title: Baicalein alleviates doxorubicin-induced cardiotoxicity via suppression of myocardial oxidative stress and apoptosis in mice.
abstract: OBJECTIVE
  Doxorubicin is a widely used anthracycline derivative anticancer drug. Unfortunately, the clinical use of doxorubicin has the serious drawback of cardiotoxicity. In this study, we investigated whether baicalein, a bioflavonoid, can prevent doxorubicin-induced cardiotoxicity in vivo and we delineated the possible underlying mechanisms.
  
  
  METHODS
  Male BALB/c mice were treated with either intraperitoneal doxorubicin (15 mg/kg divided into three equal doses for 15 days) and/or oral baicalein (25 and 50 mg/kg for 15 days). Serum markers of cardiac injury, histology of heart, parameters related to myocardial oxidative stress, apoptosis and inflammation were investigated.
  
  
  RESULTS
  Treatment with baicalein reduced doxorubicin-induced elevation of serum creatine kinase-MB isoenzyme (CK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and ameliorated the histopathological damage. Baicalein restored the doxorubicin-induced decrease in both enzymatic and non-enzymatic myocardial antioxidants and increased the myocardial expression of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1). Further studies showed that baicalein could inverse the Bax/Bcl-2 ratio, suppress doxorubicin-induced p53, cleaved caspase-3 and PARP expression and prevented doxorubicin-induced DNA damage. Baicalein treatment also interferes with doxorubicin-induced myocardial NF-κB signaling through inhibition of IκBα phosphorylation and nuclear translocation of p65 subunit. Doxorubicin elevated iNOS and nitrites levels were also significantly decreased in baicalein treated mice. However, we did not find any significant change (p>0.05) in the myocardial TNF-α and IL-6 levels in control and treated animals.
  
  
  CONCLUSIONS
  Our finding suggests that baicalein might be a promising molecule for the prevention of doxorubicin-induced cardiotoxicity.
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad-500 007, India.
authors.forename: Bidya Dhar
authors.initials: BD
authors.lastname: Sahu
authors.affiliation: Animal House, CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad-500 007, India.
authors.forename: Jerald Mahesh
authors.initials: JM
authors.lastname: Kumar
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad-500 007, India.
authors.forename: Madhusudana
authors.initials: M
authors.lastname: Kuncha
authors.affiliation: National Centre for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad-500 007, India.
authors.forename: Roshan M
authors.initials: RM
authors.lastname: Borkar
authors.affiliation: National Centre for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad-500 007, India.
authors.forename: R
authors.initials: R
authors.lastname: Srinivas
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad-500 007, India. Electronic address: sistla@iict.res.in.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Sistla
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D066126:Cardiotoxicity; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D044950:Flavanones / Q000494:pharmacology*; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors
chemical_list: D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D015415:Biomarkers; D044950:Flavanones; D020672:I-kappa B Proteins; D009573:Nitrites; D051996:Transcription Factor RelA; C006680:baicalein; D004317:Doxorubicin; D052247:Nitric Oxide Synthase Type II
keywords: Apoptosis; Baicalein; Doxorubicin-induced cardiotoxicity; Nuclear factor E2-related factor 2 (Nrf2); Nuclear factor-kappa B (NF-κB); Oxidative stress