Antineoplastic copper coordinated complexes (Casiopeinas) uncouple oxidative phosphorylation and induce mitochondrial permeability transition in cardiac mitochondria and cardiomyocytes
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  • 作者:Christian Silva-Platas…
  • 关键词:Casiopeinas ; Cardiotoxicity ; Antineoplastic ; Permeability transition pore ; Mitochondria ; Cardiomyocytes
  • 刊名:Journal of Bioenergetics and Biomembranes
  • 出版年:2016
  • 出版时间:February 2016
  • 年:2016
  • 卷:48
  • 期:1
  • 页码:43-54
  • 全文大小:1,458 KB
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  • 作者单位:Christian Silva-Platas (1)
    Carlos Enrique Guerrero-Beltrán (1)
    Mariana Carrancá (1)
    Elena Cristina Castillo (1)
    Judith Bernal-Ramírez (1)
    Yuriana Oropeza-Almazán (1)
    Lorena N. González (1)
    Rocío Rojo (1)
    Luis Enrique Martínez (1)
    Juan Valiente-Banuet (2)
    Lena Ruiz-Azuara (3)
    María Elena Bravo-Gómez (4)
    Noemí García (1) (5)
    Karla Carvajal (6)
    Gerardo García-Rivas (1) (5)

    1. Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, Mexico
    2. Escuela de Ingeniería y Ciencias, Tecnológico de Monterrey, Monterrey, Mexico
    3. Departamento de Química Inorgánica y Nuclear, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, México
    4. Departamento de Toxicología. Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, México
    5. Centro de Investigación Biomédica. Hospital Zambrano Hellion, Tecnológico de Monterrey, San Pedro Garza-García, Mexico
    6. Laboratorio Nutrición Experimental, Instituto Nacional de Pediatría, Mexico City, México
  • 刊物类别:Chemistry and Materials Science
  • 刊物主题:Chemistry
    Bioorganic Chemistry
    Biochemistry
    Animal Anatomy, Morphology and Histology
    Animal Biochemistry
    Organic Chemistry
  • 出版者:Springer New York
  • ISSN:1573-6881
文摘
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. Keywords Casiopeinas Cardiotoxicity Antineoplastic Permeability transition pore Mitochondria Cardiomyocytes
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