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Mitochondrial Cumulative Damage Induced by Mitoxantrone: Late Onset Cardiac Energetic Impairment

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Abstract

Mitoxantrone (MTX) is a chemotherapeutic agent, which presents late irreversible cardiotoxicity. This work aims to highlight the mechanisms involved in the MTX-induced cardiotoxicity, namely the effects toward mitochondria using in vivo and in vitro studies. Male Wistar rats were treated with 3 cycles of 2.5 mg/kg MTX at day 0, 10, and 20. One treated group was euthanized on day 22 (MTX22) to evaluate the early MTX cardiac toxic effects, while the other was euthanized on day 48 (MTX48), to allow the evaluation of MTX late cardiac effects. Cardiac mitochondria isolated from 4 adult untreated rats were also used to evaluate in vitro the MTX (10 nM, 100 nM, and 1 μM) direct effects upon mitochondria functionality. Two rats of MTX48 died on day 35, and MTX treatment caused a reduction in relative body weight gain in both treated groups with no significant changes in water and food intake. Decreased levels of plasma total creatine kinase and CK-MB were detected in the MTX22 group, and increased plasma levels of lactate were seen in MTX48. Increased cardiac relative mass and microscopic changes were evident in both treated groups. Considering mitochondrial effects, for the first time, it was evidenced that MTX induced an increase in the complex IV and complex V activities in MTX22 group, while a decrease in the complex V activity was accompanied by the reduction in ATP content in the MTX48 rats. No alterations in mitochondria transmembrane potential were found in isolated mitochondria from MTX48 rats or in isolated mitochondria directly incubated with MTX. This study highlights the relevance of the cumulative MTX-induced in vivo mitochondriopathy to the MTX cardiotoxicity.

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Abbreviations

ATP:

Adenosine 5′-triphosphate

AST:

Aspartate aminotransferase

BN-PAGE:

Blue native polyacrylamide gel electrophoresis

CK:

Creatine kinase

DAB:

Diaminobenzidine

DTNB:

5,5-Dithio-bis(2-nitrobenzoic acid)

GSH:

Reduced glutathione

GSHt:

Total glutathione

GSSG:

Oxidized glutathione

HClO4 :

Perchloric acid

LDH:

Lactate dehydrogenase

MTX:

Mitoxantrone

β-NADPH:

Reduced β-nicotinamidephosphate adenine dinucleotide

TPP+ :

Tetraphenylphosphonium

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Acknowledgments

This work was supported by the Fundação para a Ciência e Tecnologia (FCT)—project (EXPL/DTP-FTO/0290/2012)—QREN initiative with EU/FEDER financing through COMPETE—Operational Programme for Competitiveness Factors. LGR, VMC, and RJD-O thank FCT for their PhD Grant (SFRH/BD/63473/2009) and Post-doc Grants (SFRH/BPD/63746/2009) and (SFRH/BPD/36865/2007), respectively. The authors are grateful to Fundação para a Ciência e Tecnologia for grant no. Pest C/EQB/LA0006/2011.

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Authors and Affiliations

  1. REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal

    Luciana Grazziotin Rossato, Vera Marisa Costa, Eliane Dallegrave, Marcelo Arbo, Renata Silva, Ricardo Jorge Dinis-Oliveira, Maria de Lourdes Bastos & Fernando Remião

  2. Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil

    Eliane Dallegrave

  3. QOPNA, Departamento de Química, Universidade de Aveiro, Aveiro, Portugal

    Rita Ferreira

  4. Departamento de Medicina Legal e Ciências Forenses, Faculdade de Medicina, Universidade do Porto, Porto, Portugal

    Ricardo Jorge Dinis-Oliveira

  5. CIAFEL, Faculdade de Desporto, Universidade do Porto, Porto, Portugal

    José Alberto Duarte

  6. Centro de Neurociências e Biologia Celular de Coimbra, Departamento de Ciências da Vida, Universidade de Coimbra, Coimbra, Portugal

    Carlos Palmeira

  7. Department of Sciences, Advanced Institute of Health Sciences - North, CESPU, CRL, Gandra, Portugal

    Ricardo Jorge Dinis-Oliveira

  8. Escola Superior de Saúde, Universidade de Aveiro (ESSUA), Aveiro, Portugal

    Francisco Amado

Authors
  1. Luciana Grazziotin Rossato
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  2. Vera Marisa Costa
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  3. Eliane Dallegrave
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  4. Marcelo Arbo
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  5. Renata Silva
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  6. Rita Ferreira
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  8. Ricardo Jorge Dinis-Oliveira
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  9. José Alberto Duarte
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  10. Maria de Lourdes Bastos
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  11. Carlos Palmeira
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  12. Fernando Remião
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Corresponding authors

Correspondence to Luciana Grazziotin Rossato or Fernando Remião.

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Rossato, L.G., Costa, V.M., Dallegrave, E. et al. Mitochondrial Cumulative Damage Induced by Mitoxantrone: Late Onset Cardiac Energetic Impairment. Cardiovasc Toxicol 14, 30–40 (2014). https://doi.org/10.1007/s12012-013-9230-2

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  • DOI: https://doi.org/10.1007/s12012-013-9230-2

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