Anthracyclines/trastuzumab: new aspects of cardiotoxicity and molecular mechanisms

Rochette, Luc; Guenancia, Charles; Gudjoncik, Aurélie; Hachet, Olivier; Zeller, Marianne; Cottin, Yves; Vergely, Catherine

doi:10.1016/j.tips.2015.03.005

Cited by 211 publications

(149 citation statements)

References 204 publications

(189 reference statements)

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“…Over the past decade, despite survival rates improving due to advances in cancer biology and therapeutics, immunosuppressive and cytotoxic adverse effects still limit the therapeutic use of anticancer drugs [1][2][3]. Doxorubicin (Dox) is widely used for the treatment of solid tumors and hematologic malignancies [4,5].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-29b Regulates the Mitochondria-Dependent Apoptotic Pathway by Targeting Bax in Doxorubicin Cardiotoxicity

Jing

Yang²,

Jiang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Myocardial apoptosis plays an important role in doxorubicin (Dox) cardiotoxicity. MicroRNA-29 (miR-29) is suggested to function as an anti-fibrotic factor with potential therapeutic effects on cardiac fibrosis. However, it has not been shown whether there is an association between miR-29b and myocardial apoptosis. Methods: Male Wistar rats were transfected with miR-29b agomir by local delivery to the myocardium prior to Dox treatment. Rat cardiomyocytes were pretreated with miR-29b mimics or inhibitor followed by Dox incubation in vitro. Cardiac function and underlying mechanisms were evaluated by echocardiography, immunofluorescence, flow cytometry, real-time PCR, and western blotting. Results: Our results revealed that miR-29b is the only member of the miR-29 family that was significantly downregulated in myocardium from Dox-treated rats. Delivery of miR-29b agomir to myocardium resulted in a marked improvement of cardiac function. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining showed that rescue of miR-29b expression inhibited Dox-induced myocardial apoptosis, concomitantly with increased Bcl-2 expression and decreased Bax expression and caspase-3 activity. In vitro, miR-29b overexpression mitigated, whereas inhibition of miR-29b promoted, Dox-induced cardiomyocyte apoptosis. Mechanistically, miR-29b negatively regulated Bax expression by directly targeting the 3′ untranslated region of Bax. In Dox-treated cardiomyocytes, upregulation of miR-29b resulted in a significant decrease in Bax expression, with an increase in Bcl-2 expression, accompanied by inhibition of mitochondrial membrane depolarization, cytochrome c release, and caspase activation. However, inhibition of miR-29b produced the opposite effects by further augmenting the effects of Dox. Conclusions: These data demonstrate that miR-29b prevents Dox-induced myocardial apoptosis through inhibition of the mitochondria-dependent pathway by directly targeting Bax, suggesting that miR-29b is a potential novel therapeutic target for the treatment of Dox cardiotoxicity.

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Section: Introductionmentioning

confidence: 99%

MicroRNA-29b Regulates the Mitochondria-Dependent Apoptotic Pathway by Targeting Bax in Doxorubicin Cardiotoxicity

Jing

Yang²,

Jiang

et al. 2018

Cell Physiol Biochem

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“…2-4 After administration of anthracyclines in an adjuvant setting of breast cancer, trastuzumab (Herceptin; Genentech, South San Francisco, CA), a humanized monoclonal antibody against the human epidermal growth factor receptor 2 (HER2 or ErbB2) protein, 5 is effective in patients who overexpress this receptor. Combination of trastuzumab and chemotherapy provides a clinical benefit in terms of disease-free survival and overall survival compared with chemotherapy alone.…”

Section: Introductionmentioning

confidence: 99%

Obesity As a Risk Factor for Anthracyclines and Trastuzumab Cardiotoxicity in Breast Cancer: A Systematic Review and Meta-Analysis

Guenancia

Lefebvre

Cardinale

et al. 2016

JCO

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154

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International audiencePurposePatients with metabolic syndrome have a greater risk of cardiovascular disease, although their susceptibility to chemotherapy-induced cardiac disease is not well documented. The aim of this meta-analysis was to assess associations between obesity or being overweight and cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab in patients with breast cancer.MethodsWe performed a random-effects analysis and a network meta-analysis and assessed publication bias. We included 15 studies and 8,745 patients with breast cancers who were treated with anthracyclines and sequential anthracyclines and trastuzumab.ResultsCombination of obesity and being overweight was significantly associated with a greater risk of developing cardiotoxicity after anthracyclines and a sequential anthracyclines and trastuzumab regimen in patients with breast cancer. Pooled odds ratio for cardiotoxicity was 1.38 (95% CI, 1.06 to 1.80; I-2 = 43%; N = 8,745) for overweight or obesity (body mass index. 25 kg/m(2)), 1.47 (95% CI, 0.95 to 2.28; I-2 = 47%; n = 2,615) for obesity, and 1.15 (95% CI, 0.83 to 1.58; I-2 = 27%; n = 2,708) for overweight. Associations were independent of study design, year of publication, drug regimen (anthracyclines alone v sequential anthracyclines and trastuzumab), or definitions of cardiotoxicity and of overweight or obesity. There was no evidence of publication bias; however, we could not separate the contributions of obesity-related cardiovascular risk factors, such as diabetes and hypertension, from that of obesity itself in this largely unadjusted analysis.ConclusionOur findings in a largely unadjusted analysis suggest that overweight and obesity are risk factors for cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab

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“…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).…”

mentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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

Guenancia

Rochette

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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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...

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Anthracyclines/trastuzumab: new aspects of cardiotoxicity and molecular mechanisms

Cited by 211 publications

References 204 publications

MicroRNA-29b Regulates the Mitochondria-Dependent Apoptotic Pathway by Targeting Bax in Doxorubicin Cardiotoxicity

MicroRNA-29b Regulates the Mitochondria-Dependent Apoptotic Pathway by Targeting Bax in Doxorubicin Cardiotoxicity

Obesity As a Risk Factor for Anthracyclines and Trastuzumab Cardiotoxicity in Breast Cancer: A Systematic Review and Meta-Analysis

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

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