Baicalein alleviates doxorubicin-induced cardiotoxicity via suppression of myocardial oxidative stress and apoptosis in mice

Life Sci. 2016 Jan 1;144:8-18. doi: 10.1016/j.lfs.2015.11.018. Epub 2015 Nov 29.

Abstract

Aims: 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.

Main 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.

Key findings: 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.

Significance: Our finding suggests that baicalein might be a promising molecule for the prevention of doxorubicin-induced cardiotoxicity.

Keywords: Apoptosis; Baicalein; Doxorubicin-induced cardiotoxicity; Nuclear factor E2-related factor 2 (Nrf2); Nuclear factor-kappa B (NF-κB); Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / toxicity*
  • Antioxidants / metabolism
  • Apoptosis / drug effects*
  • Biomarkers / metabolism
  • Cardiotoxicity
  • Doxorubicin / antagonists & inhibitors*
  • Doxorubicin / toxicity*
  • Flavanones / pharmacology*
  • Heart Diseases / chemically induced*
  • Heart Diseases / pathology
  • Heart Diseases / prevention & control*
  • I-kappa B Proteins / antagonists & inhibitors
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Nitrites / metabolism
  • Organ Size / drug effects
  • Oxidative Stress / drug effects*
  • Transcription Factor RelA / antagonists & inhibitors

Substances

  • Antibiotics, Antineoplastic
  • Antioxidants
  • Biomarkers
  • Flavanones
  • I-kappa B Proteins
  • Nitrites
  • Transcription Factor RelA
  • baicalein
  • Doxorubicin
  • Nitric Oxide Synthase Type II