Abstract
Doxorubicin (DOX) is an anticancer drug widely used in oncology, especially for breast cancer. The main limitation of DOX treatment is its cardiotoxicity due to the cumulative dose. Clinically, DOX-induced cardiomyopathy develops as a progressive heart failure caused by a progressive cardiomyocyte’s death. For long, the oxidative stress induced by DOX was considered as the main toxic mechanism responsible for heart damage, but it is now controverted, and other processes are investigated to develop cardioprotective strategies. Previously, we studied DOX-induced cardiotoxicity and dexrazoxane (DEX), the only cardioprotective compound authorized by the FDA, by 1H-NMR metabonomics in H9C2 cells. We observed an increased succinate secretion in the extracellular fluid of DEX-exposed cardiomyocytes, a finding that led us to the hypothesis of a possible protective role of this agonist of the GPR91 receptor. The objective of the present work was to study the effect of succinate (SUC) and cis-epoxysuccinate (cis-ES), two agonists of the GPR91 receptor, on DOX-induced cardiotoxicity to H9C2 cells. To this purpose, several toxicity parameters, including cell viability, oxidative stress and apoptosis, as well as the GPR91 expression, were measured to assess the effects of DEX, SUC and cis-ES either alone or in combination with DOX in H9C2 cells. A 1H-NMR-based metabonomic study was carried out on cellular fluids collected after 24 h to highlight the metabolic changes induced by those protective compounds. Moreover, the effects of each agonist given either alone or in combination with DOX were evaluated on MCF-7 breast cancer cells. GPR91 expression was confirmed in H9C2 cells, while no expression was found in MCF-7 cells. Under such experimental conditions, both SUC and cis-ES decreased partially the cellular mortality, the oxidative stress and the apoptosis induced by DOX. The SUC protective effect was similar to the DEX effect, but the protective effect of cis-ES was higher on oxidative stress and apoptosis. In addition, the metabonomics findings pointed out several metabolic pathways involved in the cardioprotective effects of both GPR91 agonists: the stimulation of aerobic metabolism with glucose as the main fuel, redox balance and phospholipids synthesis. Finally, none of the GPR91 agonists jeopardized the pharmacological effects of DOX on MCF-7 breast cancer cells.
Highlights
Doxorubicin (DOX) is a widely used anticancer drug belonging to the anthracyclines family and used in the treatment of carcinomas, sarcomas and hematologic tumors
GPR91 is diffusedly expressed on H9C2 cells, while no expression was found for MCF-7 (Figure 1)
The important elevation of reactive oxygen species (ROS) levels caused by DOX was partially prevented by SUC and DEX to a similar extent, whereas cis-ES showed a more drastic effect. These results suggest that agonism of the GPR91 receptor protects H9C2 cells against DOX-induced toxicity, especially when using cis-ES as the agonist. cis-ES was used in this study because of its higher specificity and affinity to GPR91 than SUC [34] and to avoid any possible additional effects of SUC that are involved in cell respiration
Summary
Doxorubicin (DOX) is a widely used anticancer drug belonging to the anthracyclines family and used in the treatment of carcinomas, sarcomas and hematologic tumors. The main limitation of DOX treatment comes from its problematic cardiotoxicity [1,2]. The severity and irreversibility of the DOX-induced cardiotoxicity depends on the cumulated DOX doses and range from subclinical myopathy to severe heart failure, leading to the patient’s death in the worst cases [3]. Cardiotoxicity is believed to result from excessive oxidative stress induced by DOX in cardiomyocytes through the overproduction of reactive oxygen species (ROS) [1,4,5], which impair the mitochondrial function and membrane integrity [4]. Cardiomyocytes undergo increasing apoptosis and necrosis, clinically expressed by progressive heart failure [6]
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