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Erschienen in:

01.06.2011 | Main topic/CME

Mechanisms and management of doxorubicin cardiotoxicity

verfasst von: Y. Shi, M. Moon, S. Dawood, B. McManus, P.P. Liu, MD

Erschienen in: Herz | Ausgabe 4/2011

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Abstract

Doxorubicin is an effective anti-tumor agent with a cumulative dose-dependent cardiotoxicity. In addition to its principal toxic mechanisms involving iron and redox reactions, recent studies have described new mechanisms of doxorubicin-induced cell death, including abnormal protein processing, hyper-activated innate immune responses, inhibition of neuregulin-1 (NRG1)/ErbB(HER) signalling, impaired progenitor cell renewal/cardiac repair, and decreased vasculogenesis. Although multiple mechanisms involved in doxorubicin cardiotoxicity have been studied, there is presently no clinically proven treatment established for doxorubicin cardiomyopathy. Iron chelator dexrazoxane, angiotensin converting enzyme (ACE) inhibitors, and β-blockade have been proposed as potential preventive strategies for doxorubicin cardiotoxicity. Novel approaches such as anti-miR-146 or recombinant NRG1 to increase cardiomyocyte resistance to toxicity may be of interest in the future.

Pommier Y, Leo E, Zhang H, Marchand C (2010) DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol 17:421–433PubMedCrossRef

Chatterjee K, Zhang J, Honbo N, Karliner JS (2010) Doxorubicin cardiomyopathy. Cardiology 115:155–162PubMedCrossRef

Robert J, Gianni L (1993) Pharmacokinetics and metabolism of anthracyclines. Cancer Surv 17:219–252PubMed

Cartoni A, Menna P, Salvatorelli E et al (2004) Oxidative degradation of cardiotoxic anticancer anthracyclines to phthalic acids. Novel function or ferrylmyoglobin. J Biol Chem 279:5088–5099PubMedCrossRef

Minotti G, Menna P, Salvatorelli E et al (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229PubMedCrossRef

Shin M, Matsunaga H, Fujiwara K (2010) Differences in accumulation of anthracyclines daunorubicin, doxorubicin and epirubicin in rat tissues revealed by immunocytochemistry. Histochem Cell Biol 133:677–682PubMedCrossRef

Menna P, Salvatorelli E, Minotti G (2010) Anthracycline degradation in cardiomyocytes: a journey to oxidative survival. Chem Res Toxicol 23:6–10PubMedCrossRef

Menna P, Salvatorelli E, Minotti G (2007) Doxorubicin degradation in cardiomyocytes. J Pharmacol Exp Ther 322:408–419PubMedCrossRef

Yi X, Bekeredjian R, De Filippis NJ et al (2006) Transcriptional analysis of doxorubicin-induced cardiotoxicity. Am J Physiol Heart Circ Physiol 290:H1098–H1102PubMedCrossRef

10.

Umlauf J, Horky M (2002) Molecular biology of doxorubicin-induced cardiomyopathy. Exp Clin Cardiol 7:35–39PubMed

11.

Xu X, Persson HL, Richardson DR (2005) Molecular pharmacology of the interaction of anthracyclines with iron. Mol Pharmacol 68:261–271PubMed

12.

Minotti G, Ronchi R, Salvatorelli E et al (2001) Doxorubicin irreversibly inactivates iron regulatory proteins 1 and 2 in cardiomyocytes: evidence for distinct metabolic pathways and implications for iron-mediated cardiotoxicity of antitumor therapy. Cancer Res 61:8422–8428PubMed

13.

Ducroq J, Moha ou Maati H, Guilbot S et al (2010) Dexrazoxane protects the heart from acute doxorubicin-induced QT prolongation: a key role for I(Ks). Br J Pharmacol 159:93–101PubMedCrossRef

14.

Xiang P, Deng HY, Li K et al (2009) Dexrazoxane protects against doxorubicin-induced cardiomyopathy: upregulation of Akt and Erk phosphorylation in a rat model. Cancer Chemother Pharmacol 63:343–349PubMedCrossRef

15.

Miranda CJ, Makui H, Soares RJ et al (2003) Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin. Blood 102:2574–2580PubMedCrossRef

16.

Menna P, Salvatorelli E, Minotti G (2008) Cardiotoxicity of antitumor drugs. Chem Res Toxicol 21:978–989PubMedCrossRef

17.

Simunek T, Sterba M, Popelova O et al (2009) Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol Rep 61:154–171PubMed

18.

Zhang YW, Shi J, Li YJ, Wei L (2009) Cardiomyocyte death in doxorubicin-induced cardiotoxicity. Arch Immunol Ther Exp (Warsz) 57:435–445CrossRef

19.

Lebrecht D, Walker UA (2007) Role of mtDNA lesions in anthracycline cardiotoxicity. Cardiovasc Toxicol 7:108–113PubMedCrossRef

20.

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–H1280CrossRef

21.

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 28:1023–1032PubMedCrossRef

22.

Wallace KB (2003) Doxorubicin-induced cardiac mitochondrionopathy. J Pharmacol Toxicol Methods 93:105–115

23.

Wallace KB (2007) Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis. Cardiovasc Toxicol 7:101–107PubMedCrossRef

24.

Zhou S, Starkov A, Froberg MK et al (2001) Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Res 61:771–777PubMed

25.

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–H939PubMedCrossRef

26.

Liu J, Mao W, Ding B, Liang CS (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–H1965PubMedCrossRef

27.

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 U S A 101:6975–6980PubMedCrossRef

28.

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 63:368–377PubMedCrossRef

29.

Park AM, Nagase H, Liu L et al (2010) Mechanism of anthracycline-mediated down-regulation of GATA4 in the heart. Cardiovasc Res 90:97–104PubMedCrossRef

30.

Kawamura T, Hasegawa K, Morimoto T et al (2004) Expression of p300 protects cardiac myocytes from apoptosis in vivo. Biochem Biophys Res Commun 315:733–738PubMedCrossRef

31.

Poizat C, Puri PL, Bai Y, Kedes L (2005) Phosphorylation-dependent degradation of p300 by doxorubicin-activated p38 mitogen-activated protein kinase in cardiac cells. Mol Cell Biol 25:2673–2687PubMedCrossRef

32.

Vo N, Goodman RH (2001) CREB-binding protein and p300 in transcriptional regulation. J Biol Chem 276:13505–13508PubMed

33.

Yuan ZM, Huang Y, Ishiko T et al (1999) Function for p300 and not CBP in the apoptotic response to DNA damage. Oncogene 18:5714–5717PubMedCrossRef

34.

Kobayashi S, Volden P, Timm D et al (2010) Transcription factor GATA4 inhibits doxorubicin-induced autophagy and cardiomyocyte death. J Biol Chem 285:793–804PubMedCrossRef

35.

Terman A, Brunk UT (2005) Autophagy in cardiac myocyte homeostasis, aging, and pathology. Cardiovasc Res 68:355–365PubMedCrossRef

36.

Terman A, Kurz T, Gustafsson B, Brunk UT (2008) The involvement of lysosomes in myocardial aging and disease. Curr Cardiol Rev 4:107–115PubMedCrossRef

37.

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 25:193–205PubMedCrossRef

38.

Hoyer-Hansen M, Jaattela M (2007) Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ 14:1576–1582PubMedCrossRef

39.

Kumar D, Lou H, Singal PK (2002) Oxidative stress and apoptosis in heart dysfunction. Herz 27:662–668PubMedCrossRef

40.

Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216PubMedCrossRef

41.

Ehrke MJ, Ryoyama K, Cohen SA (1984) Cellular basis for adriamycin-induced augmentation of cell-mediated cytotoxicity in culture. Cancer Res 44:2497–2504PubMed

42.

Maccubbin DL, Wing KR, Mace KF et al (1992) Adriamycin-induced modulation of host defenses in tumor-bearing mice. Cancer Res 52:3572–3576PubMed

43.

Haskill JS (1981) Adriamycin-activated macrophages as tumor growth inhibitors. Cancer Res 41:3852–3856PubMed

44.

Methe H, Kim JO, Kofler S et al (2005) Statins decrease toll-like receptor 4 expression and downstream signaling in human CD14+ monocytes. Arterioscler Thromb Vasc Biol 25:1439–1445PubMedCrossRef

45.

Mann DL, Topkara VK, Evans S, Barger PM (2010) Innate immunity in the adult mammalian heart: for whom the cell tolls. Trans Am Clin Climatol Assoc 121:34–50; discussion 50–31PubMed

46.

Apetoh L, Ghiringhelli F, Tesniere A et al (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13:1050–1059PubMedCrossRef

47.

Apetoh L, Tesniere A, Ghiringhelli F et al (2008) Molecular interactions between dying tumor cells and the innate immune system determine the efficacy of conventional anticancer therapies. Cancer Res 68:4026–4030PubMedCrossRef

48.

Kast RE, Foley KF, Focosi D (2007) Doxorubicin cardiomyopathy via TLR-2 stimulation: potential for prevention using current anti-retroviral inhibitors such as ritonavir and nelfinavir. Hematol Oncol 25:96–97PubMedCrossRef

49.

Methe H, Kim JO, Kofler S et al (2005) Expansion of circulating Toll-like receptor 4-positive monocytes in patients with acute coronary syndrome. Circulation 111:2654–2661PubMedCrossRef

50.

Nozaki N, Shishido T, Takeishi Y, Kubota I (2004) Modulation of doxorubicin-induced cardiac dysfunction in toll-like receptor-2-knockout mice. Circulation 110:2869–2874PubMedCrossRef

51.

Riad A, Bien S, Gratz M et al (2008) Toll-like receptor-4 deficiency attenuates doxorubicin-induced cardiomyopathy in mice. Eur J Heart Fail 10:233–243PubMedCrossRef

52.

Sakata Y, Dong JW, Vallejo JG et al (2007) Toll-like receptor 2 modulates left ventricular function following ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 292:H503–H509PubMedCrossRef

53.

Shishido T, Nozaki N, Yamaguchi S et al (2003) Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction. Circulation 108:2905–2910PubMedCrossRef

54.

Fairweather D, Frisancho-Kiss S, Rose NR (2005) Viruses as adjuvants for autoimmunity: evidence from Coxsackievirus-induced myocarditis. Rev Med Virol 15:17–27PubMedCrossRef

55.

Zhu J, Zhang J, Xiang D et al (2010) Recombinant human interleukin-1 receptor antagonist protects mice against acute doxorubicin-induced cardiotoxicity. Eur J Pharmacol 643:247–253PubMedCrossRef

56.

Frantz S, Kelly RA, Bourcier T (2001) Role of TLR-2 in the activation of nuclear factor kappaB by oxidative stress in cardiac myocytes. J Biol Chem 276:5197–5203PubMedCrossRef

57.

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 367:729–740PubMedCrossRef

58.

Timmers L, Sluijter JP, Keulen JK van et al (2008) Toll-like receptor 4 mediates maladaptive left ventricular remodeling and impairs cardiac function after myocardial infarction. Circ Res 102:257–264PubMedCrossRef

59.

Dunne A, O’Neill LA (2003) The interleukin-1 receptor/toll-like receptor superfamily: signal transduction during inflammation and host defense. Sci STKE 2003:re3PubMedCrossRef

60.

Berthiaume JM, Wallace KB (2007) Persistent alterations to the gene expression profile of the heart subsequent to chronic Doxorubicin treatment. Cardiovasc Toxicol 7:178–191PubMedCrossRef

61.

Herman EH, Lipshultz SE, Rifai N et al (1998) Use of cardiac troponin T levels as an indicator of doxorubicin-induced cardiotoxicity. Cancer Res 58:195–197PubMed

62.

Saadane N, Alpert L, Chalifour LE (1999) TAFII250, egr-1, and D-type cyclin expression in mice and neonatal rat cardiomyocytes treated with doxorubicin. Am J Physiol 276:H803–H814PubMed

63.

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 272:22800–22808PubMedCrossRef

64.

Zordoky BN, Anwar-Mohamed A, Aboutabl ME, El-Kadi AO (2010) Acute doxorubicin cardiotoxicity alters cardiac cytochrome P450 expression and arachidonic acid metabolism in rats. Toxicol Appl Pharmacol 242:38–46PubMedCrossRef

65.

Sayed-Ahmed MM, Al-Shabanah OA, Hafez MM et al (2010) Inhibition of gene expression of heart fatty acid binding protein and organic cation/carnitine transporter in doxorubicin cardiomyopathic rat model. Eur J Pharmacol 640:143–149PubMedCrossRef

66.

Pointon AV, Walker TM, Phillips KM et al (2010) Doxorubicin in vivo rapidly alters expression and translation of myocardial electron transport chain genes, leads to ATP loss and caspase 3 activation. PLoS One 5:e12733PubMedCrossRef

67.

Maeda A, Honda M, Kuramochi T, Takabatake T (1998) Doxorubicin cardiotoxicity: diastolic cardiac myocyte dysfunction as a result of impaired calcium handling in isolated cardiac myocytes. Jpn Circ J 62:505–511PubMedCrossRef

68.

Jeyaseelan R, Poizat C, Wu HY, Kedes L (1997) 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 272:5828–5832PubMedCrossRef

69.

Arai M, Tomaru K, Takizawa T et al (1998) Sarcoplasmic reticulum genes are selectively down-regulated in cardiomyopathy produced by doxorubicin in rabbits. J Mol Cell Cardiol 30:243–254PubMedCrossRef

70.

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 7:125–136PubMedCrossRef

71.

Kajstura J, Rota M, Urbanek K et al (2006) The telomere-telomerase axis and the heart. Antioxid Redox Signal 8:2125–2141PubMedCrossRef

72.

Bernhard D, Laufer G (2008) The aging cardiomyocyte: a mini-review. Gerontology 54:24–31PubMedCrossRef

73.

Wang X, Su H, Ranek MJ (2008) Protein quality control and degradation in cardiomyocytes. J Mol Cell Cardiol 45:11–27PubMedCrossRef

74.

Ranek MJ, Wang X (2009) Activation of the ubiquitin-proteasome system in doxorubicin cardiomyopathy. Curr Hypertens Rep 11:389–395PubMedCrossRef

75.

Wang X, Robbins J (2006) Heart failure and protein quality control. Circ Res 99:1315–1328PubMedCrossRef

76.

Patterson C, Ike C, Willis PWT et al (2007) The bitter end: the ubiquitin-proteasome system and cardiac dysfunction. Circulation 115:1456–1463PubMedCrossRef

77.

Tu D, Li W, Ye Y, Brunger AT (2007) Structure and function of the yeast U-box-containing ubiquitin ligase Ufd2p. Proc Natl Acad Sci U S A 104:15599–15606PubMedCrossRef

78.

Powell SR (2006) The ubiquitin-proteasome system in cardiac physiology and pathology. Am J Physiol Heart Circ Physiol 291:H1–H19PubMedCrossRef

79.

Davies KJ (2001) Degradation of oxidized proteins by the 20S proteasome. Biochimie 83:301–310PubMedCrossRef

80.

Liu J, Zheng H, Tang M et al (2008) A therapeutic dose of doxorubicin activates ubiquitin-proteasome system-mediated proteolysis by acting on both the ubiquitination apparatus and proteasome. Am J Physiol Heart Circ Physiol 295:H2541–2550PubMedCrossRef

81.

Li YZ, Lu DY, Tan WQ et al (2008) p53 initiates apoptosis by transcriptionally targeting the antiapoptotic protein ARC. Mol Cell Biol 28:564–574PubMedCrossRef

82.

Nam YJ, Mani K, Wu L et al (2007) The apoptosis inhibitor ARC undergoes ubiquitin-proteasomal-mediated degradation in response to death stimuli: identification of a degradation-resistant mutant. J Biol Chem 282:5522–5528PubMedCrossRef

83.

Fukuda N, Sasaki D, Ishiwata S, Kurihara S (2001) Length dependence of tension generation in rat skinned cardiac muscle: role of titin in the frank-starling mechanism of the heart. Circulation 104:1639–1645PubMedCrossRef

84.

Lim CC, Zuppinger C, Guo X et al (2004) Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes. J Biol Chem 279:8290–8299PubMedCrossRef

85.

Haq S, Michael A, Andreucci M et al (2003) Stabilization of beta-catenin by a wnt-independent mechanism regulates cardiomyocyte growth. Proc Natl Acad Sci U S A 100:4610–4615PubMedCrossRef

86.

Poizat C, Sartorelli V, Chung G et al (2000) Proteasome-mediated degradation of the coactivator p300 impairs cardiac transcription. Mol Cell Biol 20:8643–8654PubMedCrossRef

87.

Li Q, Sanlioglu S, Li S et al (2001) GPx-1 gene delivery modulates NFkappaB activation following diverse environmental injuries through a specific subunit of the IKK complex. Antioxid Redox Signal 3:415–432PubMedCrossRef

88.

Yamamoto Y, Hoshino Y, Ito T et al (2008) Atrogin-1 ubiquitin ligase is upregulated by doxorubicin via p38-MAP kinase in cardiac myocytes. Cardiovasc Res 79:89–96PubMedCrossRef

89.

Xie P, Guo S, Fan Y et al (2009) Atrogin-1/MAFbx enhances simulated ischemia/reperfusion-induced apoptosis in cardiomyocytes through degradation of MAPK phosphatase-1 and sustained JNK activation. J Biol Chem 284:5488–5496PubMedCrossRef

90.

Gomes MD, Lecker SH, Jagoe RT et al (2001) Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci U S A 98:14440–14445PubMedCrossRef

91.

Stitt TN, Drujan D, Clarke BA et al (2004) The IGF-1/PI3 K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell 14:395–403PubMedCrossRef

92.

Razeghi P, Baskin KK, Sharma S et al (2006) Atrophy, hypertrophy, and hypoxemia induce transcriptional regulators of the ubiquitin proteasome system in the rat heart. Biochem Biophys Res Commun 342:361–364PubMedCrossRef

93.

Razeghi P, Taegtmeyer H (2006) Hypertrophy and atrophy of the heart: the other side of remodeling. Ann N Y Acad Sci 1080:110–119PubMedCrossRef

94.

Li HH, Kedar V, Zhang C et al (2004) Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex. J Clin Invest 114:1058–1071PubMed

95.

Bodine SC, Latres E, Baumhueter S et al (2001) Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294:1704–1708PubMedCrossRef

96.

Murton AJ, Constantin D, Greenhaff PL (2008) The involvement of the ubiquitin proteasome system in human skeletal muscle remodelling and atrophy. Biochim Biophys Acta 1782:730–743PubMed

97.

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 389:527–539PubMedCrossRef

98.

Ito T, Fujio Y, Takahashi K, Azuma J (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 282:1152–1160PubMedCrossRef

99.

Ito T, Fujio Y, Schaffer SW, Azuma J (2009) Involvement of transcriptional factor TonEBP in the regulation of the taurine transporter in the cardiomyocyte. Adv Exp Med Biol 643:523–532PubMedCrossRef

100.

LoConte NK, Thomas JP, Alberti D et al (2008) A phase I pharmacodynamic trial of bortezomib in combination with doxorubicin in patients with advanced cancer. Cancer Chemother Pharmacol 63:109–115PubMedCrossRef

101.

Burden S, Yarden Y (1997) Neuregulins and their receptors: a versatile signaling module in organogenesis and oncogenesis. Neuron 18:847–855PubMedCrossRef

102.

Li JY, Wang H, May S et al (2008) Constitutive activation of c-jun N-terminal kinase correlates with histologic grade and EGFR expression in diffuse gliomas. J Neurooncol 88:11–17PubMedCrossRef

103.

Steinthorsdottir V, Stefansson H, Ghosh S et al (2004) Multiple novel transcription initiation sites for NRG1. Gene 342:97–105PubMedCrossRef

104.

Bublil EM, Yarden Y (2007) The EGF receptor family: spearheading a merger of signaling and therapeutics. Curr Opin Cell Biol 19:124–134PubMedCrossRef

105.

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

106.

Zhao YY, Sawyer DR, Baliga RR et al (1998) Neuregulins promote survival and growth of cardiac myocytes. Persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes. J Biol Chem 273:10261–10269PubMedCrossRef

107.

Spector NL, Blackwell KL (2009) Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 27:5838–5847PubMedCrossRef

108.

Garrett TP, McKern NM, Lou M et al (2002) Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha. Cell 110:763–773PubMedCrossRef

109.

Lemmens K, Doggen K, De Keulenaer GW (2007) Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure. Circulation 116:954–960PubMedCrossRef

110.

Engelman JA, Zejnullahu K, Mitsudomi T et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–1043PubMedCrossRef

111.

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

112.

Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2:127–137PubMedCrossRef

113.

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

114.

Crone SA, Zhao YY, Fan L et al (2002) ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 8:459–465PubMedCrossRef

115.

Sawyer DB, Zuppinger C, Miller TA et al (2002) Modulation of anthracycline-induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1beta and anti-erbB2: potential mechanism for trastuzumab-induced cardiotoxicity. Circulation 105:1551–1554PubMedCrossRef

116.

Pentassuglia L, Graf M, Lane H et al (2009) Inhibition of ErbB2 by receptor tyrosine kinase inhibitors causes myofibrillar structural damage without cell death in adult rat cardiomyocytes. Exp Cell Res 315:1302–1312PubMedCrossRef

117.

Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792PubMedCrossRef

118.

Christodoulou C, Kostopoulos I, Kalofonos HP et al (2009) Trastuzumab combined with pegylated liposomal doxorubicin in patients with metastatic breast cancer. phase II Study of the Hellenic Cooperative Oncology Group (HeCOG) with biomarker evaluation. the International Society for Cellular 76:275–285

119.

Rayson D, Richel D, Chia S et al (2008) Anthracycline-trastuzumab regimens for HER2/neu-overexpressing breast cancer: current experience and future strategies. Ann Oncol 19:1530–1539PubMedCrossRef

120.

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

121.

Liu FF, Stone JR, Schuldt AJ et al (2005) Heterozygous knockout of neuregulin-1 gene in mice exacerbates doxorubicin-induced heart failure. Am J Physiol Heart Circ Physiol 289:H660–H666PubMedCrossRef

122.

Bian Y, Sun M, Silver M et al (2009) Neuregulin-1 attenuated doxorubicin-induced decrease in cardiac troponins. Am J Physiol Heart Circ Physiol 297:H1974–H1983PubMedCrossRef

123.

Hosoda T, Kajstura J, Leri A, Anversa P (2010) Mechanisms of myocardial regeneration. Circ J 74:13–17PubMedCrossRef

124.

Di Nardo P, Forte G, Ahluwalia A, Minieri M (2010) Cardiac progenitor cells: potency and control. J Cell Physiol 224:590–600CrossRef

125.

De Angelis A, Piegari E, Cappetta D et al (2010) Anthracycline cardiomyopathy is mediated by depletion of the cardiac stem cell pool and is rescued by restoration of progenitor cell function. Circulation 121:276–292CrossRef

126.

Huang C, Zhang X, Ramil JM et al (2010) Juvenile exposure to anthracyclines impairs cardiac progenitor cell function and vascularization resulting in greater susceptibility to stress-induced myocardial injury in adult mice. Circulation 121:675–683PubMedCrossRef

127.

Yasuda K, Park HC, Ratliff B et al (2010) Adriamycin nephropathy: a failure of endothelial progenitor cell-induced repair. Am J Pathol 176:1685–1695PubMedCrossRef

128.

Yin D, Li C, Kao RL et al (2004) Angiopoietin-1 inhibits doxorubicin-induced human umbilical vein endothelial cell death by modulating fas expression and via the PI3 K/Akt pathway. Endothelium 11:247–252PubMedCrossRef

129.

Ewer MS, Ewer SM (2010) Cardiotoxicity of anticancer treatments: what the cardiologist needs to know. Nat Rev Cardiol 7:564–575PubMedCrossRef

130.

Takemura G, Fujiwara H (2007) Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Prog Cardiovasc Dis 49:330–352PubMedCrossRef

131.

Lipshultz SE, Alvarez JA, Scully RE (2008) Anthracycline associated cardiotoxicity in survivors of childhood cancer. Heart 94:525–533PubMedCrossRef

132.

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 37:837–846PubMedCrossRef

133.

Malcom J, Arnold O, Howlett JG et al (2008) Canadian Cardiovascular Society Consensus Conference guidelines on heart failure–2008 update: best practices for the transition of care of heart failure patients, and the recognition, investigation and treatment of cardiomyopathies. Can J Cardiol 24:21–40PubMedCrossRef

134.

Shaddy RE, Olsen SL, Bristow MR et al (1995) Efficacy and safety of metoprolol in the treatment of doxorubicin-induced cardiomyopathy in pediatric patients. Am Heart J 129:197–199PubMedCrossRef

135.

Hiona A, Lee AS, Nagendran J et al (2010) Pretreatment with angiotensin-converting enzyme inhibitor improves doxorubicin-induced cardiomyopathy via preservation of mitochondrial function. J Thorac Cardiovasc Surg

136.

Sacco G, Mario B, Lopez G et al (2009) ACE inhibition and protection from doxorubicin-induced cardiotoxicity in the rat. Vascul Pharmacol 50:166–170PubMedCrossRef

137.

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 27:127–145PubMedCrossRef

138.

Lipshultz SE, Scully RE, Lipsitz SR 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 11:950–961PubMedCrossRef

139.

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 151:771–778PubMedCrossRef

140.

Cardinale D, Colombo A, Sandri MT et al (2006) Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 114:2474–2481PubMedCrossRef

141.

Kalay N, Basar E, Ozdogru I et al (2006) Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol 48:2258–2262PubMedCrossRef

142.

Sawyer DB, Peng X, Chen B et al (2010) Mechanisms of anthracycline cardiac injury: can we identify strategies for cardioprotection? Prog Cardiovasc Dis 53:105–113PubMedCrossRef

143.

Shi R, Huang CC, Aronstam RS et al (2009) N-acetylcysteine amide decreases oxidative stress but not cell death induced by doxorubicin in H9c2 cardiomyocytes. BMC Pharmacol 9:7PubMedCrossRef

144.

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–H1930PubMedCrossRef

145.

Ito T, Muraoka S, Takahashi K et al (2009) Beneficial effect of taurine treatment against doxorubicin-induced cardiotoxicity in mice. Adv Exp Med Biol 643:65–74PubMedCrossRef

146.

Berthiaume JM, Oliveira PJ, Fariss MW, Wallace KB (2005) Dietary vitamin E decreases doxorubicin-induced oxidative stress without preventing mitochondrial dysfunction. Cardiovasc Toxicol 5:257–267PubMedCrossRef

147.

Daosukho C, Chen Y, Noel T et al (2007) Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury. Free Radic Biol Med 42:1818–1825PubMedCrossRef

148.

Merten KE, Jiang Y, Kang YJ (2007) Zinc inhibits doxorubicin-activated calcineurin signal transduction pathway in H9c2 embryonic rat cardiac cells. Exp Biol Med (Maywood) 232:682–689

149.

Chatterjee K, Zhang J, Tao R et al (2008) Vincristine attenuates doxorubicin cardiotoxicity. Biochem Biophys Res Commun 373:555–560PubMedCrossRef

150.

Konishi M, Haraguchi G, Ohigashi H et al (2011) Adiponectin protects against doxorubicin-induced cardiomyopathy by anti-apoptotic effects through AMPK up-regulation. Cardiovasc Res 89:309–319PubMedCrossRef

151.

Chao HH, Liu JC, Hong HJ et al (2011) L-carnitine reduces doxorubicin-induced apoptosis through a prostacyclin-mediated pathway in neonatal rat cardiomyocytes. Int J Cardiol 146:145–152PubMedCrossRef

152.

Little GH, Saw A, Bai Y et al (2009) Critical role of nuclear calcium/calmodulin-dependent protein kinase IIdeltaB in cardiomyocyte survival in cardiomyopathy. J Biol Chem 284:24857–24868PubMedCrossRef

153.

Koka S, Das A, Zhu SG et al (2010) Long-acting phosphodiesterase-5 inhibitor tadalafil attenuates doxorubicin-induced cardiomyopathy without interfering with chemotherapeutic effect. J Pharmacol Exp Ther 334:1023–1030PubMedCrossRef

Titel: Mechanisms and management of doxorubicin cardiotoxicity
verfasst von: Y. Shi
M. Moon
S. Dawood
B. McManus
P.P. Liu, MD
Publikationsdatum: 01.06.2011
Verlag: Urban and Vogel
Erschienen in: Herz / Ausgabe 4/2011
Print ISSN: 0340-9937
Elektronische ISSN: 1615-6692
DOI: https://doi.org/10.1007/s00059-011-3470-3

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