All‐trans retinoic acid protects against doxorubicin‐induced cardiotoxicity by activating the ERK2 signalling pathway

Background and Purpose Doxorubicin is a powerful antineoplastic agent for treating a wide range of cancers. However, doxorubicin cardiotoxicity of the heart has largely limited its clinical use. All‐trans retinoic acid (ATRA) plays an important role in many cardiac biological processes, but its prot...

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Bibliographic Details
Published in:British journal of pharmacology 2016-01, Vol.173 (2), p.357-371
Main Authors: Yang, Liang, Luo, Cheng, Chen, Cong, Wang, Xun, Shi, Wen, Liu, Jiankang
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn
Apoptosis
Cancer
Cardiomyocytes
Cardiotonic Agents - pharmacology
Cardiotonic Agents - therapeutic use
Cardiotoxicity
Cardiotoxicity - metabolism
Cardiotoxicity - prevention & control
Cell Survival - drug effects
Cell Survival - physiology
Cells, Cultured
Dose-Response Relationship, Drug
Doxorubicin
Doxorubicin - toxicity
Electron transport
Extracellular signal-regulated kinase
Gastric cancer
Gene expression
Haem
Heme oxygenase (decyclizing)
Humans
Manganese
Mitochondrial DNA
Mitogen-Activated Protein Kinase 1 - metabolism
Molecular modelling
mRNA
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Oxygenase
Proteins
Rats
Rats, Sprague-Dawley
Razoxane
Reactive oxygen species
Research Paper
Research Papers
Respiration
Resveratrol
Retinoic acid
Signal transduction
Signal Transduction - drug effects
Signal Transduction - physiology
siRNA
Superoxide dismutase
Toxicity
Tretinoin - pharmacology
Tretinoin - therapeutic use
Western blotting
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Summary:Background and Purpose Doxorubicin is a powerful antineoplastic agent for treating a wide range of cancers. However, doxorubicin cardiotoxicity of the heart has largely limited its clinical use. All‐trans retinoic acid (ATRA) plays an important role in many cardiac biological processes, but its protective effects on doxorubicin‐induced cardiotoxicity remain unknown. Here, we studied the effect of ATRA on doxorubicin cardiotoxicity and the underlying mechanisms. Experimental Approaches Cellular viability assays, Western blotting and mitochondrial respiration analyses were employed to evaluate the cellular response to ATRA in H9c2 cells and primary cardiomyocytes. Quantitative PCR and gene knockdown were performed to investigate the underlying molecular mechanisms of ATRA's effects on doxorubicin cardiotoxicity. Key Results ATRA significantly inhibited doxorubicin‐induced apoptosis in H9c2 cells and primary cardiomyocytes. ATRA was more effective against doxorubicin cardiotoxicity than resveratrol and dexrazoxane. ATRA also suppressed reactive oxygen species generation and restored expression levels of mRNA and proteins in the phase II detoxifying enzyme system: nuclear factor‐E2‐related factor 2, manganese superoxide dismutase, haem oxygenase‐1, and mitochondrial function (mitochondrial membrane integrity, mitochondrial DNA copy numbers and mitochondrial respiration capacity, biogenesis and dynamics). Both a ERK1/2 inhibitor (U0126) and ERK2 siRNA, but not ERK1 siRNA, abolished the protective effect of ATRA against doxorubicin‐induced toxicity in H9c2 cells. Remarkably, ATRA did not compromise the anticancer efficacy of doxorubicin in gastric carcinoma cells. Conclusions and Implications ATRA protected cardiomyocytes against doxorubicin‐induced toxicity, by activating the ERK2 pathway, without compromising its anticancer efficacy. Therefore, ATRA is a promising candidate as a cardioprotective agent against doxorubicin cardiotoxicity.
ISSN:0007-1188
1476-5381
DOI:10.1111/bph.13377