Archivum Immunologiae et Therapiae Experimentalis

, Volume 57, Issue 6, pp 435–445 | Cite as

Cardiomyocyte death in doxorubicin-induced cardiotoxicity



Doxorubicin (DOX) is one of the most widely used and successful antitumor drugs, but its cumulative and dose-dependent cardiac toxicity has been a major concern of oncologists in cancer therapeutic practice for decades. With the increasing population of cancer survivors, there is a growing need to develop preventive strategies and effective therapies against DOX-induced cardiotoxicity, in particular late-onset cardiomyopathy. Although intensive investigations on DOX-induced cardiotoxicity have continued for decades, the underlying mechanisms responsible for DOX-induced cardiotoxicity have not been completely elucidated. A rapidly expanding body of evidence supports the notion that cardiomyocyte death by apoptosis and necrosis is a primary mechanism of DOX-induced cardiomyopathy and that other types of cell death, such as autophagy and senescence/aging, may participate in this process. This review focuses on the current understanding of the molecular mechanisms underlying DOX-induced cardiomyocyte death, including the major primary mechanism of excess production of reactive oxygen species (ROS) and other recently discovered ROS-independent mechanisms. The different sensitivities to DOX-induced cell death signals between adult and young cardiomyocytes will also be discussed.


cardiomyocyte doxorubicin apoptosis necrosis autophagy 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aihara Y, Kurabayashi M, Tanaka T et al (2000) Doxorubicin represses CARP gene transcription through the generation of oxidative stress in neonatal rat cardiac myocytes: possible role of serine/threonine kinase-dependent pathways. J Mol Cell Cardiol 32: 1401–1414PubMedCrossRefGoogle Scholar
  2. Aliprantis AO, Yang RB, Weiss DS et al (2000) The apoptotic signaling pathway activated by Toll-like receptor-2. EMBO J 19: 3325–3336PubMedCrossRefGoogle Scholar
  3. An J, Li P, Li J et al (2009) ARC is a critical cardiomyocyte survival switch in doxorubicin cardiotoxicity. J Mol Med 87: 401–410PubMedCrossRefGoogle Scholar
  4. Aries A, Paradis P, Lefebvre C et al (2004) Essential role of GATA-4 in cell survival and drug-induced cardiotoxicity. Proc Natl Acad Sci USA 101: 6975–6980PubMedCrossRefGoogle Scholar
  5. Armstrong SC (2004) Anti-oxidants and apoptosis: attenuation of doxorubicin induced cardiomyopathy by carvedilol. J Mol Cell Cardiol 37: 817–821PubMedCrossRefGoogle Scholar
  6. Arola OJ, Saraste A, Pulkki K et al (2000) Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis. Cancer Res 60: 1789–1792PubMedGoogle Scholar
  7. Bahi N, Zhang J, Llovera M et al (2006) Switch from caspasedependent to caspase-independent death during heart development: essential role of endonuclease G in ischemia-induced DNA processing of differentiated cardiomyocytes. J Biol Chem 281: 22943–22952PubMedCrossRefGoogle Scholar
  8. Bast A, Haenen GR, Bruynzeel AM et al (2007) Protection by flavonoids against anthracycline cardiotoxicity: from chemistry to clinical trials. Cardiovasc Toxicol 7: 154–159PubMedCrossRefGoogle Scholar
  9. Bennink RJ, VanDen Hoff MJ, Van Hemert FJ et al (2004) Annexin V imaging of acute doxorubicin cardiotoxicity (apoptosis) in rats. J Nucl Med 45: 842–848PubMedGoogle Scholar
  10. Bergmann MW, Zelarayan L, Gehrke C (2008) Treatment-sensitive premature renal and heart senescence in hypertension. Hypertension 52: 61–62PubMedCrossRefGoogle Scholar
  11. Bernhard D, Laufer G (2008) The aging cardiomyocyte: a mini-review. Gerontology 54: 24–31PubMedCrossRefGoogle Scholar
  12. Bernuzzi F, Recalcati S, Alberghini A et al (2009) Reactive oxygen species-independent apoptosis in doxorubicin-treated H9c2 cardiomyocytes: role for heme oxygenase-1 down-modulation. Chem Biol Interact 177: 12–20PubMedCrossRefGoogle Scholar
  13. Bruynzeel AM, Abou El Hassan MA, Torun E et al (2007) Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells. Br J Cancer 96: 450–456PubMedCrossRefGoogle Scholar
  14. Burgess DH, Svensson M, Dandrea T et al (1999) Human skeletal muscle cytosols are refractory to cytochrome c-dependent activation of type-II caspases and lack APAF-1. Cell Death Differ 6: 256–261PubMedCrossRefGoogle Scholar
  15. Burkhart DJ, Barthel BL, Post GC et al (2006) Design, synthesis, and preliminary evaluation of doxazolidine carbamates as prodrugs activated by carboxylesterases. J Med Chem 49: 7002–7012PubMedCrossRefGoogle Scholar
  16. Camello-Almaraz C, Gomez-Pinilla PJ, Pozo MJ et al (2006) Mitochondrial reactive oxygen species and Ca2+ signaling. Am J Physiol Cell Physiol 291: C1082–1088PubMedCrossRefGoogle Scholar
  17. Casey TM, Arthur PG, Bogoyevitch MA (2007) Necrotic death without mitochondrial dysfunction-delayed death of cardiac myocytes following oxidative stress. Biochim Biophys Acta 1773: 342–351PubMedCrossRefGoogle Scholar
  18. Chang J, Xie M, Shah VR et al (2006) Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosis. Proc Natl Acad Sci USA 103: 14495–14500PubMedCrossRefGoogle Scholar
  19. Childs AC, Phaneuf SL, Dirks AJ et al (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: 4592–4598PubMedGoogle Scholar
  20. Chua CC, Liu X, Gao J et al (2006) Multiple actions of pifithrin-alpha on doxorubicin-induced apoptosis in rat myoblastic H9c2 cells. Am J Physiol Heart Circ Physiol. 290: H2606–2613PubMedCrossRefGoogle Scholar
  21. Cusack BJ, Musser B, Gambliel H et al (2003) Effect of dexrazoxane on doxorubicin pharmacokinetics in young and old rats. Cancer Chemother Pharmacol 51: 139–146PubMedGoogle Scholar
  22. D’Anglemont De Tassigny A, Souktani R, Henry P et al (2004) Volume-sensitive chloride channels (ICl,vol) mediate doxorubicin-induced apoptosis through apoptotic volume decrease in cardiomyocytes. Fundam Clin Pharmacol 18: 531–538CrossRefGoogle Scholar
  23. Davani S, Deschaseaux F, Chalmers D et al (2005) Can stem cells mend a broken heart? Cardiovasc Res 65: 305–316PubMedCrossRefGoogle Scholar
  24. De Meyer GR, Martinet W (2008) Autophagy in the cardiovascular system. Biochim Biophys Acta 1793: 1485–1495PubMedGoogle Scholar
  25. Deniaud A, Sharaf El Dein O, Maillier E et al (2008) Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. Oncogene 27: 285–299PubMedCrossRefGoogle Scholar
  26. Diwan A, Matkovich SJ, Yuan Q et al (2009) Endoplasmic reticulum-mitochondria crosstalk in NIX-mediated murine cell death. J Clin Invest 119: 203–212PubMedGoogle Scholar
  27. Dorn GW 2nd (2009) Apoptotic and non-apoptotic programmed cardiomyocyte death in ventricular remodelling. Cardiovasc Res 81: 465–473PubMedCrossRefGoogle Scholar
  28. Fan GC, Zhou X, Wang X et al (2008) Heat shock protein 20 interacting with phosphorylated Akt reduces doxorubicin-triggered oxidative stress and cardiotoxicity. Circ Res 103: 1270–1279PubMedCrossRefGoogle Scholar
  29. Fisher PW, Salloum F, Das A et al (2005) Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation 111: 1601–1610PubMedCrossRefGoogle Scholar
  30. Gen W, Tani M, Takeshita J et al (2001) Mechanisms of Ca2+ overload induced by extracellular H2O2 in quiescent isolated rat cardiomyocytes. Basic Res Cardiol 96: 623–629PubMedCrossRefGoogle Scholar
  31. Gianni L, Herman EH, Lipshultz SE et al (2008) Anthracycline cardiotoxicity: from bench to bedside. J Clin Oncol 26: 3777–3784PubMedCrossRefGoogle Scholar
  32. Gustafsson AB, Gottlieb RA (2008) Heart mitochondria: gates of life and death. Cardiovasc Res 77: 334–343PubMedCrossRefGoogle Scholar
  33. Gustafsson AB, Gottlieb RA (2009) Autophagy in ischemic heart disease. Circ Res 104: 150–158PubMedCrossRefGoogle Scholar
  34. Hensley ML, Hagerty KL, Kewalramani T et al (2009) American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol 27: 127–145PubMedCrossRefGoogle Scholar
  35. Hoyer-Hansen M, Bastholm L, Szyniarowski P et al (2007) Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol Cell 25: 193–205PubMedCrossRefGoogle Scholar
  36. Iarussi D, Indolfi P, Casale F et al (2001) Recent advances in the prevention of anthracycline cardiotoxicity in childhood. Curr Med Chem 8: 1649–1660PubMedGoogle Scholar
  37. Ikegami E, Fukazawa R, Kanbe M et al (2007) Edaravone, a potent free radical scavenger, prevents anthracycline-induced myocardial cell death. Circ J 71: 1815–1820PubMedCrossRefGoogle Scholar
  38. Ito T, Fujio Y, Takahashi K et al (2007) Degradation of NFAT5, a transcriptional regulator of osmotic stress-related genes, is a critical event for doxorubicin-induced cytotoxicity in cardiac myocytes. J Biol Chem 282: 1152–1160PubMedCrossRefGoogle Scholar
  39. Jang Y M, Kendaiah S, Drew B et al (2004) Doxorubicin treatment in vivo activates caspase-12 mediated cardiac apoptosis in both male and female rats. FEBS Lett 577: 483–490PubMedCrossRefGoogle Scholar
  40. Jeyaseelan R, Poizat C, Baker RK et al (1997) A novel cardiac- restricted target for doxorubicin. CARP, a nuclear modulator of gene expression in cardiac progenitor cells and cardiomyocytes. J Biol Chem 272: 22800–22808PubMedCrossRefGoogle Scholar
  41. Kajstura J, Rota M, Urbanek K et al (2006) The telomere-telomerase axis and the heart. Antioxid Redox Signal 8: 2125–2141PubMedCrossRefGoogle Scholar
  42. Kalivendi SV, Konorev EA, Cunningham S et al (2005) Doxorubicin activates nuclear factor of activated T-lymphocytes and Fas ligand transcription: role of mitochondrial reactive oxygen species and calcium. Biochem J 389: 527–539PubMedCrossRefGoogle Scholar
  43. Kawamura T, Hasegawa K, Morimoto T et al (2004) Expression of p300 protects cardiac myocytes from apoptosis in vivo. Biochem Biophys Res Commun 315: 733–738PubMedCrossRefGoogle Scholar
  44. Khan M, Varadharaj S, Shobha JC et al (2006) C-phycocyanin ameliorates doxorubicin-induced oxidative stress and apoptosis in adult rat cardiomyocytes. J Cardiovasc Pharmacol 47: 9–20PubMedCrossRefGoogle Scholar
  45. Kim DS, Kim HR, Woo ER et al (2005) Inhibitory effects of rosmarinic acid on adriamycin-induced apoptosis in H9c2 cardiac muscle cells by inhibiting reactive oxygen species and the activations of c-Jun N-terminal kinase and extracellular signal-regulated kinase. Biochem Pharmacol 70: 1066–1078PubMedCrossRefGoogle Scholar
  46. Kim DS, Woo ER, Chae SW et al (2007) Plantainoside D protects adriamycin-induced apoptosis in H9c2 cardiac muscle cells via the inhibition of ROS generation and NF-kappaB activation. Life Sci 80: 314–323PubMedCrossRefGoogle Scholar
  47. Kim SY, Kim SJ, Kim BJ et al (2006) Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+ increase are reciprocally modulated in rat cardiomyocytes. Exp Mol Med 38: 535–545PubMedGoogle Scholar
  48. Kim Y, Ma AG, Kitta K et al (2003) Anthracycline-induced suppression of GATA-4 transcription factor: implication in the regulation of cardiac myocyte apoptosis. Mol Pharmacol 63: 368–377PubMedCrossRefGoogle Scholar
  49. Kluza J, Marchetti P, Gallego MA et al (2004) Mitochondrial proliferation during apoptosis induced by anticancer agents: effects of doxorubicin and mitoxantrone on cancer and cardiac cells. Oncogene 23: 7018–7030PubMedCrossRefGoogle Scholar
  50. Konorev EA, Vanamala S, Kalyanaraman B (2008) Differences in doxorubicin-induced apoptotic signaling in adult and immature cardiomyocytes. Free Radic Biol Med 45: 1723–1728PubMedCrossRefGoogle Scholar
  51. Kotamraju S, Konorev EA, Joseph J et al (2000) Doxorubicin- induced apoptosis in endothelial cells and cardiomyocytes is ameliorated by nitrone spin traps and ebselen. Role of reactive oxygen and nitrogen species. J Biol Chem 275: 33585–33592PubMedCrossRefGoogle Scholar
  52. Kratz F, Ehling G, Kauffmann HM et al (2007) Acute and repeat-dose toxicity studies of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH), an albumin-binding prodrug of the anticancer agent doxorubicin. Hum Exp Toxicol 26: 19–35PubMedCrossRefGoogle Scholar
  53. L’Ecuyer T, Sanjeev S, Thomas R et al (2006) DNA damage is an early event in doxorubicin-induced cardiac myocyte death. Am J Physiol Heart Circ Physiol 291: H1273–280PubMedCrossRefGoogle Scholar
  54. Lebrecht D, Geist A, Ketelsen UP et al (2007) The 6-maleimidocaproyl hydrazone derivative of doxorubicin (DOXO-EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage. Int J Cancer 120: 927–934PubMedCrossRefGoogle Scholar
  55. Lebrecht D, Geist A, Ketelsen UP et al (2007) Dexrazoxane prevents doxorubicin-induced long-term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats. Br J Pharmacol 151: 771–778PubMedCrossRefGoogle Scholar
  56. Lebrecht D, Walker UA (2007) Role of mtDNA lesions in anthracycline cardiotoxicity. Cardiovasc Toxicol 7: 108–113PubMedCrossRefGoogle Scholar
  57. Levine B, Sinha S, Kroemer G (2008) Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy 4: 600–606PubMedGoogle Scholar
  58. Li H, Gu H, Sun B (2007) Protective effects of pyrrolidine dithiocarbamate on myocardium apoptosis induced by adriamycin in rats. Int J Cardiol 114: 159–165PubMedCrossRefGoogle Scholar
  59. Li J, Gwilt PR (2003) The effect of age on the early disposition of doxorubicin. Cancer Chemother Pharmacol 51: 395–402PubMedGoogle Scholar
  60. Li K, Sung RY, Huang WZ et al (2006) Thrombopoietin protects against in vitro and in vivo cardiotoxicity induced by doxorubicin. Circulation 113: 2211–2220PubMedCrossRefGoogle Scholar
  61. Lim CC, Zuppinger C, Guo X et al (2004) Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes. J Biol Chem 279: 8290–8299PubMedCrossRefGoogle Scholar
  62. Lipshultz SE, Colan SD, Gelber RD et al (1991) Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 324: 808–815PubMedCrossRefGoogle Scholar
  63. Liu J, Mao W, Ding B et al (2008) ERKs/p53 signal transduction pathway is involved in doxorubicin-induced apoptosis in H9c2 cells and cardiomyocytes. Am J Physiol Heart Circ Physiol 295: H1956–1965PubMedCrossRefGoogle Scholar
  64. Liu X, Chen Z, Chua CC et al (2002) Melatonin as an effective protector against doxorubicin-induced cardiotoxicity. Am J Physiol Heart Circ Physiol 283: H254–263PubMedGoogle Scholar
  65. Liu X, Chua CC, Gao J et al (2004) Pifithrin-alpha protects against doxorubicin-induced apoptosis and acute cardiotoxicity in mice. Am J Physiol Heart Circ Physiol 286: H933–939PubMedCrossRefGoogle Scholar
  66. Lou H, Danelisen I, Singal PK (2005) Involvement of mitogen-activated protein kinases in adriamycin-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 288: H1925–1930PubMedCrossRefGoogle Scholar
  67. Machado V, Cabral A, Monteiro P et al (2008) Carvedilol as a protector against the cardiotoxicity induced by anthracyclines (doxorubicin). Rev Port Cardiol 27: 1277–1296PubMedGoogle Scholar
  68. Madden SD, Donovan M, Cotter TG (2007) Key apoptosis regulating proteins are down-regulated during postnatal tissue development. Int J Dev Biol 51: 415–423PubMedCrossRefGoogle Scholar
  69. Maejima Y, Adachi S, Ito H et al (2008) Induction of premature senescence in cardiomyocytes by doxorubicin as a novel mechanism of myocardial damage. Aging Cell 7: 125–136PubMedCrossRefGoogle Scholar
  70. Maejima Y, Adachi S, Morikawa K et al (2005) Nitric oxide inhibits myocardial apoptosis by preventing caspase-3 activity via S-nitrosylation. J Mol Cell Cardiol 38: 163–174PubMedCrossRefGoogle Scholar
  71. Maiuri MC, Zalckvar E, Kimchi A et al (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8: 741–752PubMedCrossRefGoogle Scholar
  72. Matsui Y, Kyoi S, Takagi H et al (2008) Molecular mechanisms and physiological significance of autophagy during myocardial ischemia and reperfusion. Autophagy 4: 409–415PubMedGoogle Scholar
  73. Mercier I, Vuolo M, Madan R et al (2005) ARC, an apoptosis suppressor limited to terminally differentiated cells, is induced in human breast cancer and confers chemo- and radiation-resistance. Cell Death Differ 12: 682–686PubMedCrossRefGoogle Scholar
  74. Mijares A, Lopez JR (2001) L-carnitine prevents increase in diastolic [CA2+] induced by doxorubicin in cardiac cells. Eur J Pharmacol 425: 117–120PubMedCrossRefGoogle Scholar
  75. Mukhopadhyay P, Batkai S, Rajesh M et al (2007) Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. J Am Coll Cardiol 50: 528–536PubMedCrossRefGoogle Scholar
  76. Munoz-Gamez JA, Rodriguez-Vargas JM, Quiles-Perez R et al (2009) PARP-1 is involved in autophagy induced by DNA damage. Autophagy 5: 61–74PubMedGoogle Scholar
  77. Nakamura T, Ueda Y, Juan Y et al (2000) Fas-mediated apoptosis in adriamycin-induced cardiomyopathy in rats: In vivo study. Circulation 102: 572–578PubMedGoogle Scholar
  78. Neilan TG, Blake SL, Ichinose F et al (2007) Disruption of nitric oxide synthase 3 protects against the cardiac injury, dysfunction, and mortality induced by doxorubicin. Circulation 116: 506–514PubMedCrossRefGoogle Scholar
  79. Nishida K, Kyoi S, Yamaguchi O et al (2009) The role of autophagy in the heart. Cell Death Differ 16: 31–38PubMedCrossRefGoogle Scholar
  80. Nishida K, Yamaguchi O, Otsu K (2008) Crosstalk between autophagy and apoptosis in heart disease. Circ Res 103: 343–351PubMedCrossRefGoogle Scholar
  81. Nitobe J, Yamaguchi S, Okuyama M et al (2003) Reactive oxygen species regulate FLICE inhibitory protein (FLIP) and susceptibility to Fas-mediated apoptosis in cardiac myocytes. Cardiovasc Res 57: 119–128PubMedCrossRefGoogle Scholar
  82. Niu J, Azfer A, Wang K et al (2009) Cardiac-targeted expression of soluble Fas attenuates doxorubicin-induced cardiotoxicity in mice. J Pharmacol Exp Ther 328: 740–748PubMedCrossRefGoogle Scholar
  83. Nozaki N, Shishido T, Takeishi Y et al (2004) Modulation of doxorubicin-induced cardiac dysfunction in toll-like receptor-2-knockout mice. Circulation 110: 2869–2874PubMedCrossRefGoogle Scholar
  84. Parra V, Eisner V, Chiong M et al (2008) Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis. Cardiovasc Res 77: 387–397PubMedCrossRefGoogle Scholar
  85. Piantadosi CA, Carraway MS, Babiker A et al (2008) Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res 103: 1232–1240PubMedCrossRefGoogle Scholar
  86. Poizat C, Puri PL, Bai Y et al (2005) Phosphorylation-dependent degradation of p300 by doxorubicin-activated p38 mitogen-activated protein kinase in cardiac cells. Mol Cell Biol 25: 2673–2687PubMedCrossRefGoogle Scholar
  87. Riad A, Bien S, Westermann D et al (2009) Pretreatment with statin attenuates the cardiotoxicity of Doxorubicin in mice. Cancer Res 69: 695–699PubMedCrossRefGoogle Scholar
  88. Rigacci L, Mappa S, Nassi L et al (2007) Liposome-encapsulated doxorubicin in combination with cyclophosphamide, vincristine, prednisone and rituximab in patients with lymphoma and concurrent cardiac diseases or pre-treated with anthracyclines. Hematol Oncol 25: 198–203PubMedCrossRefGoogle Scholar
  89. Rothermel BA, Hill JA (2008) Autophagy in load-induced heart disease. Circ Res 103: 1363–1369PubMedCrossRefGoogle Scholar
  90. Rubinsztein DC, Difiglia M, Heintz N et al (2005) Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy 1: 11–22PubMedCrossRefGoogle Scholar
  91. Salvatorelli E, Menna P, Lusini M et al (2009) Doxorubicinolone formation and efflux: a salvage pathway against epirubicin accumulation in human heart. J Pharmacol Exp Ther 329: 175–184PubMedCrossRefGoogle Scholar
  92. Sanchis D, Mayorga M, Ballester M et al (2003) Lack of Apaf-1 expression confers resistance to cytochrome c-driven apoptosis in cardiomyocytes. Cell Death Differ 10: 977–986PubMedCrossRefGoogle Scholar
  93. Schmid D, Munz C (2007) Innate and adaptive immunity through autophagy. Immunity 27: 11–21PubMedCrossRefGoogle Scholar
  94. Shi J, Wei L (2007) Rho kinase in the regulation of cell death and survival. Arch Immunol Ther Exp 55: 61–75CrossRefGoogle Scholar
  95. Shimizu S, Kanaseki T, Mizushima N et al (2004) Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol 6: 1221–1228PubMedCrossRefGoogle Scholar
  96. Shimomura H, Terasaki F, Hayashi T et al (2001) Autophagic degeneration as a possible mechanism of myocardial cell death in dilated cardiomyopathy. Jpn Circ J 65: 965–968PubMedCrossRefGoogle Scholar
  97. Shizukuda Y, Matoba S, Mian OY et al (2005) Targeted disruption of p53 attenuates doxorubicin-induced cardiac toxicity in mice. Mol Cell Biochem 273: 25–32PubMedCrossRefGoogle Scholar
  98. Singal PK, Iliskovic N (1998) Doxorubicin-induced cardiomyopathy. N Engl J Med 339: 900–905PubMedCrossRefGoogle Scholar
  99. Solem LE, Heller LJ, Wallace KB (1996) Dose-dependent increase in sensitivity to calcium-induced mitochondrial dysfunction and cardiomyocyte cell injury by doxorubicin. J Mol Cell Cardiol 28: 1023–1032PubMedCrossRefGoogle Scholar
  100. Spallarossa P, Fabbi P, Manca V et al (2005) Doxorubicin-induced expression of LOX-1 in H9c2 cardiac muscle cells and its role in apoptosis. Biochem Biophys Res Commun 335: 188–196PubMedCrossRefGoogle Scholar
  101. Spallarossa P, Garibaldi S, Altieri P et al (2004) Carvedilol prevents doxorubicin-induced free radical release and apoptosis in cardiomyocytes in vitro. J Mol Cell Cardiol 37: 837–846PubMedCrossRefGoogle Scholar
  102. Suliman HB, Carraway MS, Ali AS et al (2007) The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy. J Clin Invest 117: 3730–3741PubMedGoogle Scholar
  103. Takemura G, Fujiwara H (2007) Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Prog Cardiovasc Dis 49: 330–352PubMedCrossRefGoogle Scholar
  104. Tatlidede E, Sehirli O, Velioglu-Ogunc A et al (2009) Resveratrol treatment protects against doxorubicin-induced cardiotoxicity by alleviating oxidative damage. Free Radic Res 43: 195–205PubMedCrossRefGoogle Scholar
  105. Terman A, Brunk UT (2005) Autophagy in cardiac myocyte homeostasis, aging, and pathology. Cardiovasc Res 68: 355–365PubMedCrossRefGoogle Scholar
  106. Terman A, Gustafsson B, Brunk UT (2006) The lysosomal-mitochondrial axis theory of postmitotic aging and cell death. Chem Biol Interact 163: 29–37PubMedCrossRefGoogle Scholar
  107. Tsujimoto Y, Shimizu S (2005) Another way to die: autophagic programmed cell death. Cell Death Differ. 12(suppl 2): 1528–1534PubMedCrossRefGoogle Scholar
  108. Von Hoff DD, Rozencweig M, Layard M et al (1977) Daunomycin-induced cardiotoxicity in children and adults. A review of 110 cases. Am J Med 62: 200–208PubMedCrossRefGoogle Scholar
  109. Wallace KB (2003) Doxorubicin-induced cardiac mitochondrionopathy. Pharmacol Toxicol 93: 105–115PubMedCrossRefGoogle Scholar
  110. Wallace KB (2007) Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis. Cardiovasc Toxicol 7: 101–107PubMedCrossRefGoogle Scholar
  111. Wang GW, Klein JB, Kang YJ. (2001) Metallothionein inhibits doxorubicin-induced mitochondrial cytochrome c release and caspase-3 activation in cardiomyocytes. J Pharmacol Exp Ther 298: 461–468PubMedGoogle Scholar
  112. Wang S, Kotamraju S, Konorev E et al (2002) Activation of nuclear factor-kappaB during doxorubicin-induced apoptosis in endothelial cells and myocytes is pro-apoptotic: the role of hydrogen peroxide. Biochem J 367: 729–740PubMedCrossRefGoogle Scholar
  113. Yakovlev AG, Ota K, Wang G et al (2001) Differential expression of apoptotic protease-activating factor-1 and caspase-3 genes and susceptibility to apoptosis during brain development and after traumatic brain injury. J Neurosci 21: 7439–7446PubMedGoogle Scholar
  114. Yan C, Ding B, Shishido T et al (2007) Activation of extracellular signal-regulated kinase 5 reduces cardiac apoptosis and dysfunction via inhibition of a phosphodiesterase 3A/inducible cAMP early repressor feedback loop. Circ Res 100: 510–519PubMedCrossRefGoogle Scholar
  115. Yeh ET, Tong AT, Lenihan DJ et al (2004) Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation 109: 3122–3131PubMedCrossRefGoogle Scholar
  116. Yildirim Y, Gultekin E, Avci ME et al (2008) Cardiac safety profile of pegylated liposomal doxorubicin reaching or exceeding lifetime cumulative doses of 550 mg/m2 in patients with recurrent ovarian and peritoneal cancer. Int J Gynecol Cancer 18: 223–227PubMedCrossRefGoogle Scholar
  117. Yorimitsu T, Klionsky DJ (2005) Autophagy: molecular machinery for self-eating. Cell Death Differ 12(suppl 2): 1542–1552PubMedCrossRefGoogle Scholar
  118. Zeng Q, Zhou Q, Yao F et al (2008) Endothelin-1 regulates cardiac L-type calcium channels via NAD(P)H oxidase-derived superoxide. J Pharmacol Exp Ther 326: 732–738PubMedCrossRefGoogle Scholar
  119. Zhou S, Starkov A, Froberg MK et al (2001) Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Res 61: 771–777PubMedGoogle Scholar
  120. Zhu W, Shou W, Payne RM et al (2008) A mouse model for juvenile doxorubicin-induced cardiac dysfunction. Pediatr Res 64: 488–494PubMedCrossRefGoogle Scholar
  121. Zhu W, Soonpaa MH, Chen H (2009) Acute doxorubicin cardiotoxicity is associated with p53-induced inhibition of the mammalian target of rapamycin pathway. Circulation 119: 99–106PubMedCrossRefGoogle Scholar
  122. Zima AV, Blatter LA (2006) Redox regulation of cardiac calcium channels and transporters. Cardiovasc Res 71: 310–321PubMedCrossRefGoogle Scholar
  123. Zou Y, Evans S, Chen J et al (1997) CARP, a cardiac ankyrin repeat protein, is downstream in the Nkx2-5 homeobox gene pathway. Development 124: 793–804PubMedGoogle Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2009

Authors and Affiliations

  1. 1.Riley Heart Research Center, Wells Center for Pediatric ResearchIndiana University, School of MedicineIndianapolisUSA
  2. 2.Department of Pharmacology, School of Pharmaceutical SciencesCentral South UniversityChangshaP.R. China
  3. 3.Riley Heart Research Center, Wells Center for Pediatric ResearchIndiana University, School of MedicineIndianapolisUSA
  4. 4.Department of Pharmacology, School of Pharmaceutical SciencesCentral South UniversityChangshaChina

Personalised recommendations