Autor(es):
Rossato, Luciana Grazziotin 
; Costa, Vera Marisa ; Dallegrave, Eliane ; Arbo, Marcelo ; Silva, Renata ; Ferreira, Rita ; Amado, Francisco ; Dinis-Oliveira, Ricardo Jorge ; Duarte, José Alberto ; Bastos, Maria de Lourdes ; Palmeira, C. M. ; Remião, Fernando
Data: 2014
Identificador Persistente: http://hdl.handle.net/10316/25533
Origem: Estudo Geral - Universidade de Coimbra
Assunto(s): Mitoxantrone; Cardiotoxicity; Mitochondria
Descrição
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 lM) 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. 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.
