1932

Abstract

Anthracyclines are the cornerstone of many chemotherapy regimens for a variety of cancers. Unfortunately, their use is limited by a cumulative dose-dependent cardiotoxicity. Despite more than five decades of research, the biological mechanisms underlying anthracycline cardiotoxicity are not completely understood. In this review, we discuss the incidence, risk factors, types, and pathophysiology of anthracycline cardiotoxicity, as well as methods to prevent and treat this condition. We also summarize and discuss advances made in the last decade in the comprehension of the molecular mechanisms underlying the pathology.

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2021-01-06
2024-06-24
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Literature Cited

  1. 1. 
    Di Marco A, Cassinelli G, Arcamone F 1981. The discovery of daunorubicin. Cancer Treat. Rep. 65:Suppl. 43–8
    [Google Scholar]
  2. 2. 
    Tan C, Tasaka H, Yu KP, Murphy ML, Karnofsky DA 1967. Daunomycin, an antitumor antibiotic, in the treatment of neoplastic disease. Clinical evaluation with special reference to childhood leukemia. Cancer 20:333–53
    [Google Scholar]
  3. 3. 
    Arcamone F, Cassinelli G, Fantini G, Grein A, Orezzi P et al. 1969. Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius. Biotechnol. Bioeng. 11:1101–10
    [Google Scholar]
  4. 4. 
    Middleman E, Luce J, Frei E3rd 1971. Clinical trials with adriamycin. Cancer 28:844–50
    [Google Scholar]
  5. 5. 
    Khouri MG, Douglas PS, Mackey JR, Martin M, Scott JM et al. 2012. Cancer therapy-induced cardiac toxicity in early breast cancer: addressing the unresolved issues. Circulation 126:2749–63
    [Google Scholar]
  6. 6. 
    Nebigil CG, Désaubry L. 2018. Updates in anthracycline-mediated cardiotoxicity. Front. Pharmacol. 9:1262
    [Google Scholar]
  7. 7. 
    Yeh ET, Bickford CL. 2009. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J. Am. Coll. Cardiol. 53:2231–47
    [Google Scholar]
  8. 8. 
    Cardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA et al. 2015. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 131:1981–88
    [Google Scholar]
  9. 9. 
    Ferrans VJ. 1978. Overview of cardiac pathology in relation to anthracycline cardiotoxicity. Cancer Treat. Rep. 62:955–61
    [Google Scholar]
  10. 10. 
    Shan K, Lincoff AM, Young JB 1996. Anthracycline-induced cardiotoxicity. Ann. Intern. Med. 125:47–58
    [Google Scholar]
  11. 11. 
    Berry GJ, Jorden M. 2005. Pathology of radiation and anthracycline cardiotoxicity. Pediatr. Blood Cancer 44:630–37
    [Google Scholar]
  12. 12. 
    Swain SM, Whaley FS, Ewer MS 2003. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97:2869–79
    [Google Scholar]
  13. 13. 
    Leger K, Slone T, Lemler M, Leonard D, Cochran C et al. 2015. Subclinical cardiotoxicity in childhood cancer survivors exposed to very low dose anthracycline therapy. Pediatr. Blood Cancer 62:123–27
    [Google Scholar]
  14. 14. 
    Hsieh SY, He JR, Hsu CY, Chen WJ, Bera R et al. 2011. Neuregulin/erythroblastic leukemia viral oncogene homolog 3 autocrine loop contributes to invasion and early recurrence of human hepatoma. Hepatology 53:504–16
    [Google Scholar]
  15. 15. 
    Lee JH, Wendorff TJ, Berger JM 2017. Resveratrol: a novel type of topoisomerase II inhibitor. J. Biol. Chem. 292:21011–22
    [Google Scholar]
  16. 16. 
    Von Hoff DD, Layard MW, Basa P, Davis HL Jr., Von Hoff AL et al. 1979. Risk factors for doxorubicin-induced congestive heart failure. Ann. Intern. Med. 91:710–17
    [Google Scholar]
  17. 17. 
    Cardinale D, Sandri MT, Martinoni A, Borghini E, Civelli M et al. 2002. Myocardial injury revealed by plasma troponin I in breast cancer treated with high-dose chemotherapy. Ann. Oncol. 13:710–15
    [Google Scholar]
  18. 18. 
    Thavendiranathan P, Poulin F, Lim KD, Plana JC, Woo A, Marwick TH 2014. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J. Am. Coll. Cardiol. 63:2751–68
    [Google Scholar]
  19. 19. 
    Linschoten M, Teske AJ, Cramer MJ, van der Wall E, Asselbergs FW 2018. Chemotherapy-related cardiac dysfunction: a systematic review of genetic variants modulating individual risk. Circ. Genom. Precis. Med. 11:e001753
    [Google Scholar]
  20. 20. 
    Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR et al. 2019. Cancer treatment and survivorship statistics, 2019. CA Cancer J. Clin. 69:363–85
    [Google Scholar]
  21. 21. 
    Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R et al. 2017. 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. J. Heart Fail. 19:9–42
    [Google Scholar]
  22. 22. 
    Lipshultz SE, Miller TL, Lipsitz SR, Neuberg DS, Dahlberg SE et al. 2012. Continuous versus bolus infusion of doxorubicin in children with ALL: long-term cardiac outcomes. Pediatrics 130:1003–11
    [Google Scholar]
  23. 23. 
    Hilfiker-Kleiner D, Ardehali H, Fischmeister R, Burridge P, Hirsch E, Lyon AR 2019. Late onset heart failure after childhood chemotherapy. Eur. Heart J. 40:798–800
    [Google Scholar]
  24. 24. 
    Morris PG, Hudis CA. 2010. Trastuzumab-related cardiotoxicity following anthracycline-based adjuvant chemotherapy: How worried should we be. ? J. Clin. Oncol. 28:3407–10
    [Google Scholar]
  25. 25. 
    Russell SD, Blackwell KL, Lawrence J, Pippen JE Jr., Roe MT et al. 2010. Independent adjudication of symptomatic heart failure with the use of doxorubicin and cyclophosphamide followed by trastuzumab adjuvant therapy: a combined review of cardiac data from the National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 clinical trials. J. Clin. Oncol. 28:3416–21
    [Google Scholar]
  26. 26. 
    Aleman BM, van den Belt-Dusebout AW, De Bruin ML, van ’t Veer MB, Baaijens MH et al. 2007. Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood 109:1878–86
    [Google Scholar]
  27. 27. 
    Ryberg M, Nielsen D, Cortese G, Nielsen G, Skovsgaard T, Andersen PK 2008. New insight into epirubicin cardiac toxicity: competing risks analysis of 1097 breast cancer patients. J. Natl. Cancer Inst. 100:1058–67
    [Google Scholar]
  28. 28. 
    Lipshultz SE, Lipsitz SR, Mone SM, Goorin AM, Sallan SE et al. 1995. Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N. Engl. J. Med. 332:1738–43
    [Google Scholar]
  29. 29. 
    Lipshultz SE, Scully RE, Lipsitz SR, Sallan SE, Silverman LB et al. 2010. Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol 11:950–61
    [Google Scholar]
  30. 30. 
    Myrehaug S, Pintilie M, Yun L, Crump M, Tsang RW et al. 2010. A population-based study of cardiac morbidity among Hodgkin lymphoma patients with preexisting heart disease. Blood 116:2237–40
    [Google Scholar]
  31. 31. 
    Blanco JG, Sun C-L, Landier W, Chen L, Esparza-Duran D et al. 2012. Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes—a report from the Children's Oncology Group. J. Clin. Oncol. 30:1415–21
    [Google Scholar]
  32. 32. 
    Mordente A, Minotti G, Martorana GE, Silvestrini A, Giardina B, Meucci E 2003. Anthracycline secondary alcohol metabolite formation in human or rabbit heart: biochemical aspects and pharmacologic implications. Biochem. Pharmacol. 66:989–98
    [Google Scholar]
  33. 33. 
    Mushlin PS, Cusack BJ, Boucek RJ Jr., Andrejuk T, Li X, Olson RD 1993. Time-related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function. Br. J. Pharmacol 110:975–82
    [Google Scholar]
  34. 34. 
    Blanco JG, Leisenring WM, Gonzalez-Covarrubias VM, Kawashima TI, Davies SM et al. 2008. Genetic polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD(P)H:quinone oxidoreductase 1 gene NQO1 in patients who developed anthracycline-related congestive heart failure after childhood cancer. Cancer 112:2789–95
    [Google Scholar]
  35. 35. 
    Reinbolt RE, Patel R, Pan X, Timmers CD, Pilarski R et al. 2016. Risk factors for anthracycline-associated cardiotoxicity. Support Care Cancer 24:2173–80
    [Google Scholar]
  36. 36. 
    Garcia-Pavia P, Kim Y, Restrepo-Cordoba MA, Lunde IG, Wakimoto H et al. 2019. Genetic variants associated with cancer therapy-induced cardiomyopathy. Circulation 140:31–41
    [Google Scholar]
  37. 37. 
    Pinheiro EA, Fetterman KA, Burridge PW 2019. hiPSCs in cardio-oncology: deciphering the genomics. Cardiovasc. Res. 115:935–48
    [Google Scholar]
  38. 38. 
    Gulati G, Heck SL, Ree AH, Hoffmann P, Schulz-Menger J et al. 2016. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Eur. Heart J. 37:1671–80
    [Google Scholar]
  39. 39. 
    Avila MS, Ayub-Ferreira SM, de Barros Wanderley MR Jr., das Dores Cruz F, Gonçalves Brandão SM et al. 2018. Carvedilol for prevention of chemotherapy-related cardiotoxicity: the CECCY Trial. J. Am. Coll. Cardiol. 71:2281–90
    [Google Scholar]
  40. 40. 
    Sgobbo P, Pacelli C, Grattagliano I, Villani G, Cocco T 2007. Carvedilol inhibits mitochondrial complex I and induces resistance to H2O2-mediated oxidative insult in H9C2 myocardial cells. Biochim. Biophys. Acta Bioenerg. 1767:222–32
    [Google Scholar]
  41. 41. 
    Bosch X, Rovira M, Sitges M, Domènech A, Ortiz-Pérez JT 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. 61:2355–62
    [Google Scholar]
  42. 42. 
    Huelsenbeck J, Henninger C, Schad A, Lackner KJ, Kaina B, Fritz G 2011. Inhibition of Rac1 signaling by lovastatin protects against anthracycline-induced cardiac toxicity. Cell Death Dis 2:e190
    [Google Scholar]
  43. 43. 
    Seicean S, Seicean A, Plana JC, Budd GT, Marwick TH 2012. Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study. J. Am. Coll. Cardiol. 60:2384–90
    [Google Scholar]
  44. 44. 
    Teske AJ, Linschoten M, Kamphuis JAM, Naaktgeboren WR, Leiner T et al. 2018. Cardio-oncology: an overview on outpatient management and future developments. Neth. Heart J. 26:521–32
    [Google Scholar]
  45. 45. 
    Myers C, Bonow R, Palmeri S, Jenkins J, Corden B et al. 1983. A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine. Semin. Oncol. 10:53–55
    [Google Scholar]
  46. 46. 
    Gallegos-Castorena S, Martínez-Avalos A, Mohar-Betancourt A, Guerrero-Avendaño G, Zapata-Tarrés M, Medina-Sansón A 2007. Toxicity prevention with amifostine in pediatric osteosarcoma patients treated with cisplatin and doxorubicin. Pediatr. Hematol. Oncol. 24:403–8
    [Google Scholar]
  47. 47. 
    Waldner R, Laschan C, Lohninger A, Gessner M, Tuchler H et al. 2006. Effects of doxorubicin-containing chemotherapy and a combination with l-carnitine on oxidative metabolism in patients with non-Hodgkin lymphoma. J. Cancer Res. Clin. Oncol. 132:121–28
    [Google Scholar]
  48. 48. 
    Ladas EJ, Jacobson JS, Kennedy DD, Teel K, Fleischauer A, Kelly KM 2004. Antioxidants and cancer therapy: a systematic review. J. Clin. Oncol. 22:517–28
    [Google Scholar]
  49. 49. 
    Iarussi D, Auricchio U, Agretto A, Murano A, Giuliano M et al. 1994. Protective effect of coenzyme Q10 on anthracyclines cardiotoxicity: control study in children with acute lymphoblastic leukemia and non-Hodgkin lymphoma. Mol. Asp. Med. 15:Suppl.s207–12
    [Google Scholar]
  50. 50. 
    El-Kareh AW, Secomb TW. 2000. A mathematical model for comparison of bolus injection, continuous infusion, and liposomal delivery of doxorubicin to tumor cells. Neoplasia 2:325–38
    [Google Scholar]
  51. 51. 
    Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L 2004. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol. Rev. 56:185–229
    [Google Scholar]
  52. 52. 
    van Dalen EC, van der Pal HJ, Caron HN, Kremer LC 2009. Different dosage schedules for reducing cardiotoxicity in cancer patients receiving anthracycline chemotherapy. Cochrane Database Syst. Rev. 4:CD005008
    [Google Scholar]
  53. 53. 
    Smith LA, Cornelius VR, Plummer CJ, Levitt G, Verrill M et al. 2010. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer 10:337
    [Google Scholar]
  54. 54. 
    Ascensão A, Magalhães J, Soares JM, Ferreira R, Neuparth MJ et al. 2005. Moderate endurance training prevents doxorubicin-induced in vivo mitochondriopathy and reduces the development of cardiac apoptosis. Am. J. Physiol. Heart Circ. Physiol. 289:H722–31
    [Google Scholar]
  55. 55. 
    Cai F, Luis MAF, Lin X, Wang M, Cai L et al. 2019. Anthracycline-induced cardiotoxicity in the chemotherapy treatment of breast cancer: preventive strategies and treatment. Mol. Clin. Oncol. 11:15–23
    [Google Scholar]
  56. 56. 
    Stěrba M, Popelová O, Vávrová A, Jirkovský E, Kovaříková P et al. 2013. Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection. Antioxid. Redox Signal. 18:899–929
    [Google Scholar]
  57. 57. 
    Lotrionte M, Biondi-Zoccai G, Abbate A, Lanzetta G, D'Ascenzo F et al. 2013. Review and meta-analysis of incidence and clinical predictors of anthracycline cardiotoxicity. Am. J. Cardiol. 112:1980–84
    [Google Scholar]
  58. 58. 
    Marty M, Espie M, Llombart A, Monnier A, Rapoport BL et al. 2006. Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Ann. Oncol. 17:614–22
    [Google Scholar]
  59. 59. 
    Swain SM, Whaley FS, Gerber MC, Ewer MS, Bianchine JR, Gams RA 1997. Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. J. Clin. Oncol. 15:1333–40
    [Google Scholar]
  60. 60. 
    Swain SM, Whaley FS, Gerber MC, Weisberg S, York M et al. 1997. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J. Clin. Oncol. 15:1318–32
    [Google Scholar]
  61. 61. 
    Shaikh F, Dupuis LL, Alexander S, Gupta A, Mertens L, Nathan PC 2016. Cardioprotection and second malignant neoplasms associated with dexrazoxane in children receiving anthracycline chemotherapy: a systematic review and meta-analysis. J. Natl. Cancer Inst. 108:4djv357
    [Google Scholar]
  62. 62. 
    Buss JL, Hasinoff BB. 1993. The one-ring open hydrolysis product intermediates of the cardioprotective agent ICRF-187 (dexrazoxane) displace iron from iron-anthracycline complexes. Agents Actions 40:86–95
    [Google Scholar]
  63. 63. 
    Lipshultz SE, Cochran TR, Franco VI, Miller TL 2013. Treatment-related cardiotoxicity in survivors of childhood cancer. Nat. Rev. Clin. Oncol. 10:697–710
    [Google Scholar]
  64. 64. 
    Ichikawa Y, Ghanefar M, Bayeva M, Wu R, Khechaduri A et al. 2014. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J. Clin. Investig. 124:617–30
    [Google Scholar]
  65. 65. 
    Classen S, Olland S, Berger JM 2003. Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187. PNAS 100:10629–34
    [Google Scholar]
  66. 66. 
    Lipshultz SE, Rifai N, Dalton VM, Levy DE, Silverman LB et al. 2004. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N. Engl. J. Med. 351:145–53
    [Google Scholar]
  67. 67. 
    Liu Y, Asnani A, Zou L, Bentley VL, Yu M et al. 2014. Visnagin protects against doxorubicin-induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase. Sci. Transl. Med. 6:266ra170
    [Google Scholar]
  68. 68. 
    Asselin BL, Devidas M, Chen L, Franco VI, Pullen J et al. 2016. Cardioprotection and safety of dexrazoxane in patients treated for newly diagnosed T-cell acute lymphoblastic leukemia or advanced-stage lymphoblastic non-Hodgkin lymphoma: a report of the Children's Oncology Group Randomized Trial Pediatric Oncology Group 9404. J. Clin. Oncol. 34:854–62
    [Google Scholar]
  69. 69. 
    Reichardt P, Tabone M-D, Mora J, Morland B, Jones RL 2018. Risk-benefit of dexrazoxane for preventing anthracycline-related cardiotoxicity: re-evaluating the European labeling. Future Oncol 14:2663–76
    [Google Scholar]
  70. 70. 
    Kalay N, Basar E, Ozdogru I, Er O, Cetinkaya Y et al. 2006. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J. Am. Coll. Cardiol. 48:2258–62
    [Google Scholar]
  71. 71. 
    Simůnek T, Stěrba M, Popelová O, Adamcová M, Hrdina R, Gersl V 2009. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol. Rep. 61:154–71
    [Google Scholar]
  72. 72. 
    Xu X, Persson HL, Richardson DR 2005. Molecular pharmacology of the interaction of anthracyclines with iron. Mol. Pharmacol. 68:261–71
    [Google Scholar]
  73. 73. 
    Doroshow JH, Davies KJ. 1986. Redox cycling of anthracyclines by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical. J. Biol. Chem. 261:3068–74
    [Google Scholar]
  74. 74. 
    Winterbourn CC. 1995. Toxicity of iron and hydrogen peroxide: the Fenton reaction. Toxicol. Lett. 82–83:969–74
    [Google Scholar]
  75. 75. 
    Keizer HG, Pinedo HM, Schuurhuis GJ, Joenje H 1990. Doxorubicin (adriamycin): a critical review of free radical-dependent mechanisms of cytotoxicity. Pharmacol. Ther. 47:219–31
    [Google Scholar]
  76. 76. 
    Myers CE, Gianni L, Simone CB, Klecker R, Greene R 1982. Oxidative destruction of erythrocyte ghost membranes catalyzed by the doxorubicin-iron complex. Biochemistry 21:1707–12
    [Google Scholar]
  77. 77. 
    Minotti G, Recalcati S, Mordente A, Liberi G, Calafiore AM et al. 1998. The secondary alcohol metabolite of doxorubicin irreversibly inactivates aconitase/iron regulatory protein-1 in cytosolic fractions from human myocardium. FASEB J 12:541–52
    [Google Scholar]
  78. 78. 
    Miranda CJ, Makui H, Soares RJ, Bilodeau M, Mui J et al. 2003. Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin. Blood 102:2574–80
    [Google Scholar]
  79. 79. 
    Bugger H, Guzman C, Zechner C, Palmeri M, Russell KS, Russell RR III 2011. Uncoupling protein downregulation in doxorubicin-induced heart failure improves mitochondrial coupling but increases reactive oxygen species generation. Cancer Chemother. Pharmacol. 67:1381–88
    [Google Scholar]
  80. 80. 
    Wu XY, Luo AY, Zhou YR, Ren JH 2014. N-acetylcysteine reduces oxidative stress, nuclear factor-κβ activity and cardiomyocyte apoptosis in heart failure. Mol. Med. Rep. 10:615–24
    [Google Scholar]
  81. 81. 
    van Dalen EC, Caron HN, Dickinson HO, Kremer LC 2011. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst. Rev. 6:CD003917
    [Google Scholar]
  82. 82. 
    Jo SH, Kim LS, Kim SA, Kim HS, Han SJ et al. 2013. Evaluation of short-term use of N-acetylcysteine as a strategy for prevention of anthracycline-induced cardiomyopathy: EPOCH Trial—a prospective randomized study. Kor. Circ. J. 43:174–81
    [Google Scholar]
  83. 83. 
    Hasinoff BB, Patel D, Wu X 2003. The oral iron chelator ICL670A (deferasirox) does not protect myocytes against doxorubicin. Free Radic. Biol. Med. 35:1469–79
    [Google Scholar]
  84. 84. 
    Popelová O, Stěrba M, Simůnek T, Mazurová Y, Guncová I et al. 2008. Deferiprone does not protect against chronic anthracycline cardiotoxicity in vivo. J. Pharmacol. Exp. Ther. 326:259–69
    [Google Scholar]
  85. 85. 
    Elihu N, Anandasbapathy S, Frishman WH 1998. Chelation therapy in cardiovascular disease: ethylenediaminetetraacetic acid, deferoxamine, and dexrazoxane. J. Clin. Pharmacol. 38:101–5
    [Google Scholar]
  86. 86. 
    Giordano FJ. 2005. Oxygen, oxidative stress, hypoxia, and heart failure. J. Clin. Investig. 115:500–8
    [Google Scholar]
  87. 87. 
    Goormaghtigh E, Chatelain P, Caspers J, Ruysschaert JM 1980. Evidence of a complex between adriamycin derivatives and cardiolipin: possible role in cardiotoxicity. Biochem. Pharmacol. 29:3003–10
    [Google Scholar]
  88. 88. 
    Childs AC, Phaneuf SL, Dirks AJ, Phillips T, Leeuwenburgh C 2002. Doxorubicin treatment in vivo causes cytochrome c release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio. Cancer Res 62:4592–98
    [Google Scholar]
  89. 89. 
    Tewey KM, Rowe TC, Yang L, Halligan BD, Liu LF 1984. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science 226:466–68
    [Google Scholar]
  90. 90. 
    Wang JC. 2002. Cellular roles of DNA topoisomerases: a molecular perspective. Nat. Rev. Mol. Cell Biol. 3:430–40
    [Google Scholar]
  91. 91. 
    Zhang S, Liu X, Bawa-Khalfe T, Lu LS, Lyu YL et al. 2012. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat. Med. 18:1639–42
    [Google Scholar]
  92. 92. 
    Vavrova A, Jansova H, Mackova E, Machacek M, Haskova P et al. 2013. Catalytic inhibitors of topoisomerase II differently modulate the toxicity of anthracyclines in cardiac and cancer cells. PLOS ONE 8:e76676
    [Google Scholar]
  93. 93. 
    Khiati S, Dalla Rosa I, Sourbier C, Ma X, Rao VA et al. 2014. Mitochondrial topoisomerase I (Top1mt) is a novel limiting factor of doxorubicin cardiotoxicity. Clin. Cancer Res. 20:4873–81
    [Google Scholar]
  94. 94. 
    Lebrecht D, Kokkori A, Ketelsen UP, Setzer B, Walker UA 2005. Tissue-specific mtDNA lesions and radical-associated mitochondrial dysfunction in human hearts exposed to doxorubicin. J. Pathol. 207:436–44
    [Google Scholar]
  95. 95. 
    Lebrecht D, Setzer B, Ketelsen UP, Haberstroh J, Walker UA 2003. Time-dependent and tissue-specific accumulation of mtDNA and respiratory chain defects in chronic doxorubicin cardiomyopathy. Circulation 108:2423–29
    [Google Scholar]
  96. 96. 
    Yin J, Guo J, Zhang Q, Cui L, Zhang L et al. 2018. Doxorubicin-induced mitophagy and mitochondrial damage is associated with dysregulation of the PINK1/parkin pathway. Toxicol. In Vitro 51:1–10
    [Google Scholar]
  97. 97. 
    Cappetta D, Esposito G, Piegari E, Russo R, Ciuffreda LP et al. 2016. SIRT1 activation attenuates diastolic dysfunction by reducing cardiac fibrosis in a model of anthracycline cardiomyopathy. Int. J. Cardiol. 205:99–110
    [Google Scholar]
  98. 98. 
    Vega RB, Horton JL, Kelly DP 2015. Maintaining ancient organelles: mitochondrial biogenesis and maturation. Circ. Res. 116:1820–34
    [Google Scholar]
  99. 99. 
    Kruiswijk F, Labuschagne CF, Vousden KH 2015. p53 in survival, death and metabolic health: a lifeguard with a license to kill. Nat. Rev. Mol. Cell Biol. 16:393–405
    [Google Scholar]
  100. 100. 
    Zhuang J, Ma W, Lago CU, Hwang PM 2012. Metabolic regulation of oxygen and redox homeostasis by p53: lessons from evolutionary biology. ? Free Radic. Biol. Med. 53:1279–85
    [Google Scholar]
  101. 101. 
    Hoshino A, Mita Y, Okawa Y, Ariyoshi M, Iwai-Kanai E et al. 2013. Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart. Nat. Commun. 4:2308
    [Google Scholar]
  102. 102. 
    Dhingra R, Margulets V, Chowdhury SR, Thliveris J, Jassal D et al. 2014. Bnip3 mediates doxorubicin-induced cardiac myocyte necrosis and mortality through changes in mitochondrial signaling. PNAS 111:E5537–44
    [Google Scholar]
  103. 103. 
    Fang X, Wang H, Han D, Xie E, Yang X et al. 2019. Ferroptosis as a target for protection against cardiomyopathy. PNAS 116:2672–80
    [Google Scholar]
  104. 104. 
    Zhu W, Soonpaa MH, Chen H, Shen W, Payne RM et al. 2009. Acute doxorubicin cardiotoxicity is associated with p53-induced inhibition of the mammalian target of rapamycin pathway. Circulation 119:99–106
    [Google Scholar]
  105. 105. 
    Zhu W, Zhang W, Shou W, Field LJ 2014. p53 inhibition exacerbates late-stage anthracycline cardiotoxicity. Cardiovasc. Res. 103:81–89
    [Google Scholar]
  106. 106. 
    Nithipongvanitch R, Ittarat W, Velez JM, Zhao R, St Clair DK, Oberley TD 2007. Evidence for p53 as guardian of the cardiomyocyte mitochondrial genome following acute adriamycin treatment. J. Histochem. Cytochem. 55:629–39
    [Google Scholar]
  107. 107. 
    Li J, Wang PY, Long NA, Zhuang J, Springer DA et al. 2019. p53 prevents doxorubicin cardiotoxicity independently of its prototypical tumor suppressor activities. PNAS 116:19626–34
    [Google Scholar]
  108. 108. 
    Park JH, Zhuang J, Li J, Hwang PM 2016. p53 as guardian of the mitochondrial genome. FEBS Lett 590:924–34
    [Google Scholar]
  109. 109. 
    Park JY, Wang PY, Matsumoto T, Sung HJ, Ma W et al. 2009. p53 improves aerobic exercise capacity and augments skeletal muscle mitochondrial DNA content. Circ. Res. 105:705–12
    [Google Scholar]
  110. 110. 
    Zhuang J, Wang PY, Huang X, Chen X, Kang JG, Hwang PM 2013. Mitochondrial disulfide relay mediates translocation of p53 and partitions its subcellular activity. PNAS 110:17356–61
    [Google Scholar]
  111. 111. 
    Saleme B, Gurtu V, Zhang Y, Kinnaird A, Boukouris AE et al. 2019. Tissue-specific regulation of p53 by PKM2 is redox dependent and provides a therapeutic target for anthracycline-induced cardiotoxicity. Sci. Transl. Med. 11:478eaau8866
    [Google Scholar]
  112. 112. 
    Sala V, Li M, Ghigo A 2019. New avenues in cardio-oncology. Aging 11:1075–76
    [Google Scholar]
  113. 113. 
    Sawyer DB, Zuppinger C, Miller TA, Eppenberger HM, Suter TM 2002. Modulation of anthracycline-induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1β and anti-erbB2: potential mechanism for trastuzumab-induced cardiotoxicity. Circulation 105:1551–54
    [Google Scholar]
  114. 114. 
    Granzier HL, Labeit S. 2004. The giant protein titin: a major player in myocardial mechanics, signaling, and disease. Circ. Res. 94:284–95
    [Google Scholar]
  115. 115. 
    Ali MA, Cho WJ, Hudson B, Kassiri Z, Granzier H, Schulz R 2010. Titin is a target of matrix metalloproteinase-2: implications in myocardial ischemia/reperfusion injury. Circulation 122:2039–47
    [Google Scholar]
  116. 116. 
    Lim CC, Zuppinger C, Guo X, Kuster GM, Helmes M et al. 2004. Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes. J. Biol. Chem. 279:8290–99
    [Google Scholar]
  117. 117. 
    Sala V, Della Sala A, Hirsch E, Ghigo A 2020. Signaling pathways underlying anthracycline cardiotoxicity. Antioxid. Redox Signal. 32:151098–114
    [Google Scholar]
  118. 118. 
    Storr SJ, Carragher NO, Frame MC, Parr T, Martin SG 2011. The calpain system and cancer. Nat. Rev. Cancer 11:364–74
    [Google Scholar]
  119. 119. 
    Galvez AS, Diwan A, Odley AM, Hahn HS, Osinska H et al. 2007. Cardiomyocyte degeneration with calpain deficiency reveals a critical role in protein homeostasis. Circ. Res. 100:1071–78
    [Google Scholar]
  120. 120. 
    Taneike M, Mizote I, Morita T, Watanabe T, Hikoso S et al. 2011. Calpain protects the heart from hemodynamic stress. J. Biol. Chem. 286:32170–77
    [Google Scholar]
  121. 121. 
    Wang Y, Zheng D, Wei M, Ma J, Yu Y et al. 2013. Over-expression of calpastatin aggravates cardiotoxicity induced by doxorubicin. Cardiovasc. Res. 98:381–90
    [Google Scholar]
  122. 122. 
    Leloup L, Wells A. 2011. Calpains as potential anti-cancer targets. Expert Opin. Ther. Targets 15:309–23
    [Google Scholar]
  123. 123. 
    Chan BYH, Roczkowsky A, Moser N, Poirier M, Hughes BG et al. 2018. Doxorubicin induces de novo expression of N-terminal-truncated matrix metalloproteinase-2 in cardiac myocytes. Can. J. Physiol. Pharmacol. 96:1238–45
    [Google Scholar]
  124. 124. 
    Doucet A, Overall CM. 2008. Protease proteomics: revealing protease in vivo functions using systems biology approaches. Mol. Asp. Med. 29:339–58
    [Google Scholar]
  125. 125. 
    McCawley LJ, Matrisian LM. 2001. Matrix metalloproteinases: They're not just for matrix anymore. ! Curr. Opin. Cell Biol. 13:534–40
    [Google Scholar]
  126. 126. 
    Gao CQ, Sawicki G, Suarez-Pinzon WL, Csont T, Wozniak M et al. 2003. Matrix metalloproteinase-2 mediates cytokine-induced myocardial contractile dysfunction. Cardiovasc. Res. 57:426–33
    [Google Scholar]
  127. 127. 
    Wang W, Schulze CJ, Suarez-Pinzon WL, Dyck JR, Sawicki G, Schulz R 2002. Intracellular action of matrix metalloproteinase-2 accounts for acute myocardial ischemia and reperfusion injury. Circulation 106:1543–49
    [Google Scholar]
  128. 128. 
    Sawicki G, Leon H, Sawicka J, Sariahmetoglu M, Schulze CJ et al. 2005. Degradation of myosin light chain in isolated rat hearts subjected to ischemia-reperfusion injury: a new intracellular target for matrix metalloproteinase-2. Circulation 112:544–52
    [Google Scholar]
  129. 129. 
    Sung MM, Schulz CG, Wang W, Sawicki G, Bautista-López NL, Schulz R 2007. Matrix metalloproteinase-2 degrades the cytoskeletal protein α-actinin in peroxynitrite mediated myocardial injury. J. Mol. Cell. Cardiol. 43:429–36
    [Google Scholar]
  130. 130. 
    Bergman MR, Teerlink JR, Mahimkar R, Li L, Zhu BQ et al. 2007. Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction. Am. J. Physiol. Heart Circ. Physiol. 292:H1847–60
    [Google Scholar]
  131. 131. 
    Chan BYH, Roczkowsky A, Cho WJ, Poirier M, Sergi C et al. 2020. MMP inhibitors attenuate doxorubicin cardiotoxicity by preventing intracellular and extracellular matrix remodeling. Cardiovasc. Res. 2020:cvaa017 https://doi.org/10.1093/cvr/cvaa017
    [Crossref] [Google Scholar]
  132. 132. 
    Tanihata J, Nishioka N, Inoue T, Bando K, Minamisawa S 2019. Urinary titin is increased in patients after cardiac surgery. Front. Cardiovasc. Med. 6:7
    [Google Scholar]
  133. 133. 
    Matsuo M, Awano H, Maruyama N, Nishio H 2019. Titin fragment in urine: a noninvasive biomarker of muscle degradation. Adv. Clin. Chem. 90:1–23
    [Google Scholar]
  134. 134. 
    Misaka T, Yoshihisa A, Takeishi Y 2019. Titin in muscular dystrophy and cardiomyopathy: urinary titin as a novel marker. Clin. Chim. Acta 495:123–28
    [Google Scholar]
  135. 135. 
    Zhang T, Zhang Y, Cui M, Jin L, Wang Y et al. 2016. CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis. Nat. Med. 22:175–82
    [Google Scholar]
  136. 136. 
    Meng L, Lin H, Zhang J, Lin N, Sun Z et al. 2019. Doxorubicin induces cardiomyocyte pyroptosis via the TINCR-mediated posttranscriptional stabilization of NLR family pyrin domain containing 3. J. Mol. Cell. Cardiol. 136:15–26
    [Google Scholar]
  137. 137. 
    Zheng X, Zhong T, Ma Y, Wan X, Qin A et al. 2020. Bnip3 mediates doxorubicin-induced cardiomyocyte pyroptosis via caspase-3/GSDME. Life Sci 242:117186
    [Google Scholar]
  138. 138. 
    Zhang J, Ney PA. 2009. Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ 16:939–46
    [Google Scholar]
  139. 139. 
    Arola OJ, Saraste A, Pulkki K, Kallajoki M, Parvinen M, Voipio-Pulkki L-M 2000. Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis. Cancer Res 60:1789–92
    [Google Scholar]
  140. 140. 
    Bartlett JJ, Trivedi PC, Pulinilkunnil T 2017. Autophagic dysregulation in doxorubicin cardiomyopathy. J. Mol. Cell. Cardiol. 104:1–8
    [Google Scholar]
  141. 141. 
    Koleini N, Kardami E. 2017. Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity. Oncotarget 8:46663–80
    [Google Scholar]
  142. 142. 
    Li M, Russo M, Pirozzi F, Tocchetti CG, Ghigo A 2020. Autophagy and cancer therapy cardiotoxicity: from molecular mechanisms to therapeutic opportunities. Biochim. Biophys. Acta Mol. Cell Res. 1867:118493
    [Google Scholar]
  143. 143. 
    Xiao B, Hong L, Cai X, Mei S, Zhang P, Shao L 2019. The true colors of autophagy in doxorubicin-induced cardiotoxicity. Oncol. Lett. 18:2165–72
    [Google Scholar]
  144. 144. 
    Bartlett JJ, Trivedi PC, Yeung P, Kienesberger PC, Pulinilkunnil T 2016. Doxorubicin impairs cardiomyocyte viability by suppressing transcription factor EB expression and disrupting autophagy. Biochem. J. 473:3769–89
    [Google Scholar]
  145. 145. 
    Li DL, Wang ZV, Ding G, Tan W, Luo X et al. 2016. Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation 133:1668–87
    [Google Scholar]
  146. 146. 
    Li M, Sala V, De Santis MC, Cimino J, Cappello P et al. 2018. Phosphoinositide 3-kinase gamma inhibition protects from anthracycline cardiotoxicity and reduces tumor growth. Circulation 138:696–711
    [Google Scholar]
  147. 147. 
    Ejiri J, Inoue N, Kobayashi S, Shiraki R, Otsui K et al. 2005. Possible role of brain-derived neurotrophic factor in the pathogenesis of coronary artery disease. Circulation 112:2114–20
    [Google Scholar]
  148. 148. 
    Meloni M, Caporali A, Graiani G, Lagrasta C, Katare R et al. 2010. Nerve growth factor promotes cardiac repair following myocardial infarction. Circ. Res. 106:1275–84
    [Google Scholar]
  149. 149. 
    Liao D, Zhang C, Liu N, Cao L, Wang C et al. 2020. Involvement of neurotrophic signaling in doxorubicin-induced cardiotoxicity. Exp. Ther. Med. 19:1129–35
    [Google Scholar]
  150. 150. 
    Hang P, Zhao J, Sun L, Li M, Han Y et al. 2017. Brain-derived neurotrophic factor attenuates doxorubicin-induced cardiac dysfunction through activating Akt signalling in rats. J. Cell. Mol. Med. 21:685–96
    [Google Scholar]
  151. 151. 
    Zhao J, Du J, Pan Y, Chen T, Zhao L et al. 2019. Activation of cardiac TrkB receptor by its small molecular agonist 7,8-dihydroxyflavone inhibits doxorubicin-induced cardiotoxicity via enhancing mitochondrial oxidative phosphorylation. Free Radic. Biol. Med. 130:557–67
    [Google Scholar]
  152. 152. 
    Zhang X, Hu C, Kong CY, Song P, Wu HM et al. 2020. FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT. Cell Death Differ 27:540–55
    [Google Scholar]
  153. 153. 
    Hu X, Liu H, Wang Z, Hu Z, Li L 2019. miR-200a attenuated doxorubicin-induced cardiotoxicity through upregulation of Nrf2 in mice. Oxidative Med. Cell. Longev. 2019:1512326
    [Google Scholar]
  154. 154. 
    Li S, Wang W, Niu T, Wang H, Li B et al. 2014. Nrf2 deficiency exaggerates doxorubicin-induced cardiotoxicity and cardiac dysfunction. Oxidative Med. Cell. Longev. 2014:748524
    [Google Scholar]
  155. 155. 
    Zhao L, Qi Y, Xu L, Tao X, Han X et al. 2018. MicroRNA-140-5p aggravates doxorubicin-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2. Redox Biol 15:284–96
    [Google Scholar]
  156. 156. 
    Wojnowski L, Kulle B, Schirmer M, Schluter G, Schmidt A et al. 2005. NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity. Circulation 112:3754–62
    [Google Scholar]
  157. 157. 
    Schneider BP, Shen F, Gardner L, Radovich M, Li L et al. 2017. Genome-wide association study for anthracycline-induced congestive heart failure. Clin. Cancer Res. 23:43–51
    [Google Scholar]
  158. 158. 
    Wells QS, Veatch OJ, Fessel JP, Joon AY, Levinson RT et al. 2017. Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults. Pharmacogenet. Genom. 27:247–54
    [Google Scholar]
  159. 159. 
    Burridge PW, Li YF, Matsa E, Wu H, Ong SG et al. 2016. Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat. Med. 22:547–56
    [Google Scholar]
  160. 160. 
    Ky B, Putt M, Sawaya H, French B, Januzzi JL Jr. et al. 2014. Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab. J. Am. Coll. Cardiol. 63:809–16
    [Google Scholar]
  161. 161. 
    Chaosuwannakit N, D'Agostino R Jr., Hamilton CA, Lane KS, Ntim WO et al. 2010. Aortic stiffness increases upon receipt of anthracycline chemotherapy. J. Clin. Oncol. 28:166–72
    [Google Scholar]
  162. 162. 
    Jenkins GR, Lee T, Moland CL, Vijay V, Herman EH et al. 2016. Sex-related differential susceptibility to doxorubicin-induced cardiotoxicity in B6C3F1 mice. Toxicol. Appl. Pharmacol. 310:159–74
    [Google Scholar]
  163. 163. 
    Rafiyath SM, Rasul M, Lee B, Wei G, Lamba G, Liu D 2012. Comparison of safety and toxicity of liposomal doxorubicin versus conventional anthracyclines: a meta-analysis. Exp. Hematol. Oncol. 1:10
    [Google Scholar]
  164. 164. 
    Gabizon A, Shmeeda H, Barenholz Y 2003. Pharmacokinetics of pegylated liposomal doxorubicin: review of animal and human studies. Clin. Pharmacokinet. 42:419–36
    [Google Scholar]
  165. 165. 
    Bigagli E, Luceri C, De Angioletti M, Chegaev K, D'Ambrosio M et al. 2018. New NO- and H2S-releasing doxorubicins as targeted therapy against chemoresistance in castration-resistant prostate cancer: in vitro and in vivo evaluations. Investig. New Drugs 36:985–98
    [Google Scholar]
  166. 166. 
    Chamberlain GR, Tulumello DV, Kelley SO 2013. Targeted delivery of doxorubicin to mitochondria. ACS Chem. Biol. 8:1389–95
    [Google Scholar]
  167. 167. 
    Buondonno I, Gazzano E, Jean SR, Audrito V, Kopecka J et al. 2016. Mitochondria-targeted doxorubicin: a new therapeutic strategy against doxorubicin-resistant osteosarcoma. Mol. Cancer Ther. 15:2640–52
    [Google Scholar]
  168. 168. 
    Sun N, Zhao C, Cheng R, Liu Z, Li X et al. 2018. Cargo-free nanomedicine with pH sensitivity for codelivery of DOX conjugated prodrug with SN38 to synergistically eradicate breast cancer stem cells. Mol. Pharm. 15:3343–55
    [Google Scholar]
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