Mechanistic clues to the protective effect of chrysin against doxorubicin-induced cardiomyopathy: Plausible roles of p53, MAPK and AKT pathways

• Published in: Scientific reports Vol. 7; no. 1; pp. 4795 - 13
• Main Authors: Mantawy, Eman M., Esmat, Ahmed, El-Bakly, Wesam M., Salah ElDin, Rania A., El-Demerdash, Ebtehal
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.07.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/28; 14/3; 14/35; 38; 38/1; 631/154/570; 692/4019/592/75/230; AKT protein; Animals; Antioxidants; Antioxidants - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Bcl-2 protein; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Cancer; Cardiomyopathies - chemically induced; Cardiomyopathies - genetics; Cardiomyopathies - pathology; Cardiomyopathies - prevention & control; Cardiomyopathy; Cardiotonic Agents - pharmacology; Cardiotoxicity; Cardiotoxicity - prevention & control; Caspase; Caspase 3 - genetics; Caspase 3 - metabolism; Caspase-3; Conduction; Cytochrome c; Cytochromes c - genetics; Cytochromes c - metabolism; Doxorubicin; Doxorubicin - toxicity; Drug Administration Schedule; Flavonoids - pharmacology; Gene Expression Regulation - drug effects; Humanities and Social Sciences; Inflammation; JNK protein; Lipid peroxidation; Male; MAP kinase; Molecular modelling; multidisciplinary; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Oxidative stress; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; p53 Protein; Peroxidation; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; PTEN protein; Rats; Rats, Sprague-Dawley; Rodents; Science; Science (multidisciplinary); Signal Transduction; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-05005-9

Doxorubicin (DOX) is the mainstay chemotherapeutic agent against a variety of human neoplasmas. However, its clinical utility is limited by its marked cardiotoxicity. Chrysin, is a natural flavone which possesses antioxidant, anti-inflammatory and anti-cancer properties. The current study aimed to investigate the potential protective effect of chrysin against DOX-induced chronic cardiotoxicity and the underlying molecular mechanisms. Male Sprague-Dawley rats were treated with either DOX (5 mg/kg, once a week) and/or chrysin (50 mg/kg, four times a week) for four weeks. Chrysin prevented DOX-induced cardiomyopathy which was evident by conduction abnormalities, elevated serum CKMB and LDH and histopathological changes. Chrysin also ameliorated DOX-induced oxidative stress by decreasing lipid peroxidation and upregulating the antioxidant enzymes. Moreover, chrysin attenuated DOX-induced apoptosis via decreasing expression of p53, Bax, Puma, Noxa, cytochrome c and caspase-3 while increasing expression of Bcl-2. DOX induced activation of MAPK; p38 and JNK and increased expression of NF-κB. Meanwhile, DOX suppressed AKT pathway via decreasing expression of its upstream activator VEGF and increasing expression of PTEN. Conversely, chrysin effectively neutralised all these effects. Collectively, these findings indicate that chrysin effectively protected against DOX-induced cardiomyopathy via suppressing oxidative stress, p53-dependent apoptotic pathway, MAPK and NF-κB pathways while augmenting the VEGF/AKT pathway.