Research Article: Doxorubicin Impairs the Insulin-Like Growth Factor-1 System and Causes Insulin-Like Growth Factor-1 Resistance in Cardiomyocytes

Date Published: May 8, 2015

Publisher: Public Library of Science

Author(s): 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, Partha Mukhopadhyay.


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.

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.

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.

Partial Text

Cardiac toxicity occurs in a significant percentage of patients treated with drugs belonging to the anthracycline class, among which doxorubicin [1]. One of the features of anthracycline cardiotoxicity is the induction of apoptosis of both terminally differentiated cardiomyocytes and cardiac progenitor cells (CPCs), resulting in the loss of myocardial tissue and intrinsic regenerative capacity, respectively [2,3].

A number of tumors, including common ones such as those of the breast or lymphomas, are treated with anthracyclines and especially doxorubicin [1]. Unfortunately, up to one in five patients develop some degree of cardiac toxicity following anthracycline chemotherapy, varying from subclinical left ventricular dysfunction to overt congestive heart failure [25]. Although the pathogenesis of this cardiotoxicity is multifactorial [23], experimental data indicate that apoptosis of cardiac cells may play an important role [26]. Remarkably, anthracycline-initiated apoptosis involves not only terminally differentiated cardiomyocytes, but also CPCs [2,3]. By depleting the CPC compartment, anthracyclines may impede the cardiac regeneration process and, thus, make the loss of cardiac tissue permanent [2].

By altering the expression of IGF-1R and IGFBP-3, doxorubicin makes H9c2 cells unresponsive to a key pro-survival factor with ensuing apoptosis. Further research work is needed to confirm these findings in human cardiomyocytes and to determine whether pharmacological manipulation of the myocardial IGF-1 system may be an effective strategy to prevent anthracycline cardiotoxicity.