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The novel butyrate derivative phenylalanine‐butyramide protects from doxorubicin‐induced cardiotoxicity
Author(s) -
Russo Michele,
Guida Fiorentina,
Paparo Lorella,
Trinchese Giovanna,
Aitoro Rosita,
Avagliano Carmen,
Fiordelisi Antonella,
Napolitano Fabiana,
Mercurio Valentina,
Sala Valentina,
Li Mingchuan,
Sorriento Daniela,
Ciccarelli Michele,
Ghigo Alessandra,
Hirsch Emilio,
Bianco Roberto,
Iaccarino Guido,
Abete Pasquale,
Bonaduce Domenico,
Calignano Antonio,
Berni Canani Roberto,
Tocchetti Carlo G.
Publication year - 2019
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1002/ejhf.1439
Subject(s) - cardiotoxicity , medicine , doxorubicin , oxidative stress , butyrate , pharmacology , reactive oxygen species , nitrotyrosine , endocrinology , chemistry , nitric oxide synthase , nitric oxide , biochemistry , toxicity , chemotherapy , fermentation
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 H 2 O 2 , 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.