Doxorubicin impairs the insulin-like growth factor-1 system and causes insulin-like growth factor-1 resistance in cardiomyocytes

Patrizia Fabbi, Paolo Spallarossa, Silvano Garibaldi, Chiara Barisione, Marzia Mura, Paola Altieri, Barbara Rebesco, Maria Gaia Monti, Marco Canepa, Giorgio Ghigliotti, Claudio Brunelli, Pietro Ameri

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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. Methods and 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 fromapoptosis 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-a, 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.

Original languageEnglish
Article number0124643
JournalPLoS One
Volume10
Issue number5
DOIs
Publication statusPublished - May 1 2015

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doxorubicin
somatomedins
Somatomedins
Cardiac Myocytes
Doxorubicin
Insulin-Like Growth Factor Binding Protein 3
insulin-like growth factor binding proteins
anthracyclines
apoptosis
Apoptosis
Anthracyclines
pretreatment
Dexrazoxane
cardiomyocytes
IGF Type 1 Receptor
acetylcysteine
Phosphorylation
Oxidative stress
Acetylcysteine
Transcription

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Fabbi, P., Spallarossa, P., Garibaldi, S., Barisione, C., Mura, M., Altieri, P., ... Ameri, P. (2015). Doxorubicin impairs the insulin-like growth factor-1 system and causes insulin-like growth factor-1 resistance in cardiomyocytes. PLoS One, 10(5), [0124643]. https://doi.org/10.1371/journal.pone.0124643

Doxorubicin impairs the insulin-like growth factor-1 system and causes insulin-like growth factor-1 resistance in cardiomyocytes. / Fabbi, Patrizia; Spallarossa, Paolo; Garibaldi, Silvano; Barisione, Chiara; Mura, Marzia; Altieri, Paola; Rebesco, Barbara; Monti, Maria Gaia; Canepa, Marco; Ghigliotti, Giorgio; Brunelli, Claudio; Ameri, Pietro.

In: PLoS One, Vol. 10, No. 5, 0124643, 01.05.2015.

Research output: Contribution to journalArticle

Fabbi, P, Spallarossa, P, Garibaldi, S, Barisione, C, Mura, M, Altieri, P, Rebesco, B, Monti, MG, Canepa, M, Ghigliotti, G, Brunelli, C & Ameri, P 2015, 'Doxorubicin impairs the insulin-like growth factor-1 system and causes insulin-like growth factor-1 resistance in cardiomyocytes', PLoS One, vol. 10, no. 5, 0124643. https://doi.org/10.1371/journal.pone.0124643
Fabbi, Patrizia ; Spallarossa, Paolo ; Garibaldi, Silvano ; Barisione, Chiara ; Mura, Marzia ; Altieri, Paola ; Rebesco, Barbara ; Monti, Maria Gaia ; Canepa, Marco ; Ghigliotti, Giorgio ; Brunelli, Claudio ; Ameri, Pietro. / Doxorubicin impairs the insulin-like growth factor-1 system and causes insulin-like growth factor-1 resistance in cardiomyocytes. In: PLoS One. 2015 ; Vol. 10, No. 5.
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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. Methods and 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 fromapoptosis 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-a, 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.",
author = "Patrizia Fabbi and Paolo Spallarossa and Silvano Garibaldi and Chiara Barisione and Marzia Mura and Paola Altieri and Barbara Rebesco and Monti, {Maria Gaia} and Marco Canepa and Giorgio Ghigliotti and Claudio Brunelli and Pietro Ameri",
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T1 - Doxorubicin impairs the insulin-like growth factor-1 system and causes insulin-like growth factor-1 resistance in cardiomyocytes

AU - Fabbi, Patrizia

AU - Spallarossa, Paolo

AU - Garibaldi, Silvano

AU - Barisione, Chiara

AU - Mura, Marzia

AU - Altieri, Paola

AU - Rebesco, Barbara

AU - Monti, Maria Gaia

AU - Canepa, Marco

AU - Ghigliotti, Giorgio

AU - Brunelli, Claudio

AU - Ameri, Pietro

PY - 2015/5/1

Y1 - 2015/5/1

N2 - 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. Methods and 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 fromapoptosis 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-a, 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.

AB - 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. Methods and 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 fromapoptosis 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-a, 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.

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