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.