Baicalein alleviates doxorubicin-induced cardiotoxicity via suppression of myocardial oxidative stress and apoptosis in mice
Graphical abstract
Introduction
Doxorubicin is an effective and widely used anthracycline derivative cytotoxic antibiotic. It is used for the treatment of a variety of neoplasm's including leukemias, lymphomas and solid human malignancies [26]. Despite being a highly targeted molecule for cancer therapy, the clinical use of doxorubicin is limited because of cardiotoxicity leading to dilated cardiomyopathy with congestive heart failure [18]. The mechanism involved in doxorubicin-induced cardiotoxicity is complex and multifactorial and is known to involve, at least in part, oxidative stress and mitochondrial dysfunction, which eventually lead to cardiomyocyte death by apoptosis and/or necrosis [27]. Cardiomyocytes are highly prone to reactive oxygen species (ROS)-induced damage because of lesser amount of antioxidant defense, higher density of mitochondria occupancy and high aerobic metabolism when compared to cells of other tissues [11]. It has also been demonstrated that doxorubicin-induced ROS generation activates NF-κB to elicit subsequent apoptosis in cardiomyocytes [8], [10]. Moreover, generation of ROS promotes lipid peroxidation and apoptotic change due to loss of mitochondrial membrane integrity and p53 activity [31]. Although extensive efforts have been made to prevent doxorubicin-induced cardiotoxicity, there is little harmony and agreement in the best approach.
The health benefits of polyphenolic compounds of plant origin have been widely studied. Baicalein (5, 6, 7-trihydroxy flavone) is a major active constituent in the roots of medicinal herb Scutellaria baicalensis Georgi (Lamiaceae family) [33]. The root of S. baicalensis has been used as folk medicine in China for the treatment of inflammatory diseases, chronic hepatitis, bacterial and viral infections, allergy and thrombotic stroke [14]. Baicalein is also known to exhibit therapeutic effect in endotoxin-induced myocardial dysfunction [20] and ameliorates myocardial ischemic/reperfusion injury in rats [16], [36]. It has also been reported that baicalein attenuates ROS generation and cell death during doxorubicin exposure and exhibits cytoprotective effect against doxorubicin-induced cardiomyocyte injury [4]. Although an in vitro study conducted by Chang et al. [4] addressed the beneficial effects of baicalein on doxorubicin-induced cardiomyocyte injury, there is no in vivo study conducted as yet to understand the mechanism of action and beneficial effect of baicalein on heart in doxorubicin-induced cardiotoxic animals. Hence, present study was designed to elucidate the molecular mechanisms underlying the protective effect of baicalein on heart using doxorubicin-induced cardiotoxicity model in mice.
Section snippets
Chemicals, kits and antibodies
Baicalein (≥ 98.0% purity), doxorubicin, superoxide dismutase (SOD) assay kit, catalase, β-nicotinamide adenine dinucleotide 3-phosphate reduced form (NADPH), 2-thiobarbituric acid (TBA), 1-chloro-2, 4-dinitrobenzene (CDNB), 2, 6-dichlorophenolindophenol (DCIP), reduced glutathione (GSH), 5, 5-dithio-bis (2-nitrobenzoic acid) (DTNB) were purchased from Sigma-Aldrich Co, St. Louis, MO, USA. Halt protease inhibitor cocktail, Bicinchoninic acid (BCA) protein assay kit, NE-PER nuclear and
Effect of baicalein on doxorubicin-induced cardiac injury in mice
As shown in Table 1, in doxorubicin alone treated group of mice, the body weight of mice and the relative weight of heart were significantly (p < 0.001 for body weight; p < 0.05 for relative weight of heart) decreased when compared with the vehicle control mice. A significant (p < 0.001 for CK-MB and AST; p < 0.01 for LDH and ALT) increase in serum levels of CK-MB, LDH, AST and ALT were observed in mice administered with doxorubicin. Interestingly, treatment with baicalein (50 mg/kg) along with
Discussion
The results of the present study demonstrated that the effectiveness of the baicalein in ameliorating doxorubicin-induced cardiotoxicity in mice. Consistent with the changes in serum biochemistry and histological findings caused by doxorubicin in other studies, doxorubicin administration produced a significant elevation of serum CK-MB, LDH, AST and ALT activities and extensive myofibrillar degeneration with severe cytoplasmic vacuolation in heart tissue. The body weight and relative weight of
Conflict of interest statement
The authors declared that there are no conflicts of interest.
Acknowledgments
Authors thank Director, CSIR-IICT for constant support and encouragement. Bidya Dhar Sahu is thankful to Council of Scientific and Industrial Research (CSIR, New Delhi) for providing Senior Research Fellowship.
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