initials: C
authors.lastname: Silva-Platas
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, Mexico.
authors.forename: Carlos Enrique
authors.initials: CE
authors.lastname: Guerrero-Beltrán
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, Mexico.
authors.forename: Mariana
authors.initials: M
authors.lastname: Carrancá
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, Mexico.
authors.forename: Elena Cristina
authors.initials: EC
authors.lastname: Castillo
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, Mexico.
authors.forename: Judith
authors.initials: J
authors.lastname: Bernal-Ramírez
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, Mexico.
authors.forename: Yuriana
authors.initials: Y
authors.lastname: Oropeza-Almazán
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, Mexico.
authors.forename: Lorena N
authors.initials: LN
authors.lastname: González
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, Mexico.
authors.forename: Rocío
authors.initials: R
authors.lastname: Rojo
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, Mexico.
authors.forename: Luis Enrique
authors.initials: LE
authors.lastname: Martínez
authors.affiliation: Escuela de Ingeniería y Ciencias, Tecnológico de Monterrey, Monterrey, Mexico.
authors.forename: Juan
authors.initials: J
authors.lastname: Valiente-Banuet
authors.affiliation: Departamento de Química Inorgánica y Nuclear, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, México.
authors.forename: Lena
authors.initials: L
authors.lastname: Ruiz-Azuara
authors.affiliation: Departamento de Toxicología. Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, México.
authors.forename: María Elena
authors.initials: ME
authors.lastname: Bravo-Gómez
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, Mexico.|Centro de Investigación Biomédica. Hospital Zambrano Hellion, Tecnológico de Monterrey, San Pedro Garza-García, Mexico.
authors.forename: Noemí
authors.initials: N
authors.lastname: García
authors.affiliation: Laboratorio Nutrición Experimental, Instituto Nacional de Pediatría, Mexico City, México.
authors.forename: Karla
authors.initials: K
authors.lastname: Carvajal
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, Mexico. gdejesus@itesm.mx.|Centro de Investigación Biomédica. Hospital Zambrano Hellion, Tecnológico de Monterrey, San Pedro Garza-García, Mexico. gdejesus@itesm.mx.
authors.forename: Gerardo
authors.identifier: http://orcid.org/0000-0003-4731-3293
authors.initials: G
authors.lastname: García-Rivas
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology; D003300:Copper / Q000009:adverse effects / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D051336:Mitochondrial Membranes / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010539:Permeability / Q000187:drug effects; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D003300:Copper
keywords: Antineoplastic; Cardiomyocytes; Cardiotoxicity; Casiopeinas; Mitochondria; Permeability transition pore