title: Acute doxorubicin cardiotoxicity is associated with p53-induced inhibition of the mammalian target of rapamycin pathway.
abstract: BACKGROUND
  Doxorubicin is used to treat childhood and adult cancer. Doxorubicin treatment is associated with both acute and chronic cardiotoxicity. The cardiotoxic effects of doxorubicin are cumulative, which limits its chemotherapeutic dose. Free radical generation and p53-dependent apoptosis are thought to contribute to doxorubicin-induced cardiotoxicity.
  
  
  RESULTS
  Adult transgenic (MHC-CB7) mice expressing cardiomyocyte-restricted dominant-interfering p53 and their nontransgenic littermates were treated with doxorubicin (20 mg/kg cumulative dose). Nontransgenic mice exhibited reduced left ventricular systolic function (predoxorubicin fractional shortening [FS] 61+/-2%, postdoxorubicin FS 45+/-2%, mean+/-SEM, P<0.008), reduced cardiac mass, and high levels of cardiomyocyte apoptosis 7 days after the initiation of doxorubicin treatment. In contrast, doxorubicin-treated MHC-CB7 mice exhibited normal left ventricular systolic function (predoxorubicin FS 63+/-2%, postdoxorubicin FS 60+/-2%, P>0.008), normal cardiac mass, and low levels of cardiomyocyte apoptosis. Western blot analyses indicated that mTOR (mammalian target of rapamycin) signaling was inhibited in doxorubicin-treated nontransgenic mice but not in doxorubicin-treated MHC-CB7 mice. Accordingly, transgenic mice with cardiomyocyte-restricted, constitutively active mTOR expression (MHC-mTORca) were studied. Left ventricular systolic function (predoxorubicin FS 64+/-2%, postdoxorubicin FS 60+/-3%, P>0.008) and cardiac mass were normal in doxorubicin-treated MHC-mTORca mice, despite levels of cardiomyocyte apoptosis similar to those seen in doxorubicin-treated nontransgenic mice.
  
  
  CONCLUSIONS
  These data suggest that doxorubicin treatment induces acute cardiac dysfunction and reduces cardiac mass via p53-dependent inhibition of mTOR signaling and that loss of myocardial mass, and not cardiomyocyte apoptosis, is the major contributor to acute doxorubicin cardiotoxicity.
authors.affiliation: Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Indianapolis, IN 46202-5225, USA.
authors.forename: Wuqiang
authors.initials: W
authors.lastname: Zhu
authors.forename: Mark H
authors.initials: MH
authors.lastname: Soonpaa
authors.forename: Hanying
authors.initials: H
authors.lastname: Chen
authors.forename: Weihua
authors.initials: W
authors.lastname: Shen
authors.forename: R Mark
authors.initials: RM
authors.lastname: Payne
authors.forename: Edward A
authors.initials: EA
authors.lastname: Liechty
authors.forename: Randall L
authors.initials: RL
authors.lastname: Caldwell
authors.forename: Weinian
authors.initials: W
authors.lastname: Shou
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Field
mesh_terms: D000208:Acute Disease; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000633:toxicity*; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases