Letter to the editor: “Doxorubicin and ErbB2 overexpression: another piece in the mitochondrial jigsaw”

Abstract

TO THE EDITOR We read with great interest the recent article, published in American Journal of by Belmonte et al. (2), the results of which were discussed by Rocic (12) in an editorial focus. The authors highlight for the first time the key-role of ErbB2 upregulation on the redox dysregulation involved in doxorubicin (DOX) cardiotoxicity. Interestingly, mice overexpressing ErbB2 displayed a "cardioprotected" phenotype with lower mitochondrial reactive oxygen species (ROS) levels and increased expression/activity of cardiac antioxidant enzymes, probably through c-Abl and Arg nonreceptor tyrosine kinases overexpression.These results add another piece in the complex jigsaw of mitochondrial interactions between anthracyclines and trastuzumab (TRZ). Indeed, TRZ, a humanized monoclonal antibody against the human epidermal growth factor receptor 2 (HER 2 or ErbB2) protein, has been reported to induce an unexpected incidence of cardiac side effects (13), especially when administrated following anthracycline treatment. Therefore, TRZ is now believed to potentiate the cardiotoxic effects of anthracyclines (11). In in vivo murine models that combined DOX with TRZ, a synergetic interaction was reported, leading to increased deterioration in cardiac function and cardiomyocyte apoptosis (4). In addition, in vitro in cardiomyocytes, HER2 blockage was accompanied by apoptotic processes and by an increase in oxidative stress level (11).In the light of these findings, the authors may have performed an in vivo model of DOX cardiotoxicity to confirm that the cardioprotection afforded by selective cardiac ErbB2 overexpression through ROS production decrease. Moreover, evaluating the effects of the administration of TRZ (15) or of a distinct ErbB2 blocker (5) could have confirmed this hypothesis if the benefits of the knockout phenotype had been reversed by ErbB2 inhibitors.The second part of our reflection is related to the crucial role of a transition metal, iron, in the ROS production following anthracycline administration (6, 7). Thomas and Aust (14) showed that DOX-induced superoxide anion may increase the amount of free, redox-active iron through the slow reductive release of iron from ferritin. However, the localization of iron inside the mitochondria seems to be a key event in DOXinduced cardiotoxicity since it was recently observed that mice lacking mitochondrial ferritin are more sensitive to doxorubicin-mediated cardiotoxicity (10). The authors convincingly demonstrate that mitochondria are at the crossroads of all the modifications in the cell redox potential induced by ErbB2 overexpression. Ichikawa et al. (8) have shown that DOXinduced cardiotoxicity originates from the specific mitochondrial accumulation of iron, which leads to increased ROS production in this organelle, but also that DOX represses the expression of ATP-binding cassette subfamily B transporter-8 (ABCB8), a protein that exports iron out of the mitochondria (8). However, such findings have not been described with TRZ, although a mitochondrial ErbB2 (m...