title: Doxorubicin in vivo rapidly alters expression and translation of myocardial electron transport chain genes, leads to ATP loss and caspase 3 activation.
abstract: BACKGROUND
  Doxorubicin is one of the most effective anti-cancer drugs but its use is limited by cumulative cardiotoxicity that restricts lifetime dose. Redox damage is one of the most accepted mechanisms of toxicity, but not fully substantiated. Moreover doxorubicin is not an efficient redox cycling compound due to its low redox potential. Here we used genomic and chemical systems approaches in vivo to investigate the mechanisms of doxorubicin cardiotoxicity, and specifically test the hypothesis of redox cycling mediated cardiotoxicity.
  
  
  RESULTS
  Mice were treated with an acute dose of either doxorubicin (DOX) (15 mg/kg) or 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) (25 mg/kg). DMNQ is a more efficient redox cycling agent than DOX but unlike DOX has limited ability to inhibit gene transcription and DNA replication. This allowed specific testing of the redox hypothesis for cardiotoxicity. An acute dose was used to avoid pathophysiological effects in the genomic analysis. However similar data were obtained with a chronic model, but are not specifically presented. All data are deposited in the Gene Expression Omnibus (GEO). Pathway and biochemical analysis of cardiac global gene transcription and mRNA translation data derived at time points from 5 min after an acute exposure in vivo showed a pronounced effect on electron transport chain activity. This led to loss of ATP, increased AMPK expression, mitochondrial genome amplification and activation of caspase 3. No data gathered with either compound indicated general redox damage, though site specific redox damage in mitochondria cannot be entirely discounted.
  
  
  CONCLUSIONS
  These data indicate the major mechanism of doxorubicin cardiotoxicity is via damage or inhibition of the electron transport chain and not general redox stress. There is a rapid response at transcriptional and translational level of many of the genes coding for proteins of the electron transport chain complexes. Still though ATP loss occurs with activation caspase 3 and these events probably account for the heart damage.
authors.affiliation: Medical Research Council Toxicology Unit, Systems Toxicology Group, Leicester, United Kingdom.
authors.forename: Amy V
authors.initials: AV
authors.lastname: Pointon
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Walker
authors.forename: Kate M
authors.initials: KM
authors.lastname: Phillips
authors.forename: Jinli
authors.initials: J
authors.lastname: Luo
authors.forename: Joan
authors.initials: J
authors.lastname: Riley
authors.forename: Shu-Dong
authors.initials: SD
authors.lastname: Zhang
authors.forename: Joel D
authors.initials: JD
authors.lastname: Parry
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Lyon
authors.forename: Emma L
authors.initials: EL
authors.lastname: Marczylo
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Gant
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology*; D004579:Electron Transport / Q000187:drug effects; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D006321:Heart / Q000187:drug effects; D051379:Mice; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects*
chemical_list: D045222:Electron Transport Chain Complex Proteins; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D053148:Caspase 3