title: Doxorubicin impairs the insulin-like growth factor-1 system and causes insulin-like growth factor-1 resistance in cardiomyocytes.
abstract: BACKGROUND
  Insulin-like growth factor-1 (IGF-1) promotes the survival of cardiomyocytes by activating type 1 IGF receptor (IGF-1R). Within the myocardium, IGF-1 action is modulated by IGF binding protein-3 (IGFBP-3), which sequesters IGF-1 away from IGF-1R. Since cardiomyocyte apoptosis is implicated in anthracycline cardiotoxicity, we investigated the effects of the anthracycline, doxorubicin, on the IGF-1 system in H9c2 cardiomyocytes.
  
  
  RESULTS
  Besides inducing apoptosis, concentrations of doxorubicin comparable to those observed in patients after bolus infusion (0.1-1 µM) caused a progressive decrease in IGF-1R and increase in IGFBP-3 expression. Exogenous IGF-1 was capable to rescue cardiomyocytes from apoptosis triggered by 0.1 and 0.5 µM, but not 1 µM doxorubicin. The loss of response to IGF-1 was paralleled by a significant reduction in IGF-1 availability and signaling, as assessed by free hormone levels in conditioned media and Akt phosphorylation in cell lysates, respectively. Doxorubicin also dose-dependently induced p53, which is known to repress the transcription of IGF1R and induce that of IGFBP3. Pre-treatment with the p53 inhibitor, pifithrin-α, prevented apoptosis and the changes in IGF-1R and IGFBP-3 elicited by doxorubicin. The decrease in IGF-1R and increase in IGFBP-3, as well as apoptosis, were also antagonized by pre-treatment with the antioxidant agents, N-acetylcysteine, dexrazoxane, and carvedilol.
  
  
  CONCLUSIONS
  Doxorubicin down-regulates IGF-1R and up-regulates IGFBP-3 via p53 and oxidative stress in H9c2 cells. This leads to resistance to IGF-1 that may contribute to doxorubicin-initiated apoptosis. Further studies are needed to confirm these findings in human cardiomyocytes and explore the possibility of manipulating the IGF-1 axis to protect against anthracycline cardiotoxicity.
authors.affiliation: Research Center of Cardiovascular Biology, Department of Internal Medicine, University of Genova, Genova, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Fabbi
authors.affiliation: Research Center of Cardiovascular Biology, Department of Internal Medicine, University of Genova, Genova, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Spallarossa
authors.affiliation: Research Center of Cardiovascular Biology, Department of Internal Medicine, University of Genova, Genova, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Garibaldi
authors.affiliation: Research Center of Cardiovascular Biology, Department of Internal Medicine, University of Genova, Genova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Barisione
authors.affiliation: Research Center of Cardiovascular Biology, Department of Internal Medicine, University of Genova, Genova, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Mura
authors.affiliation: Research Center of Cardiovascular Biology, Department of Internal Medicine, University of Genova, Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Altieri
authors.affiliation: Antiblastic Drug Unit, IRCCS AOU San Martino-IST, Genova, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rebesco
authors.affiliation: Department of Medical Translational Sciences, University of Napoli Federico II, Napoli, Italy.
authors.forename: Maria Gaia
authors.initials: MG
authors.lastname: Monti
authors.affiliation: Research Center of Cardiovascular Biology, Department of Internal Medicine, University of Genova, Genova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Canepa
authors.affiliation: Research Center of Cardiovascular Biology, Department of Internal Medicine, University of Genova, Genova, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ghigliotti
authors.affiliation: Research Center of Cardiovascular Biology, Department of Internal Medicine, University of Genova, Genova, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Brunelli
authors.affiliation: Research Center of Cardiovascular Biology, Department of Internal Medicine, University of Genova, Genova, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Ameri
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D042541:Intracellular Space / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D011419:Propidium / Q000378:metabolism; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D017304:Annexin A5; D000975:Antioxidants; D018972:Insulin-Like Growth Factor Binding Protein 3; D016159:Tumor Suppressor Protein p53; D011419:Propidium; D007334:Insulin-Like Growth Factor I; D004317:Doxorubicin; D017526:Receptor, IGF Type 1; D053148:Caspase 3; D053179:Caspase 7