Phenylalanine-butyramide protected against experimental doxorubicin cardiotoxicity by preventing left ventricular dilatation, reducing oxidative stress, and improving mitochondrial function.
Does phenylalanine-butyramide prevent doxorubicin-induced cardiotoxicity in experimental models?
Phenylalanine-butyramide protects against doxorubicin-induced cardiotoxicity in experimental models by reducing oxidative stress and preserving mitochondrial function.
Abstract Aims Butyric acid (BUT), a short chain fatty acid produced daily by the gut microbiota, has proven beneficial in models of cardiovascular diseases. With advancements in cancer survival, an increasing number of patients are at risk of anticancer drug cardiotoxicity. Here we assess whether the novel BUT derivative phenylalanine-butyramide (FBA) protects from doxorubicin (DOXO) cardiotoxicity, by decreasing oxidative stress and improving mitochondrial function. Methods and results In C57BL6 mice, DOXO produced left ventricular dilatation assessed by echocardiography. FBA prevented left ventricular dilatation, fibrosis and cardiomyocyte apoptosis when co-administered with DOXO. DOXO increased atrial natriuretic peptide, brain natriuretic peptide, connective tissue growth factor, and matrix metalloproteinase-2 mRNAs, which were not elevated on co-treatment with FBA. DOXO, but not FBA + DOXO mice, also showed higher nitrotyrosine levels, and increased inducible nitric oxide synthase expression. Accordingly, DOXO hearts showed lower levels of intracellular catalase vs. sham, while pre-treatment with FBA prevented this decrease. We then assessed for reactive oxygen species (ROS) emission: DOXO induced increased activity of mitochondrial superoxide dismutase and higher production of H2O2, which were blunted by FBA pre-treatment. FBA also ameliorated mitochondrial state 3 and state 4 respiration rates that were compromised by DOXO. Furthermore, in DOXO animals, the mitochondrial degree of coupling was significantly increased vs. sham, while FBA was able to prevent such increase, contributing to limit ROS production, Finally, FBA reduced DOXO damage in human cellular models, and increased the tumour-killing action of DOXO. Conclusions Phenylalanine-butyramide protects against experimental doxorubicin cardiotoxicity. Such protection is accompanied by reduction in oxidative stress and amelioration of mitochondrial function.
Russo et al. (Wed,) conducted a other in Doxorubicin-induced cardiotoxicity. Phenylalanine-butyramide (FBA) vs. Doxorubicin alone and sham was evaluated on Left ventricular dilatation, oxidative stress, and mitochondrial function. Phenylalanine-butyramide protected against experimental doxorubicin cardiotoxicity by preventing left ventricular dilatation, reducing oxidative stress, and improving mitochondrial function.