Skip to main content
SpringerLink
Log in

Chemotherapy-Induced Cardiotoxicity in Cancer Treatment: Mechanisms and Its Prevention

  • Living reference work entry
  • First Online:
Handbook of Cancer and Immunology

  • 94 Accesses

Abstract

Current cancer therapies improve the overall survival of cancer patients. However, cardiotoxicity is one of the most recognized complications following treatment with conventional chemotherapy, targeted drugs, and chest irradiation. Cardiotoxicity can range from subclinical myocardial injury to symptomatic heart failure. Once left ventricular dysfunction or heart failure is clinically detected, these cancer therapies need to be suspended, leading to the risk of cancer progression or recurrence. Anthracyclines and HER2-targeted drugs are notably common chemotherapeutic drugs that directly impair the myocardium. Doxorubicin, a widely used anthracycline, causes irreversible cardiotoxicity in a cumulative dose-related manner through oxidative stress, mitochondrial dysfunction, and DNA double-strand breakdown. Trastuzumab is the first monoclonal antibody to be selectively effective against HER2-overexpressing cancers. Unlike anthracycline, trastuzumab-induced cardiotoxicity is believed not to be dose-related and is typically manifested during treatment. HER2 inhibition impairs mitochondrial function and defense mechanisms against oxidative stress, leading to cardiac dysfunction. The cardiotoxicity is reversible after trastuzumab discontinuation and the rechallenge of the treatment is potentially safe. HER-2-positive breast cancer is typically treated with anthracyclines and sequentially followed by trastuzumab; however, trastuzumab may augment doxorubicin-induced cardiotoxicity. Close monitoring and periodic surveillance of left ventricular function are critical during and after cancer treatment to enable detection of cardiotoxicity. Although several drugs, including dexrazoxane and angiotensin-converting enzyme inhibitors, have been demonstrated to be beneficial in attenuating cardiotoxicity, there is still no effective prevention to reduce cardiovascular events in patients receiving either anthracyclines or trastuzumab. Novel preventive interventions involving oxidative stress, mitochondrial function, and autophagy have been reported in preclinical models, and they could potentially be clinically effective in preventing this cardiotoxicity in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Acar Z et al (2011) Efficiency of atorvastatin in the protection of anthracycline-induced cardiomyopathy. J Am Coll Cardiol 58(9):988–989

    Article  PubMed  Google Scholar 

  • Akpek M et al (2015) Protective effects of spironolactone against anthracycline-induced cardiomyopathy. Eur J Heart Fail 17(1):81–89

    Article  CAS  PubMed  Google Scholar 

  • Arinno A et al (2021) Cardioprotective effects of melatonin and metformin against doxorubicin-induced cardiotoxicity in rats are through preserving mitochondrial function and dynamics. Biochem Pharmacol 192:114743

    Article  CAS  PubMed  Google Scholar 

  • Belmonte F et al (2015) ErbB2 overexpression upregulates antioxidant enzymes, reduces basal levels of reactive oxygen species, and protects against doxorubicin cardiotoxicity. Am J Physiol Heart Circ Physiol 309(8):H1271–H1280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ben Kridis W et al (2020) A prospective study about trastuzumab-induced cardiotoxicity in HER2-positive breast cancer. Am J Clin Oncol 43(7):510–516

    Article  CAS  PubMed  Google Scholar 

  • Boekhout AH et al (2016) Angiotensin II-receptor inhibition with candesartan to prevent trastuzumab-related cardiotoxic effects in patients with early breast cancer: a randomized clinical trial. JAMA Oncol 2(8):1030–1037

    Article  PubMed  Google Scholar 

  • Bolli R et al (2020) Allogeneic mesenchymal cell therapy in anthracycline-induced cardiomyopathy heart failure patients: the CCTRN SENECA trial. JACC CardioOncol 2(4):581–595

    Article  PubMed  PubMed Central  Google Scholar 

  • Bosch X et al (2013) Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol 61(23):2355–2362

    Article  CAS  PubMed  Google Scholar 

  • Cardinale D et al (2006) Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 114(23):2474–2481

    Article  CAS  PubMed  Google Scholar 

  • Cardinale D et al (2010) Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 55(3):213–220

    Article  CAS  PubMed  Google Scholar 

  • Cardinale D et al (2018) Anthracycline-induced cardiotoxicity: a multicenter randomised trial comparing two strategies for guiding prevention with enalapril: the International CardioOncology Society-one trial. Eur J Cancer 94:126–137

    Article  CAS  PubMed  Google Scholar 

  • Cheung KG et al (2015) Sirtuin-3 (SIRT3) protein attenuates doxorubicin-induced oxidative stress and improves mitochondrial respiration in H9c2 cardiomyocytes. J Biol Chem 290(17):10981–10993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Curigliano G et al (2020) Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol 31(2):171–190

    Article  CAS  PubMed  Google Scholar 

  • De Lorenzo C et al (2018) Cardiotoxic effects of the novel approved anti-ErbB2 agents and reverse cardioprotective effects of ranolazine. Onco Targets Ther 11:2241–2250

    Article  PubMed  PubMed Central  Google Scholar 

  • Dhingra R et al (2014) Bnip3 mediates doxorubicin-induced cardiac myocyte necrosis and mortality through changes in mitochondrial signaling. Proc Natl Acad Sci U S A 111(51):E5537–E5544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dong WG et al (2003) Effects of melatonin on the expression of iNOS and COX-2 in rat models of colitis. World J Gastroenterol 9(6):1307–1311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • El-Sherbeny WS, Sabry NM, Sharbay RM (2019) Prediction of trastuzumab-induced cardiotoxicity in breast cancer patients receiving anthracycline-based chemotherapy. J Echocardiogr 17(2):76–83

    Article  PubMed  Google Scholar 

  • Ewer MS et al (2005) Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol 23(31):7820–7826

    Article  CAS  PubMed  Google Scholar 

  • Fedele C et al (2012) Mechanisms of cardiotoxicity associated with ErbB2 inhibitors. Breast Cancer Res Treat 134(2):595–602

    Article  CAS  PubMed  Google Scholar 

  • Ferreira A et al (2017) Altered mitochondrial epigenetics associated with subchronic doxorubicin cardiotoxicity. Toxicology 390:63–73

    Article  CAS  PubMed  Google Scholar 

  • Garbade J et al (2009) Bone marrow-derived stem cells attenuate impaired contractility and enhance capillary density in a rabbit model of Doxorubicin-induced failing hearts. J Card Surg 24(5):591–599

    Article  PubMed  Google Scholar 

  • Garcia-Rivello H et al (2005) Dilated cardiomyopathy in Erb-b4-deficient ventricular muscle. Am J Physiol Heart Circ Physiol 289(3):H1153–H1160

    Article  CAS  PubMed  Google Scholar 

  • Gordon LI et al (2009) Blockade of the erbB2 receptor induces cardiomyocyte death through mitochondrial and reactive oxygen species-dependent pathways. J Biol Chem 284(4):2080–2087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grazette LP et al (2004) Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy. J Am Coll Cardiol 44(11):2231–2238

    Article  CAS  PubMed  Google Scholar 

  • Guglin M et al (2019) Randomized trial of lisinopril versus carvedilol to prevent trastuzumab cardiotoxicity in patients with breast cancer. J Am Coll Cardiol 73(22):2859–2868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gulati G et al (2016) Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 x 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Eur Heart J 37(21):1671–1680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo J et al (2014) Cardioprotection against doxorubicin by metallothionein is associated with preservation of mitochondrial biogenesis involving PGC-1alpha pathway. Eur J Pharmacol 737:117–124

    Article  CAS  PubMed  Google Scholar 

  • Haykowsky MJ et al (2009) Adjuvant trastuzumab induces ventricular remodeling despite aerobic exercise training. Clin Cancer Res 15(15):4963–4967

    Article  CAS  PubMed  Google Scholar 

  • Herrmann J (2020) Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia. Nat Rev Cardiol 17(8):474–502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hiona A et al (2011) Pretreatment with angiotensin-converting enzyme inhibitor improves doxorubicin-induced cardiomyopathy via preservation of mitochondrial function. J Thorac Cardiovasc Surg 142(2):396–403 e3

    Article  CAS  PubMed  Google Scholar 

  • Horie T et al (2010) Acute doxorubicin cardiotoxicity is associated with miR-146a-induced inhibition of the neuregulin-ErbB pathway. Cardiovasc Res 87(4):656–664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu S et al (2015) Molecular architecture of the ErbB2 extracellular domain homodimer. Oncotarget 6(3):1695–1706

    Article  PubMed  PubMed Central  Google Scholar 

  • Ichikawa Y et al (2014) Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Invest 124(2):617–630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Janbabai G et al (2017) Effect of enalapril on preventing anthracycline-induced cardiomyopathy. Cardiovasc Toxicol 17(2):130–139

    Article  CAS  PubMed  Google Scholar 

  • Kabel AM, Elkhoely AA (2017) Targeting proinflammatory cytokines, oxidative stress, TGF-beta1 and STAT-3 by rosuvastatin and ubiquinone to ameliorate trastuzumab cardiotoxicity. Biomed Pharmacother 93:17–26

    Article  CAS  PubMed  Google Scholar 

  • Kaya MG et al (2013) Protective effects of nebivolol against anthracycline-induced cardiomyopathy: a randomized control study. Int J Cardiol 167(5):2306–2310

    Article  PubMed  Google Scholar 

  • Kelly CM, Janjigian YY (2016) The genomics and therapeutics of HER2-positive gastric cancer-from trastuzumab and beyond. J Gastrointest Oncol 7(5):750–762

    Article  PubMed  PubMed Central  Google Scholar 

  • Kertmen N et al (2015) Which sequence best protects the heart against trastuzumab and anthracycline toxicity? An electron microscopy study in rats. Anticancer Res 35(2):857–864

    CAS  PubMed  Google Scholar 

  • Kheiri B et al (2018) Meta-analysis of carvedilol for the prevention of anthracycline-induced cardiotoxicity. Am J Cardiol 122(11):1959–1964

    Article  CAS  PubMed  Google Scholar 

  • Khuanjing T et al (2021) Acetylcholinesterase inhibitor ameliorates doxorubicin-induced cardiotoxicity through reducing RIP1-mediated necroptosis. Pharmacol Res 173:105882

    Article  CAS  PubMed  Google Scholar 

  • Koleini N, Kardami E (2017) Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity. Oncotarget 8(28):46663–46680

    Article  PubMed  PubMed Central  Google Scholar 

  • Lau ES et al (2021) Cardiovascular risk factors are associated with future cancer. JACC CardioOncol 3(1):48–58

    Article  PubMed  PubMed Central  Google Scholar 

  • Lemmens K et al (2004) Neuregulin-1 induces a negative inotropic effect in cardiac muscle: role of nitric oxide synthase. Circulation 109(3):324–326

    Article  CAS  PubMed  Google Scholar 

  • Lemmens K et al (2006) Role of neuregulin-1/ErbB2 signaling in endothelium-cardiomyocyte cross-talk. J Biol Chem 281(28):19469–19477

    Article  CAS  PubMed  Google Scholar 

  • Li J et al (2014) Mitofusin 1 is negatively regulated by microRNA 140 in cardiomyocyte apoptosis. Mol Cell Biol 34(10):1788–1799

    Article  PubMed  PubMed Central  Google Scholar 

  • Li DL et al (2016) Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation 133(17):1668–1687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Linggi B, Carpenter G (2006) ErbB receptors: new insights on mechanisms and biology. Trends Cell Biol 16(12):649–656

    Article  CAS  PubMed  Google Scholar 

  • Liu G et al (2016) Spironolactone attenuates doxorubicin-induced cardiotoxicity in rats. Cardiovasc Ther 34(4):216–224

    Article  CAS  PubMed  Google Scholar 

  • Lyu YL et al (2007) Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res 67(18):8839–8846

    Article  CAS  PubMed  Google Scholar 

  • Milano G et al (2020) Intravenous administration of cardiac progenitor cell-derived exosomes protects against doxorubicin/trastuzumab-induced cardiac toxicity. Cardiovasc Res 116(2):383–392

    CAS  PubMed  Google Scholar 

  • O’Brien CG et al (2021) Mitochondria-rich extracellular vesicles rescue patient-specific cardiomyocytes from doxorubicin injury: insights into the SENECA trial. JACC CardioOncol 3(3):428–440

    Article  PubMed  PubMed Central  Google Scholar 

  • Okoshi K et al (2004) Neuregulins regulate cardiac parasympathetic activity: muscarinic modulation of beta-adrenergic activity in myocytes from mice with neuregulin-1 gene deletion. Circulation 110(6):713–717

    Article  CAS  PubMed  Google Scholar 

  • Osataphan N et al (2020) Effects of doxorubicin-induced cardiotoxicity on cardiac mitochondrial dynamics and mitochondrial function: insights for future interventions. J Cell Mol Med 24(12):6534–6557

    Article  PubMed  PubMed Central  Google Scholar 

  • Ozcelik C et al (2002) Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc Natl Acad Sci U S A 99(13):8880–8885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ozturk M et al (2011) Efficacy of melatonin, mercaptoethylguanidine and 1400W in doxorubicin- and trastuzumab-induced cardiotoxicity. J Pineal Res 50(1):89–96

    Article  CAS  PubMed  Google Scholar 

  • Pentassuglia L et al (2007) Inhibition of ErbB2/neuregulin signaling augments paclitaxel-induced cardiotoxicity in adult ventricular myocytes. Exp Cell Res 313(8):1588–1601

    Article  CAS  PubMed  Google Scholar 

  • Perez IE et al (2019) Cancer therapy-related cardiac dysfunction: an overview for the clinician. Clin Med Insights Cardiol 13:1179546819866445

    Article  PubMed  PubMed Central  Google Scholar 

  • Piccart-Gebhart MJ et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353(16):1659–1672

    Article  CAS  PubMed  Google Scholar 

  • Pivot X et al (2015) Cardiac toxicity events in the PHARE trial, an adjuvant trastuzumab randomised phase III study. Eur J Cancer 51(13):1660–1666

    Article  CAS  PubMed  Google Scholar 

  • Plana JC et al (2014) Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 27(9):911–939

    Article  PubMed  Google Scholar 

  • Quartino AL et al (2016) Population pharmacokinetic and exposure-response analysis for trastuzumab administered using a subcutaneous “manual syringe” injection or intravenously in women with HER2-positive early breast cancer. Cancer Chemother Pharmacol 77(1):77–88

    Article  CAS  PubMed  Google Scholar 

  • Rafiyath SM et al (2012) Comparison of safety and toxicity of liposomal doxorubicin vs. conventional anthracyclines: a meta-analysis. Exp. Hematol Oncol 1(1):10

    CAS  Google Scholar 

  • Riad A et al (2009) Pretreatment with statin attenuates the cardiotoxicity of Doxorubicin in mice. Cancer Res 69(2):695–699

    Article  CAS  PubMed  Google Scholar 

  • Riccio G et al (2018) Ranolazine attenuates trastuzumab-induced heart dysfunction by modulating ROS production. Front Physiol 9:38

    Article  PubMed  PubMed Central  Google Scholar 

  • Rohrbach S et al (2005) Apoptosis-modulating interaction of the neuregulin/erbB pathway with anthracyclines in regulating Bcl-xS and Bcl-xL in cardiomyocytes. J Mol Cell Cardiol 38(3):485–493

    Article  CAS  PubMed  Google Scholar 

  • Shell SA et al (2008) Activation of AMPK is necessary for killing cancer cells and sparing cardiac cells. Cell Cycle 7(12):1769–1775

    Article  CAS  PubMed  Google Scholar 

  • Slamon DJ et al (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177–182

    Article  CAS  PubMed  Google Scholar 

  • Slamon DJ et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792

    Article  CAS  PubMed  Google Scholar 

  • Slamon D et al (2011) Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365(14):1273–1283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thavendiranathan P et al (2021) Strain-guided management of potentially cardiotoxic cancer therapy. J Am Coll Cardiol 77(4):392–401

    Article  CAS  PubMed  Google Scholar 

  • Timolati F et al (2006) Neuregulin-1 beta attenuates doxorubicin-induced alterations of excitation-contraction coupling and reduces oxidative stress in adult rat cardiomyocytes. J Mol Cell Cardiol 41(5):845–854

    Article  CAS  PubMed  Google Scholar 

  • van Dalen EC et al (2008) Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev (2):CD003917

    Google Scholar 

  • Wang Y et al (2021) atg7-based autophagy activation reverses doxorubicin-induced cardiotoxicity. Circ Res 129(8):e166–e182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xia Y et al (2017) LCZ696 improves cardiac function via alleviating Drp1-mediated mitochondrial dysfunction in mice with doxorubicin-induced dilated cardiomyopathy. J Mol Cell Cardiol 108:138–148

    Article  CAS  PubMed  Google Scholar 

  • Zamorano JL et al (2016) 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 37(36):2768–2801

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the NSTDA Research Chair grant from the National Science and Technology Development Agency Thailand (NC), the Senior Research Scholar grant from the National Research Council of Thailand (SCC), and the Center of Excellence Award from Chiang Mai University (NC).

Author information

Author notes

  1. Nichanan Osataphan and Krit Leemasawat contributed equally to this work.

Authors and Affiliations

  1. Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

    Nichanan Osataphan, Krit Leemasawat, Arintaya Phrommintikul, Siriporn C. Chattipakorn & Nipon Chattipakorn

  2. Cardiology Division, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

    Nichanan Osataphan, Krit Leemasawat & Arintaya Phrommintikul

  3. Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand

    Nichanan Osataphan, Krit Leemasawat, Arintaya Phrommintikul, Siriporn C. Chattipakorn & Nipon Chattipakorn

  4. Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

    Nipon Chattipakorn

Authors
  1. Nichanan Osataphan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Krit Leemasawat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arintaya Phrommintikul
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Siriporn C. Chattipakorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nipon Chattipakorn
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Division of Clinical Immunology, Karolinska University Hospital, Huddinge, Sweden

    Nima Rezaei

Rights and permissions

Reprints and permissions

Copyright information

© 2023 Springer Nature Switzerland AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Osataphan, N., Leemasawat, K., Phrommintikul, A., Chattipakorn, S.C., Chattipakorn, N. (2023). Chemotherapy-Induced Cardiotoxicity in Cancer Treatment: Mechanisms and Its Prevention. In: Rezaei, N. (eds) Handbook of Cancer and Immunology. Springer, Cham. https://doi.org/10.1007/978-3-030-80962-1_344-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-80962-1_344-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-80962-1

  • Online ISBN: 978-3-030-80962-1

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation