title: Schisandrin B prevents doxorubicin-induced chronic cardiotoxicity and enhances its anticancer activity in vivo.
abstract: BACKGROUND
  To mitigate the cardiotoxicity of anthracycline antibiotics without compromising their anticancer activities is still an issue to be solved. We previously demonstrated that schisandrin B (Sch B) could protect against doxorubicin (Dox)-induced acute cardiotoxicity via enhancing cardiomyocytic glutathione redox cycling that could attenuate oxidative stress generated from Dox. In this study, we attempted to prove if Sch B could also protect against Dox-induced chronic cardiotoxicity, a more clinically relevant issue, without compromising its anticancer activity.
  
  
  METHODS
  Rat was given intragastrically either vehicle or Sch B (50 mg/kg) two hours prior to i.p. Dox (2.5 mg/kg) weekly over a 5-week period with a cumulative dose of Dox 12.5 mg/kg. At the 6th and 12th week after last dosing, rats were subjected to cardiac function measurement, and left ventricles were processed for histological and ultrastructural examination. Dox anticancer activity enhanced by Sch B was evaluated by growth inhibition of 4T1, a breast cancer cell line, and S180, a sarcoma cell line, in vitro and in vivo.
  
  
  RESULTS
  Pretreatment with Sch B significantly attenuated Dox-induced loss of cardiac function and damage of cardiomyocytic structure. Sch B substantially enhanced Dox cytotoxicities toward S180 in vitro and in vivo in mice, and increased Dox cytotoxcity against 4T1 in vitro. Although we did not observe this enhancement against the implanted 4T1 primary tumor, the spontaneous metastasis to lung was significantly reduced in combined treatment group than Dox alone group.
  
  
  CONCLUSIONS
  Sch B is capable of protecting Dox-induced chronic cardiotoxicity and enhancing its anticancer activity. To the best of our knowledge, Sch B is the only molecule ever proved to function as a cardioprotective agent as well as a chemotherapeutic sensitizer, which is potentially applicable for cancer treatment.
authors.affiliation: Cancer Institute, Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education, Zhejiang, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.forename: Qiangrong
authors.initials: Q
authors.lastname: Pan
authors.forename: Feifei
authors.initials: F
authors.lastname: Sun
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Yan
authors.forename: Xun
authors.initials: X
authors.lastname: Hu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D034242:Cyclooctanes / Q000494:pharmacology; D004317:Doxorubicin / Q000633:toxicity*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D017705:Lignans / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011083:Polycyclic Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D034242:Cyclooctanes; D017705:Lignans; D011083:Polycyclic Compounds; C015499:schizandrin B; D004317:Doxorubicin; D005978:Glutathione