title: Analysis of redox and apoptotic effects of anthracyclines to delineate a cardioprotective strategy.
abstract: OBJECTIVE
  Cardiotoxic side effects of anthracyclines limit their use as effective chemotherapeutics. One mechanistic model of anthracycline-induced cardiotoxicity is attributed to the generation of intracellular reactive oxygen species (ROS). However, this theory has been questioned because several cardioprotective strategies have included the use of antioxidants without significant clinical benefit. We sought to determine whether measurement of intracellular reactive oxygen species after anthracycline exposure in vivo and in vitro could provide a means for designing more effective antioxidant-based cardioprotective schemes.
  
  
  METHODS
  Intracellular levels of ROS were assessed in peripheral blood mononuclear cells from leukemia bearing mice exposed to anthracyclines and in patients receiving anthracyclines. Comparison of cell death induction and ROS levels were also conducted in vitro in cardiomyocyte and leukemia lines. ROS blockade using antioxidants was conducted, and effects on cell death were assessed.
  
  
  RESULTS
  Elevated ROS in blood of mice and representative patient samples correlated with cardiomyocyte necrosis and decreased ejection fraction. In vitro, comparison of the cytotoxic effects of anthracyclines in acute leukemia cells and in cardiomyocytes revealed distinct kinetics of cell death induction and dependence upon oxidative stress. Although apoptotic cell death was observed in both acute leukemia cells and cardiomyocytes, the antioxidant N-acetylcysteine protected cardiomyocytes but not acute leukemia cells from anthracycline cytotoxicity.
  
  
  CONCLUSIONS
  Our findings point toward revisiting the use of NAC as a cardioprotective agent since it does not appear to interfere with the cytotoxic action of anthracyclines. NAC has been evaluated clinically for cardioprotective activity but future trials must ensure that adequate dose, scheduling and incorporation of markers of oxidative stress are included.
authors.affiliation: Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0853, Box 853, Houston, TX, 77030, USA.
authors.forename: Joy Marie
authors.initials: JM
authors.lastname: Fulbright
authors.affiliation: Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0853, Box 853, Houston, TX, 77030, USA.
authors.forename: Daniela E
authors.initials: DE
authors.lastname: Egas-Bejar
authors.affiliation: Patient Care, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Winston W
authors.initials: WW
authors.lastname: Huh
authors.affiliation: Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0853, Box 853, Houston, TX, 77030, USA. jchandra@mdanderson.org.
authors.forename: Joya
authors.initials: J
authors.lastname: Chandra
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000208:Acute Disease; D000293:Adolescent; D000818:Animals; D018943:Anthracyclines / Q000009:adverse effects*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002675:Child, Preschool; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced / Q000517:prevention & control*; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018943:Anthracyclines; D000975:Antioxidants; D002316:Cardiotonic Agents; D017382:Reactive Oxygen Species; D000111:Acetylcysteine
keywords: Anthracyclines; Cardiotoxicity; Cell death; Oxidative stress