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Molecular Mechanisms of Cardiovascular Damage Induced by Anti-HER-2 Therapies

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Cardiovascular Complications in Cancer Therapy

Part of the book series: Current Clinical Pathology ((CCPATH))

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Abstract

In the last two decades, newer biological drugs have been designed in order to “target” specific proteins involved in cancer proliferation and overcome the increased risk of cardiovascular toxicity associated with “broad-spectrum” classic chemotherapeutics. Unfortunately, these proteins are also important for the maintenance of cardiovascular homeostasis. The humanized anti-ErbB2 antibody, trastuzumab, is the prototypical biological drug first introduced in antineoplastic protocols for the treatment of ErbB2+ breast cancer. Indeed, not only is this protein overexpressed in several breast cancers, but also it plays a major role in the cardiovascular system in cell growth, including myocyte growth, and inhibition of apoptosis and can modulate the oxidative damage induced by anthracyclines. Hence, patients treated with trastuzumab developed systolic dysfunction, especially when administered with or shortly after doxorubicin.

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References

  1. Hurwitz H, Fehrenbacher L. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.

    Article  CAS  Google Scholar 

  2. Ewer MS, Gibbs HR, Swafford J, Benjamin RS. Cardiotoxicity in patients receiving trastuzumab (Herceptin): primary toxicity, synergistic or sequential stress, or surveillance artifact? Semin Oncol. 1999;26:96–101.

    CAS  PubMed  Google Scholar 

  3. Cheng H, Force T. Molecular mechanisms of cardiovascular toxicity of targeted cancer therapeutics. Circ Res. 2010;106:21–34.

    Article  CAS  Google Scholar 

  4. Eschenhagen T, Force T, Ewer MS, de Keulenaer GW, Suter TM, Anker SD, et al. Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2011;13:1–10.

    Article  Google Scholar 

  5. Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer. 2007;7:332–44.

    Article  CAS  Google Scholar 

  6. De Keulenaer GW, Doggen K, Lemmens K. The vulnerability of the heart as a pluricellular paracrine organ: lessons from unexpected triggers of heart failure in targeted ErbB2 anticancer therapy. Circ Res. 2010;106:35–46.

    Article  Google Scholar 

  7. Mercurio V, Pirozzi F, Lazzarini E, Marone G, Rizzo P, Agnetti G, et al. Models of heart failure based on the cardiotoxicity of anticancer drugs. J Card Fail. 2016;22:449–58.

    Article  CAS  Google Scholar 

  8. Tocchetti CG, Ragone G, Coppola C, Rea D, Piscopo G, Scala S, et al. Detection, monitoring, and management of trastuzumab-induced left ventricular dysfunction: an actual challenge. Eur J Heart Fail. 2012;14(2):130–7.

    Article  CAS  Google Scholar 

  9. Suter TM, Ewer MS. Cancer drugs and the heart: importance and management. Eur Heart J. 2013;34(15):1102–11.

    Article  CAS  Google Scholar 

  10. Ky B, Vejpongsa P, Yeh ET, Force T, Moslehi JJ. Emerging paradigms in cardiomyopathies associated with cancer therapies. Circ Res. 2013;113:754–64. https://doi.org/10.1161/CIRCRESAHA.113.300218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tocchetti CG, Cadeddu C, Di Lisi D, Femminò S, Madonna R, Mele D, et al. From molecular mechanisms to clinical management of antineoplastic drug-induced cardiovascular toxicity: a translational overview. Antioxid Redox Signal. 2017; https://doi.org/10.1089/ars.2016.6930. [Epub ahead of print]

  12. Odiete O, Hill MF, Sawyer DB. Neuregulin in cardiovascular development and disease. Circ Res. 2012;111:1376–85.

    Article  CAS  Google Scholar 

  13. Lim SL, Lam CS, Segers VF, Brutsaert DL, De Keulenaer GW. Cardiac endothelium-myocyte interaction: clinical opportunities for new heart failure therapies regardless of ejection fraction. Eur Heart J. 2015;36:2050–60. https://doi.org/10.1093/eurheartj/ehv132.

    Article  CAS  PubMed  Google Scholar 

  14. D’Uva G, Aharonov A, Lauriola M, Kain D, Yahalom-Ronen Y, Carvalho S, et al. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nat Cell Biol. 2015;17:627–38.

    Article  Google Scholar 

  15. Gabrielson K, Bedja D, Pin S, Tsao A, Gama L, Yuan B, et al. Heat shock protein 90 and erbB2 in the cardiac response to doxorubicin injury. Cancer Res. 2007;67:1436–41.

    Article  CAS  Google Scholar 

  16. De Korte MA, de Vries EG, Lub-de Hooge MN, Jager PL, Gietema JA, van der Graaf WT, et al. 111Indium-trastuzumab visualises myocardial human epidermal growth factor receptor 2 expression shortly after anthracycline treatment but not during heart failure: a clue to uncover the mechanisms of trastuzumab-related cardiotoxicity. Eur J Cancer. 2007;43:2046–51.

    Article  Google Scholar 

  17. Ewer MS, Ewer SM. Troponin I provides insight into cardiotoxicity and the anthracycline-trastuzumab interaction. J Clin Oncol. 2010;28:3901–4.

    Article  CAS  Google Scholar 

  18. Crone SA, Zhao YY, Fan L, Gu Y, Minamisawa S, Liu Y, et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med. 2002;8:459–65.

    Article  CAS  Google Scholar 

  19. Ozcelik C, Erdmann B, Pilz B, Wettschureck N, Britsch S, Hübner N, et al. Conditional mutation of the ErbB2 (HER-2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc Natl Acad Sci U S A. 2002;99:8880–5.

    Article  CAS  Google Scholar 

  20. Belmonte F, Das S, Sysa-Shah P, Sivakumaran V, Stanley B, Guo X, et al. ErbB2 overexpression upregulates antioxidant enzymes, reduces basal levels of reactive oxygen species, and protects against doxorubicin cardiotoxicity. Am J Physiol Heart Circ Physiol. 2015;309:H1271–80.

    Article  CAS  Google Scholar 

  21. Rohrbach S, Niemann B, Silber RE, Holtz J. Neuregulin receptors erbB2 and erbB4 in failing human myocardium—depressed expression and attenuated activation. Basic Res Cardiol. 2005;100:240–9.

    Article  CAS  Google Scholar 

  22. Rohrbach S, Yan X, Weinberg EO, Hasan F, Bartunek J, Marchionni MA, et al. Neuregulin in cardiac hypertrophy in rats with aortic stenosis. Differential expression of erbB2 and erbB4 receptors. Circulation. 1999;100:407–12.

    Article  CAS  Google Scholar 

  23. Uray IP, Connelly JH, Thoma’zy V, Shipley GL, Vaughn WK, Frazier OH, et al. Left ventricular unloading alters receptor tyrosine kinase expression in the failing human heart. J Heart Lung Transplant. 2002;21:771–82.

    Article  Google Scholar 

  24. Doggen K, Ray L, Mathieu M, Mc Entee K, Lemmens K, De Keulenaer GW. Ventricular ErbB2/ErbB4 activation and downstream signaling in pacing-induced heart failure. J Mol Cell Cardiol. 2009;46:33–8.

    Article  CAS  Google Scholar 

  25. Jeon TJ, Lee JD, Ha JW, Yang WI, Cho SH. Evaluation of cardiac adrenergic neuronal damage in rats with doxorubicin-induced cardiomyopathy using iodine-131 MIBG autoradiography and PGP 9.5 immunohistochemistry. Eur J Nucl Med. 2000;27:686–93.

    Article  CAS  Google Scholar 

  26. Nousiainen T, Vanninen E, Jantunen E, Remes J, Ritanen E, Vuolteenaho O, et al. Neuroendocrine changes during the evolution of doxorubicin-induced left ventricular dysfunction in adult lymphoma patients. Clin Sci (Lond). 2001;101:601–7.

    Article  CAS  Google Scholar 

  27. Sysa-Shah P, Tocchetti CG, Gupta M, Rainer PP, Shen X, Kang BH, et al. Bidirectional cross-regulation betweenErbB2 and b-adrenergic signalling pathways. Cardiovasc Res. 2016;109:358–73.

    Article  CAS  Google Scholar 

  28. Sandoo A, Kitas G, Carmichael A. Endothelial dysfunction as a determinant of trastuzumab mediated cardiotoxicity in patients with breast cancer. Anticancer Res. 2014;1152:1147–51.

    Google Scholar 

  29. Zeglinski M, Ludke A, Jassal DS, Singal PK. Trastuzumab-induced cardiac dysfunction: a ‘dual-hit’. Exp Clin Cardiol. 2011;16(3):70–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Lemmens K, Segers VF, Demolder M, , De Keulenaer GW. Role of neuregulin-1/ErbB2 signaling in endothelium-cardiomyocyte cross-talk. J Biol Chem 2006;281:19469–19477.

    Article  CAS  Google Scholar 

  31. Sawyer DB, Zuppinger C, Miller TA, Eppenberger HM, Suter TM. Modulation of anthracycline-induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1 and anti-erbB2: potential mechanism for trastuzumab-induced cardiotoxicity. Circulation. 2002;105:1551–4.

    Article  CAS  Google Scholar 

  32. Lemmens K, Doggen K, De Keulenaer GW. Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure. Circulation. 2007;116:954–60. https://doi.org/10.1161/CIRCULATIONAHA.107.690487.

    Article  CAS  PubMed  Google Scholar 

  33. Pugatsch T, Abedat S, Lotan C, Beeri R. Anti-erbB2 treatment induces cardiotoxicity by interfering with cell survival pathways. Breast Cancer Res. 2006;8(4):R35.

    Article  Google Scholar 

  34. Albini A, Cesana E, Donatelli F, Cammarota R, Bucci EO, Baravelli M, et al. Cardio-oncology in targeting the HER receptor family: the puzzle of different cardiotoxicities of HER2 inhibitors. Futur Cardiol. 2011;7:693–704.

    Article  CAS  Google Scholar 

  35. Hervent AS, De Keulenaer GW. Molecular mechanisms of cardiotoxicity induced by ErbB receptor inhibitor cancer therapeutics. Int J Mol Sci. 2012;13(10):12268–86.

    Article  CAS  Google Scholar 

  36. Geisberg CA, Wang G, Safa RN, Smith HM, Anderson B, Peng XY, et al. Circulating neuregulin-1β levels vary according to the angiographic severity of coronary artery disease and ischemia. Coron Artery Dis. 2011;22:577–82. https://doi.org/10.1097/MCA.0b013e32834d3346.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Hedhli N, Huang Q, Kalinowski A, Palmeri M, Hu X, Russell RR, et al. Endothelium-derived neuregulin protects the heart against ischemic injury. Circulation. 2011;123:2254–62. https://doi.org/10.1161/CIRCULATIONAHA.110.991125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gui C, Zhu L, Hu M, Lei L, Long Q. Neuregulin-1/ErbB signaling is impaired in the rat model of diabetic cardiomyopathy. Cardiovasc Pathol. 2012;21:414–20. https://doi.org/10.1016/j.carpath.2011.12.006.

    Article  CAS  Google Scholar 

  39. Jay SM, Murthy AC, Hawkins JF, Wortzel JR, Steinhauser ML, Alvarez LM, et al. An engineered bivalent neuregulin protects against doxorubicin-induced cardiotoxicity with reduced proneoplastic potential. Circulation. 2013;128:152–61. https://doi.org/10.1161/CIRCULATIONAHA.113.002203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Herrmann J, Yang EH, Iliescu CA, Cilingiroglu M, Charitakis K, Hakeem A, et al. Vascular toxicities of cancer therapies: the old and the new – an evolving avenue. Circulation. 2016;133(13):1272–89.

    Article  CAS  Google Scholar 

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Disclosures

CGT received speaking fees from Alere.

Funding

CGT is funded by a Federico II University/Ricerca di Ateneo grant.

Author information

Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Valentina Mercurio

  2. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Giulio Agnetti

  3. DIBINEM, University of Bologna, Bologna, Italy

    Giulio Agnetti

  4. Clinical and Biological Sciences, AOU San Luigi Gonzaga, Orbassano, Italy

    Pasquale Pagliaro

  5. Department of Translational Medical Sciences, Federico II University, Naples, Italy

    Carlo G. Tocchetti

Authors
  1. Valentina Mercurio
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  2. Giulio Agnetti
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  3. Pasquale Pagliaro
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  4. Carlo G. Tocchetti
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Corresponding author

Correspondence to Carlo G. Tocchetti .

Editor information

Editors and Affiliations

  1. Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy

    Antonio Russo

  2. University of Palermo, School of Medicine, Palermo, Italy

    Giuseppina Novo

  3. Department of Cardiology, University of Liège, Liege, Belgium

    Patrizio Lancellotti

  4. Temple University College of Science and Technology, Philadelphia, PA, USA

    Antonio Giordano

  5. Cardiology Department, University of Lisbon, Lisbon, Portugal

    Fausto J. Pinto

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Mercurio, V., Agnetti, G., Pagliaro, P., Tocchetti, C.G. (2019). Molecular Mechanisms of Cardiovascular Damage Induced by Anti-HER-2 Therapies. In: Russo, A., Novo, G., Lancellotti, P., Giordano, A., Pinto, F. (eds) Cardiovascular Complications in Cancer Therapy. Current Clinical Pathology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-93402-0_3

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  • DOI: https://doi.org/10.1007/978-3-319-93402-0_3

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  • Publisher Name: Humana Press, Cham

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  • Online ISBN: 978-3-319-93402-0

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