tretinoin and Cardiotoxicity

The effectiveness of anthracycline chemotherapeutics (e.g., doxorubicin) is limited by anthracycline-induced cardiotoxicity (ACT). A nonsynonymous variant (S427L) in the retinoic acid receptor-γ (RARG) gene has been associated with ACT. This variant causes reduced RARG activity, which is hypothesized to lead to increased susceptibility to ACT through reduced activation of the retinoic acid pathway. This study explored the effects of activating the retinoic acid pathway using a RAR-agonist, all-trans retinoic acid (ATRA), in human cardiomyocytes and mice treated with doxorubicin. In human cardiomyocytes, ATRA induced the gene expression of RARs (RARG, RARB) and repressed the expression of topoisomerase II enzyme genes (TOP2A, TOP2B), which encode for the molecular targets of anthracyclines and repressed downstream ACT response genes. Importantly, ATRA enhanced cell survival of human cardiomyocytes exposed to doxorubicin. The protective effect of ATRA was also observed in a mouse model (B6C3F1/J) of ACT, in which ATRA treatment improved heart function compared to doxorubicin-only treated mice. Histological analyses of the heart also indicated that ATRA treatment reduced the pathology associated with ACT. These findings provide additional evidence for the retinoic acid pathway's role in ACT and suggest that the RAR activator ATRA can modulate this pathway to reduce ACT.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Cardiotoxicity; DNA Topoisomerases, Type II; Doxorubicin; Humans; Mice; Myocytes, Cardiac; Poly-ADP-Ribose Binding Proteins; Retinoic Acid Receptor gamma; Topoisomerase II Inhibitors; Tretinoin

The present study aimed to investigate the potential protective effect of all-trans-retinoic acid (ATRA, a natural derivative of vitamin A) against doxorubicin (DOX)-induced in vivo cardiac toxicity and its underlying mechanisms. Forty male albino rats were allocated into control, ATRA (0.5 mg/kg bwt, intraperitoneally daily), DOX (2.5 mg/kg bwt, intraperitoneally twice weekly for 3 weeks), and DOX + ATRA groups. Serum lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase-cardiac type (CK-MB), troponin I, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) were measured. In addition, cardiac glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT), and malondialdehyde (MDA) were determined. Cardiac tissues were examined for histopathologic changes and immunoexpression of pro-apoptotic caspase 3 and tumor-suppressor p53 proteins. DOX caused severe myocardial damage; degenerative and necrotic changes and worsened cardiac function biomarkers; and elevated serum LDH, CK, CK-MB, and troponin I. In addition, DOX inhibited cardiac antioxidative enzymes (GSH, GSH-Px, SOD, CAT) activities and enhanced MDA level. DOX increased serum proinflammatory cytokines (TNF-α, IL-6) and area percent of caspase 3 and p53 immunoexpression in heart tissues. Pretreatment with ATRA maintained cardiac function biomarkers, and reduced proinflammatory cytokines, lipid peroxidation, and immunoexpression of caspase 3 and p53. Moreover, ATRA improved cardiac histoarchitecture, as well as the activities of antioxidative enzymes. Collectively, ATRA can counteract DOX-induced cardiomyopathy through antioxidative and anti-inflammatory properties, besides suppression of the activation of the mitochondrial apoptotic pathway.

Topics: Animals; Apoptosis; Cardiotoxicity; Caspase 3; Down-Regulation; Doxorubicin; Genes, p53; Inflammation; Male; Myocardium; Oxidative Stress; Rats; Rats, Wistar; Tretinoin

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.. 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.. 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.. 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.

Topics: Animals; Animals, Newborn; Cardiotonic Agents; Cardiotoxicity; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Doxorubicin; Humans; Mitogen-Activated Protein Kinase 1; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Signal Transduction; Tretinoin