title: P53 inhibition exacerbates late-stage anthracycline cardiotoxicity.
abstract: OBJECTIVE
  Doxorubicin (DOX) is an effective anti-cancer therapeutic, but is associated with both acute and late-stage cardiotoxicity. Children are particularly sensitive to DOX-induced heart failure. Here, the impact of p53 inhibition on acute vs. late-stage DOX cardiotoxicity was examined in a juvenile model.
  
  
  RESULTS
  Two-week-old MHC-CB7 mice (which express dominant-interfering p53 in cardiomyocytes) and their non-transgenic (NON-TXG) littermates received weekly DOX injections for 5 weeks (25 mg/kg cumulative dose). One week after the last DOX treatment (acute stage), MHC-CB7 mice exhibited improved cardiac function and lower levels of cardiomyocyte apoptosis when compared with the NON-TXG mice. Surprisingly, by 13 weeks following the last DOX treatment (late stage), MHC-CB7 exhibited a progressive decrease in cardiac function and higher rates of cardiomyocyte apoptosis when compared with NON-TXG mice. p53 inhibition blocked transient DOX-induced STAT3 activation in MHC-CB7 mice, which was associated with enhanced induction of the DNA repair proteins Ku70 and Ku80. Mice with cardiomyocyte-restricted deletion of STAT3 exhibited worse cardiac function, higher levels of cardiomyocyte apoptosis, and a greater induction of Ku70 and Ku80 in response to DOX treatment during the acute stage when compared with control animals.
  
  
  CONCLUSIONS
  These data support a model wherein a p53-dependent cardioprotective pathway, mediated via STAT3 activation, mitigates DOX-induced myocardial stress during drug delivery. Furthermore, these data suggest an explanation as to how p53 inhibition can result in cardioprotection during drug treatment and, paradoxically, enhanced cardiotoxicity long after the cessation of drug treatment.
authors.affiliation: The Riley Heart Research Center, Wells Center for Pediatric Research, 1044 West Walnut Street; R4 Building Room W376, Indianapolis, IN 46202-5225, USA.
authors.forename: Wuqiang
authors.initials: W
authors.lastname: Zhu
authors.affiliation: The Riley Heart Research Center, Wells Center for Pediatric Research, 1044 West Walnut Street; R4 Building Room W376, Indianapolis, IN 46202-5225, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhang
authors.affiliation: The Riley Heart Research Center, Wells Center for Pediatric Research, 1044 West Walnut Street; R4 Building Room W376, Indianapolis, IN 46202-5225, USA.
authors.forename: Weinian
authors.initials: W
authors.lastname: Shou
authors.affiliation: The Riley Heart Research Center, Wells Center for Pediatric Research, 1044 West Walnut Street; R4 Building Room W376, Indianapolis, IN 46202-5225, USA The Krannert Institute of Cardiology, Indiana University School of Medicine, 1044 West Walnut Street, Indianapolis, IN 46202, USA ljfield@iupui.edu.
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Field
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity*; D006333:Heart Failure / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D000072200:Ku Autoantigen; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D034961:Antigens, Nuclear; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen
keywords: Apoptosis; Heart failure; Myocytes