All-trans retinoic acid protects against doxorubicin-induced cardiotoxicity by activating the ERK2 signalling pathway.
OBJECTIVE
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.


METHODS
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.


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
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.
Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
Liang
L
Yang
School of Medicine, Yichun University, Yichun, Jiangxi, China.
Cheng
C
Luo
Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
Cong
C
Chen
Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
Xun
X
Wang
Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
Wen
W
Shi
Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
Jiankang
J
Liu
D000818:Animals; D000831:Animals, Newborn; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D066126:Cardiotoxicity / Q000378:metabolism* / Q000517:prevention & control*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use*
D002316:Cardiotonic Agents; D014212:Tretinoin; D004317:Doxorubicin; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1