Oxidative stress does not play a primary role in the toxicity induced with clinical doses of doxorubicin in myocardial H9c2 cells

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• 作者：Tareck Rharass ; Adam Gbankoto ; Christophe Canal…
• 关键词：Apoptosis ; Cardiotoxicity ; Dexrazoxane ; Doxorubicin ; Necrosis ; Oxidative stress
• 刊名：Molecular and Cellular Biochemistry
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：413
• 期：1-2
• 页码：199-215
• 全文大小：1,379 KB
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• 作者单位：Tareck Rharass (1) (2)
  Adam Gbankoto (3)
  Christophe Canal (1)
  Gizem Kurşunluoğlu (4)
  Amandine Bijoux (1)
  Daniela Panáková (2)
  Anne-Cécile Ribou (1) (5)
  
  1. Institute of Modeling and Analysis in Geo-Environmental and Health (IMAGES_ESPACE-DEV), University of Perpignan Via Domitia, 66860, Perpignan, France
  2. Electrochemical Signaling in Development and Disease, Max-Delbrück-Center for Molecular Medicine (MDC), 13125, Berlin-Buch, Germany
  3. Department of Animal Physiology, Faculty of Sciences and Technics, University of Abomey-Calavi, 01 BP 526, Cotonou, Benin
  4. Department of Chemistry, Dokuz Eylül University, 35210, Izmir, Turkey
  5. ESPACE-DEV, UMR UG UA UM IRD, 34093, Montpellier, France
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Biochemistry
  Medical Biochemistry
  Oncology
  Cardiology
  
• 出版者：Springer Netherlands
• ISSN：1573-4919

文摘

The implication of oxidative stress as primary mechanism inducing doxorubicin (DOX) cardiotoxicity is still questionable as many in vitro studies implied supra-clinical drug doses or unreliable methodologies for reactive oxygen species (ROS) detection. The aim of this study was to clarify whether oxidative stress is involved in compliance with the conditions of clinical use of DOX, and using reliable tools for ROS detection. We examined the cytotoxic mechanisms of 2 μM DOX 1 day after the beginning of the treatment in differentiated H9c2 rat embryonic cardiac cells. Cells were exposed for 2 or 24 h with DOX to mimic a single chronic dosage or to favor accumulation, respectively. We found that apoptosis was prevalent in cells exposed for a short period with DOX: cells showed typical hallmarks as loss of anchorage ability, mitochondrial hyperpolarization followed by the collapse of mitochondrial activity, and nuclear condensation. Increasing the exposure period favored a shift to necrosis as the cells preferentially exhibited early DNA impairment and nuclear swelling. In either case, measuring the fluorescence lifetime of 1-pyrenebutyric acid or the intensities of dihydroethidium or amplex red showed a consistent pattern in ROS production which was a slight increased level far from representative of an oxidative stress. Moreover, pre-treatment with dexrazoxane provided a cytoprotective effect although it failed to detoxify ROS. Our data support that oxidative stress is unlikely to be the primary mechanism of DOX cardiac toxicity in vitro. Keywords Apoptosis Cardiotoxicity Dexrazoxane Doxorubicin Necrosis Oxidative stress