Abstract
BackgroundUse of the chemotherapeutic drug doxorubicin (DOX) is associated with serious cardiotoxicity, as it increases levels of reactive oxygen species (ROS). N-3 polyunsaturated fatty acid dietary supplements can be of benefit to patients undergoing cancer therapy. The aims of this study were to determine whether DOX-induced cardiotoxicity is related to mitochondrial uncoupling proteins and whether eicosapentaenoic acid (EPA, C20:5 n-3) or docosahexaenoic acid (DHA, C22:6 n-3) affects DOX-induced cardiomyocyte toxicity.ResultsTreatment of H9C2 cells with DOX resulted in decreased cell viability and UCP2 expression. Treatment with 100 μM EPA or 50 μM DHA for 24 h resulted in a maximal mitochondria concentration of these fatty acids and increased UCP2 expression. Pretreatment with 100 μM EPA or 50 μM DHA prevented the DOX-induced decrease in UCP2 mRNA and protein levels, but these effects were not seen with EPA or DHA and DOX cotreatment. In addition, the DOX-induced increase in ROS production and subsequent mitochondrial membrane potential change (∆ψ) were significantly attenuated by pretreatment with EPA or DHA.ConclusionEPA or DHA pre-treatment inhibits the DOX-induced decrease in UCP2 expression, increase in ROS production, and subsequent mitochondrial membrane potential change that contribute to the cardiotoxicity of DOX.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-014-0101-3) contains supplementary material, which is available to authorized users.
Highlights
Use of the chemotherapeutic drug doxorubicin (DOX) is associated with serious cardiotoxicity, as it increases levels of reactive oxygen species (ROS)
To examine whether this DOX-induced cell cytotoxicity was associated with altered expression of UCP2, mRNA was extracted from DOX-treated H9C2 cells and subjected by reverse transcription and quantitative real-time PCR analysis
Fatty acid composition of the cell and mitochondria after eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) treatment In order to investigate whether EPA or DHA was protective against the DOX-induced decrease in UCP2 expression in H9C2 cells, we first determined the concentrations of EPA and DHA at which the mitochondria were saturated with the respective fatty acid, measured UCP2 mRNA levels at these concentrations
Summary
Use of the chemotherapeutic drug doxorubicin (DOX) is associated with serious cardiotoxicity, as it increases levels of reactive oxygen species (ROS). Several observational and experimental studies have demonstrated the beneficial effects of n-3 poly-unsaturated fatty acids (PUFAs) in cardiovascular disease [9,10]. The results from such studies justify n-3 PUFA supplementation in the primary and secondary prevention of several clinical conditions, including coronary heart disease, sudden cardiac death, and heart failure [9,10]. The benefits of fish oil dietary supplements given before or during cancer therapy include increasing the anticancer drug efficacy [12,13,14] and reducing the cardiac side effects of various chemotherapeutic treatments [15,16]
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