title: Schisandrin B prevents doxorubicin-induced cardiotoxicity via enhancing glutathione redox cycling.
abstract: OBJECTIVE
  The dose-cumulative cardiotoxicities and the emerging cancerous apoptotic/drug resistance are two major obstacles limiting the efficacy of anthracycline antibiotics, notably doxorubicin. We attempted to prove if schisandrin B (Sch B), a dual inhibitor of P-glycoprotein and multidrug resistance-associated protein 1, could protect against doxorubicin-induced cardiotoxicity, on the premise that Sch B is an enhancer of glutathione redox cycling that may attenuate doxorubicin-induced oxidative stress in the cardiomyocytes.
  
  
  METHODS
  Mice or rat were dosed with a single injection of doxorubicin (25 mg/kg, i.p.) with or without pretreatment of Sch B. The protective roles of Sch B against doxorubicin-induced cardiac damage were evaluated on the aspects of the release of cardiac enzymes into serum, the formation of malondialdehyde, the activation of matrix metalloproteinase, the structural damage in the left ventricles, the mortality rates, and the cardiac functions.
  
  
  RESULTS
  Pretreatment of Sch B significantly attenuated doxorubicin-induced cardiotoxicities on all the aspects listed above. The underlying mechanism was associated with the effect of Sch B on maintaining the cardiomyocytic glutathione and the activities of superoxide dismutase, and the key enzymes (glutathione peroxidase, glutathione reductase, and glutathione transferase) responsible for glutathione redox cycling, which neutralized doxorubicin-induced oxidative stress.
  
  
  CONCLUSIONS
  To the best of our knowledge, Sch B is the only molecule ever proved to function as a cardioprotective agent as well as a dual inhibitor of P-glycoprotein and multidrug resistance-associated protein 1, which is potentially applicable to treat cancers, especially the multidrug-resistant cancers involving doxorubicin or its kin.
authors.affiliation: Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Qiangrong
authors.initials: Q
authors.lastname: Pan
authors.forename: Weidong
authors.initials: W
authors.lastname: Han
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Xun
authors.initials: X
authors.lastname: Hu
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000633:toxicity; D034242:Cyclooctanes / Q000627:therapeutic use; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism*; D006331:Heart Diseases / Q000139:chemically induced / Q000517:prevention & control*; D017705:Lignans / Q000627:therapeutic use*; D051379:Mice; D008813:Mice, Inbred ICR; D010084:Oxidation-Reduction; D011083:Polycyclic Compounds / Q000627:therapeutic use*
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D034242:Cyclooctanes; D017705:Lignans; D011083:Polycyclic Compounds; C015499:schizandrin B; D004317:Doxorubicin; D005978:Glutathione