Progress in Cardiovascular Diseases
Volume 53, Issue 2 , Pages 105-113 , September 2010

Mechanisms of Anthracycline Cardiac Injury: Can We Identify Strategies for Cardioprotection?

  • Douglas B. Sawyer

      Affiliations

    • Department of Medicine, Vanderbilt University, Nashville, TN
    • Corresponding Author InformationAddress reprint requests to Douglas B. Sawyer, 383 Preston Research Building, 2220 Pierce Avenue, Vanderbilt University, Nashville, TN 37232.
  • ,
  • Xuyang Peng

      Affiliations

    • Department of Medicine, Vanderbilt University, Nashville, TN
  • ,
  • Billy Chen

      Affiliations

    • Department of Molecular Medicine, Boston University, Boston, MA
  • ,
  • Laura Pentassuglia

      Affiliations

    • Department of Medicine, Vanderbilt University, Nashville, TN
  • ,
  • Chee Chew Lim

      Affiliations

    • Department of Medicine, Vanderbilt University, Nashville, TN

References 

  1. Gewirtz DA. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol. 1999;57:727–741
  2. Minotti G, Menna P, Salvatorelli E, et al. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004;56:185–229
  3. Legha SS, Benjamin RS, Mackay B, et al. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med. 1982;96:133–139
  4. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97:2869–2879
  5. Balanehru S, Nagarajan B. Intervention of adriamycin induced free radical damage. Biochem Int. 1992;28:735–744
  6. Fogli S, Nieri P, Breschi MC. The role of nitric oxide in anthracycline toxicity and prospects for pharmacologic prevention of cardiac damage. FASEB J. 2004;18:664–675
  7. Mihm MJ, Bauer JA. Peroxynitrite-induced inhibition and nitration of cardiac myofibrillar creatine kinase. Biochimie. 2002;84:1013–1019
  8. Tokarska-Schlattner M, Wallimann T, Schlattner U. Multiple interference of anthracyclines with mitochondrial creatine kinases: preferential damage of the cardiac isoenzyme and its implications for drug cardiotoxicity. Mol Pharmacol. 2002;61:516–523
  9. Olson RD, Mushlin PS. Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. FASEB J. 1990;4:3076–3086
  10. Ito H, Miller SC, Billingham ME, et al. Doxorubicin selectively inhibits muscle gene expression in cardiac muscle cells in vivo and in vitro. Proc Natl Acad Sci U S A. 1990;87:4275–4279
  11. Jeyaseelan R, Poizat C, Baker RK, et al. A novel cardiac-restricted target for doxorubicin. CARP, a nuclear modulator of gene expression in cardiac progenitor cells and cardiomyocytes. J Biol Chem. 1997;272:22800–22808
  12. Jeyaseelan R, Poizat C, Wu HY, et al. Molecular mechanisms of doxorubicin-induced cardiomyopathy. Selective suppression of Reiske iron-sulfur protein, ADP/ATP translocase, and phosphofructokinase genes is associated with ATP depletion in rat cardiomyocytes. J Biol Chem. 1997;272:5828–5832
  13. Lim CC, Zuppinger C, Guo X, et al. Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes. J Biol Chem. 2004;279:8290–8299
  14. Fu M, Matoba M, Liang QM, et al. Properties of G-protein modulated receptor-adenylyl cyclase system in myocardium of spontaneously hypertensive rats treated with adriamycin. Int J Cardiol. 1994;44:9–18
  15. Calderone A, de Champlain J, Rouleau JL. Adriamycin-induced changes to the myocardial beta-adrenergic system in the rabbit. J Mol Cell Cardiol. 1991;23:333–342
  16. Takahashi S, Denvir MA, Harder L, et al. Effects of in vitro and in vivo exposure to doxorubicin (adriamycin) on caffeine-induced Ca2+ release from sarcoplasmic reticulum and contractile protein function in ‘chemically-skinned’ rabbit ventricular trabeculae. Jpn J Pharmacol. 1998;76:405–413
  17. Unverferth DV, Fertel RH, Talley RL, et al. The effect of first-dose doxorubicin on the cyclic nucleotide levels of the human myocardium. Toxicol Appl Pharmacol. 1981;60:151–154
  18. Lipshultz SE, Rifai N, Sallan SE, et al. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation. 1997;96:2641–2648
  19. Arola OJ, Saraste A, Pulkki K, et al. Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis. Cancer Res. 2000;60:1789–1792
  20. Sawyer DB, Fukazawa R, Arstall MA, et al. Daunorubicin-induced apoptosis in rat cardiac myocytes is inhibited by dexrazoxane. Circ Res. 1999;84:257–265
  21. Buzdar AU, Marcus C, Smith TL, et al. Early and delayed clinical cardiotoxicity of doxorubicin. Cancer. 1985;55:2761–2765
  22. Gille L, Nohl H. Analyses of the molecular mechanism of adriamycin-induced cardiotoxicity. Free Radic Biol Med. 1997;23:775–782
  23. Pouna P, Bonoron-Adèle S, Gouverneur G, et al. Development of the model of rat isolated perfused heart for the evaluation of anthracycline cardiotoxicity and its circumvention. Br J Pharmacol. 1996;117:1593–1599
  24. Rajagopalan S, Politi PM, Sinha BK, et al. Adriamycin-induced free radical formation in the perfused rat heart: implications for cardiotoxicity. Cancer Res. 1988;48:4766–4769
  25. Yen HC, Oberley TD, Vichitbandha S, et al. The protective role of manganese superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice. J Clin Invest. 1996;98:1253–1260
  26. Wiseman LR, Spencer CM. Dexrazoxane. A review of its use as a cardioprotective agent in patients receiving anthracycline-based chemotherapy. Drugs. 1998;56:385–403
  27. Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med. 2004;351:145–153
  28. Zhang W, Elimban V, Nijjar MS, et al. Role of mitogen-activated protein kinase in cardiac hypertrophy and heart failure. Exp Clin Cardiol. 2003;8:173–183
  29. Lorenz K, Schmitt JP, Vidal M, et al. Cardiac hypertrophy: targeting Raf/MEK/ERK1/2-signaling. Int J Biochem Cell Biol. 2009;41:2351–2355
  30. Petrich BG, Wang Y. Stress-activated MAP kinases in cardiac remodeling and heart failure; new insights from transgenic studies. Trends Cardiovasc Med. 2004;14:50–55
  31. Laderoute KR, Webster KA. Hypoxia/reoxygenation stimulates Jun kinase activity through redox signaling in cardiac myocytes. Circ Res. 1997;80:336–344
  32. Xia Z, Dickens M, Raingeaud J, et al. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 1995;270:1326–1331
  33. Matsui T, Tao J, del Monte F, et al. Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation. 2001;104:330–335
  34. Matsui T, Davidoff AJ. Assessment of PI-3 kinase and Akt in ischemic heart diseases in diabetes. Methods Mol Med. 2007;139:329–338
  35. Chao W, Matsui T, Novikov MS, et al. Strategic advantages of insulin-like growth factor-I expression for cardioprotection. J Gene Med. 2003;5:277–286
  36. Hong F, Kwon SJ, Jhun BS, et al. Insulin-like growth factor-1 protects H9c2 cardiac myoblasts from oxidative stress-induced apoptosis via phosphatidylinositol 3-kinase and extracellular signal-regulated kinase pathways. Life Sci. 2001;68:1095–1105
  37. Lai HC, Liu TJ, Ting CT, et al. Insulin-like growth factor-1 prevents loss of electrochemical gradient in cardiac muscle mitochondria via activation of PI 3 kinase/Akt pathway. Mol Cell Endocrinol. 2003;205:99–106
  38. Fukazawa R, Miller TA, Kuramochi Y, et al. Neuregulin-1 protects ventricular myocytes from anthracycline-induced apoptosis via erbB4-dependent activation of PI3-kinase/Akt. J Mol Cell Cardiol. 2003;35:1473–1479
  39. Childs AC, Phaneuf SL, Dirks AJ, et al. 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. 2002;62:4592–4598
  40. An J, Li P, Li J, et al. ARC is a critical cardiomyocyte survival switch in doxorubicin cardiotoxicity. J Mol Med. 2009;87:401–410
  41. Kleiner Y, Bar-Am O, Amit T, et al. TVP1022 and propargylamine protect neonatal rat ventricular myocytes against doxorubicin-induced and serum starvation-induced cardiotoxicity. J Cardiovasc Pharmacol. 2008;52:268–277
  42. Goswami SK, Das DK. Autophagy in the myocardium: dying for survival?. Exp Clin Cardiol. 2006;11:183–188
  43. Jang YM, Kendaiah S, Drew B, et al. Doxorubicin treatment in vivo activates caspase-12 mediated cardiac apoptosis in both male and female rats. FEBS Lett. 2004;577:483–490
  44. Sorensen BS, Sinding J, Andersen AH, et al. Mode of action of topoisomerase II-targeting agents at a specific DNA sequence. Uncoupling the DNA binding, cleavage and religation events. J Mol Biol. 1992;228:778–786
  45. Charron F, Nemer M. GATA transcription factors and cardiac development. Semin Cell Dev Biol. 1999;10:85–91
  46. Charron F, Paradis P, Bronchain O, et al. Cooperative interaction between GATA-4 and GATA-6 regulates myocardial gene expression. Mol Cell Biol. 1999;19:4355–4365
  47. Grillot DA, González-García M, Ekhterae D, et al. Genomic organization, promoter region analysis, and chromosome localization of the mouse bcl-x gene. J Immunol. 1997;158:4750–4757
  48. Kim Y, Ma AG, Kitta K, et al. Anthracycline-induced suppression of GATA-4 transcription factor: implication in the regulation of cardiac myocyte apoptosis. Mol Pharmacol. 2003;63:368–377
  49. Aries A, Paradis P, Lefebvre C, et al. Essential role of GATA-4 in cell survival and drug-induced cardiotoxicity. Proc Natl Acad Sci U S A. 2004;101:6975–6980
  50. Cardinale D, Colombo A, Lamantia G, et al. Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol. 2010;55:213–220
  51. Rowan RA, Masek MA, Billingham ME. Ultrastructural morphometric analysis of endomyocardial biopsies. Idiopathic dilated cardiomyopathy, anthracycline cardiotoxicity, and normal myocardium. Am J Cardiovasc Pathol. 1988;2:137–144
  52. Mackay B, Ewer MS, Carrasco CH, et al. Assessment of anthracycline cardiomyopathy by endomyocardial biopsy. Ultrastruct Pathol. 1994;18:203–211
  53. Mortensen SA, Olsen HS, Baandrup U. Chronic anthracycline cardiotoxicity: haemodynamic and histopathological manifestations suggesting a restrictive endomyocardial disease. Br Heart J. 1986;55:274–282
  54. Helmes M, Trombitas K, Granzier H. Titin develops restoring force in rat cardiac myocytes. Circ Res. 1996;79:619–626
  55. Wang SM, Greaser ML, Schultz E, et al. Studies on cardiac myofibrillogenesis with antibodies to titin, actin, tropomyosin, and myosin. J Cell Biol. 1988;107:1075–1083
  56. Helmes M, Lim CC, Liao R, et al. Titin determines the Frank-Starling relation in early diastole. J Gen Physiol. 2003;121:97–110
  57. Bang ML, Mudry RE, McElhinny AS, et al. Myopalladin, a novel 145-kilodalton sarcomeric protein with multiple roles in Z-disc and I-band protein assemblies. J Cell Biol. 2001;153:413–427
  58. Poizat C, Sartorelli V, Chung G, et al. Proteasome-mediated degradation of the coactivator p300 impairs cardiac transcription. Mol Cell Biol. 2000;20:8643–8654
  59. Rajkumar T, Gullick WJ. The type I growth factor receptors in human breast cancer. Breast Cancer Res Treat. 1994;29:3–9
  60. Klapper LN, Kirschbaum MH, Sela M, et al. Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. Adv Cancer Res. 2000;77:25–79
  61. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–182
  62. Fendly BM, Kotts C, Vetterlein D, et al. The extracellular domain of HER2/neu is a potential immunogen for active specific immunotherapy of breast cancer. J Biol Response Mod. 1990;9:449–455
  63. Sliwkowski MX, Lofgren JA, Lewis GD, et al. Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol. 1999;26(4 Suppl 12):60–70
  64. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–792
  65. Feldman AM, Lorell BH, Reis SE. Trastuzumab in the treatment of metastatic breast cancer : anticancer therapy versus cardiotoxicity. Circulation. 2000;102:272–274
  66. Ewer MS, Vooletich MT, Durand JB, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol. 2005;23:7820–7826
  67. Negro A, Brar BK, Lee KF. Essential roles of Her2/erbB2 in cardiac development and function. Recent Prog Horm Res. 2004;59:1–12
  68. Ozcelik C, Erdmann B, Pilz B, et al. Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc Natl Acad Sci U S A. 2002;99:8880–8885
  69. Crone SA, Zhao YY, Fan L, et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med. 2002;8:459–465
  70. Zhao YY, Sawyer DR, Baliga RR, et al. Neuregulins promote survival and growth of cardiac myocytes. Persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes. J Biol Chem. 1998;273:10261–10269
  71. Sawyer DB, Zuppinger C, Miller TA, et al. Modulation of anthracycline-induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1beta and anti-erbB2: potential mechanism for trastuzumab-induced cardiotoxicity. Circulation. 2002;105:1551–1554
  72. Chung KY, Walker JW. Interaction and inhibitory cross-talk between endothelin and ErbB receptors in the adult heart. Mol Pharmacol. 2007;71:1494–1502
  73. Lipshultz SE. Dexrazoxane for protection against cardiotoxic effects of anthracyclines in children. J Clin Oncol. 1996;14:328–331
  74. Swain SM, Vici P. The current and future role of dexrazoxane as a cardioprotectant in anthracycline treatment: expert panel review. J Cancer Res Clin Oncol. 2004;130:1–7
  75. Liu FF, Stone JR, Schuldt AJ, et al. Heterozygous knockout of neuregulin-1 gene in mice exacerbates doxorubicin-induced heart failure. Am J Physiol Heart Circ Physiol. 2005;289:H660–666
  76. Kunisada K, Negoro S, Tone E, et al. Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy. Proc Natl Acad Sci U S A. 2000;97:315–319
  77. Suliman HB, Carraway MS, Ali AS, et al. The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy. J Clin Invest. 2007;117:3730–3741
  78. Suzuki YJ, Evans T. Regulation of cardiac myocyte apoptosis by the GATA-4 transcription factor. Life Sci. 2004;74:1829–1838
  79. Peng XI, Basak , Zhong L, et al. Membrane protein P-glycoprotein expression and activity in cardiac myocytes is regulated by ErbB2 signaling. Circulation. 2009;Abstract for American Heart Association Basic Research Annual Meeting 2009
  80. Lebrasseur NK, Coté GM, Miller TA, et al. Regulation of neuregulin/ErbB signaling by contractile activity in skeletal muscle. Am J Physiol Cell Physiol. 2003;284:C1149–1155
  81. LeBrasseur NK, Mizer KC, Parkington JD, et al. The expression of neuregulin and erbB receptors in human skeletal muscle: effects of progressive resistance training. Eur J Appl Physiol. 2005;94:371–375
  82. Jo SA, Zhu X, Marchionni MA, et al. Neuregulins are concentrated at nerve-muscle synapses and activate ACh-receptor gene expression. Nature. 1995;373:158–161
  83. Peng X, Chen B, Lim CC, et al. The cardiotoxicology of anthracycline chemotherapeutics: translating molecular mechanism into preventative medicine. Mol Interv. 2005;5:163–171
  84. Rechnitzer PA, Cunningham DA, Andrew GM, et al. Relation of exercise to the recurrence rate of myocardial infarction in men. Ontario Exercise-Heart Collaborative Study. Am J Cardiol. 1983;51:65–69
  85. Chandrashekhar Y, Anand IS. Exercise as a coronary protective factor. Am Heart J. 1991;122:1723–1739
  86. Physical Activity Guidelines Advisory Committee report, 2008. To the Secretary of Health and Human Services. Part A: executive summary. Nutr Rev. 2009;67:114–120
  87. Levine MN, Gafni A. Clinical decision making vs programme evaluation perspectives. Pharmacoeconomics. 1993;4:228–231
  88. Wiseman M. The second World Cancer Research Fund/American Institute for Cancer Research expert report. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Proc Nutr Soc. 2008;67:253–256
  89. Mock V, Frangakis C, Davidson NE, et al. Exercise manages fatigue during breast cancer treatment: a randomized controlled trial. Psychooncology. 2005;14:464–477
  90. Segal R, Evans W, Johnson D, et al. Structured exercise improves physical functioning in women with stages I and II breast cancer: results of a randomized controlled trial. J Clin Oncol. 2001;19:657–665
  91. Pinto BM, Frierson GM, Rabin C, et al. Home-based physical activity intervention for breast cancer patients. J Clin Oncol. 2005;23:3577–3587
  92. Kanter MM, Hamlin RL, Unverferth DV, et al. Effect of exercise training on antioxidant enzymes and cardiotoxicity of doxorubicin. J Appl Physiol. 1985;59:1298–1303
  93. Melling CW, Thorp DB, Noble EG. Regulation of myocardial heat shock protein 70 gene expression following exercise. J Mol Cell Cardiol. 2004;37:847–855
  94. Ito H, Shimojo T, Fujisaki H, et al. Thermal preconditioning protects rat cardiac muscle cells from doxorubicin-induced apoptosis. Life Sci. 1999;64:755–761

 Statement of Conflict of Interest: see page 110.

PII: S0033-0620(10)00119-2

doi: 10.1016/j.pcad.2010.06.007

Progress in Cardiovascular Diseases
Volume 53, Issue 2 , Pages 105-113 , September 2010