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Mechanisms and management of doxorubicin cardiotoxicity

Mechanismen und Management der Doxorubicinkardiotoxiztät

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Abstract

Doxorubicin is an effective anti-tumor agent with a cumulative dose-dependent cardiotoxicity. In addition to its principal toxic mechanisms involving iron and redox reactions, recent studies have described new mechanisms of doxorubicin-induced cell death, including abnormal protein processing, hyper-activated innate immune responses, inhibition of neuregulin-1 (NRG1)/ErbB(HER) signalling, impaired progenitor cell renewal/cardiac repair, and decreased vasculogenesis. Although multiple mechanisms involved in doxorubicin cardiotoxicity have been studied, there is presently no clinically proven treatment established for doxorubicin cardiomyopathy. Iron chelator dexrazoxane, angiotensin converting enzyme (ACE) inhibitors, and β-blockade have been proposed as potential preventive strategies for doxorubicin cardiotoxicity. Novel approaches such as anti-miR-146 or recombinant NRG1 to increase cardiomyocyte resistance to toxicity may be of interest in the future.

Zusammenfassung

Doxorubicin ist eine hochwirksame antineoplastische Substanz mit einer von der kumulativen Dosis abhängigen Kardiotoxizität. Neben den hauptsächlichen toxischen Mechanismen mit Eisen und Redoxreaktionen wurden in letzter Zeit neue Ursachen für den doxorubicininduzierten Zelltod beschrieben, u. a. eine pathologische Eiweißprozessierung, eine überproportionale Stimulation des angeborenen Immunsystems, die Inhibition der Neuregulin-1(NRG1)-ErB(HER)-Signalkaskade, eine gestörte Erneuerung der kardialen Progenitorzellen und Reparaturmechanismen und eine verminderte Vaskulogenese. Obwohl verschiedene Mechanismen der Doxorubicinkardiotoxizität bisher untersucht wurden, fehlt es bislang an einer klinisch effektiven und etablierten Behandlung der Doxorubicinkardiomyopathie. Der Eisenchelatbildner Dexrazoxan, ACE-Hemmer und Betablocker wurden als eine mögliche präventive Behandlung diskutiert. Neue Therapieansätze stützen sich auf Anti-MiR-146 oder rekombinantes NRG1 zur Verbesserung der Resistenz der Kardiomyozyten gegen die toxische Nebenwirkung und könnten zukünftig von besonderem Interesse sein.

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Acknowledgements

Supported in part by grants from the Heart and Stroke Foundation (HSF) of Ontario and the Canadian Institutes of Health Research (CIHR).

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The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Division of Cardiology, Heart and Stroke/Richard Lewar Centre of Excellence, University Health Network, University of Toronto, Toronto General Hospital, 200 Elizabeth Street, M5G 2C4, Toronto, Ontario, Canada

    Y. Shi, M. Moon & P.P. Liu MD

  2. Department of Medicine, Saint John Hospital & Medical Center, Detroit, Michigan (MI), USA

    S. Dawood

  3. Institute for HEART+LUNG Health, UBC James Hogg Research Centre, and NCE CECR PROOF Centre of Excellence, St. Paul’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada

    B. McManus

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  1. Y. Shi
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  2. M. Moon
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  3. S. Dawood
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  4. B. McManus
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  5. P.P. Liu MD
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Correspondence to P.P. Liu MD.

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Shi, Y., Moon, M., Dawood, S. et al. Mechanisms and management of doxorubicin cardiotoxicity. Herz 36, 296–305 (2011). https://doi.org/10.1007/s00059-011-3470-3

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