Doxorubicin-Induced Mitochondrial Cardiomyopathy

  • Kendall B. Wallace


Mitochondrial Permeability Transition Mitochondrial Permeability Transition Pore Redox Cycling Pyridine Nucleotide Cardiac Mitochondrion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ainger, L. E., Bushore, J., Johnson, W. W., and Ito, J., 1971, Daunomycin: A cardiotoxic agent, J. Nat. Med. Assoc. 63(4):261–267.Google Scholar
  2. Al-Shabanah, O. A., Badary, O. A., Nagi, M. N., Al-Gharably, N. M., Al-Rikabi, A. C., and Al-Bekairi, A. M., 1998, Thymoquinone protects against doxorubicin-induced cardiotoxicity without compromising its antitumor activity, J. Exp. Clin. Cancer Res. 17(2):193–198.PubMedGoogle Scholar
  3. Alexander, J., Dainiak, N., Berger, H. J., Goldman, L., Johnstone, D., Reduto, L., Duffy, T., Schwartz, P., Gottschalk, A., and Zaret, B. L., 1979, Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography, N. Engl. J. Med. 300(6):278–283.PubMedGoogle Scholar
  4. Aversano, R. C., and Boor, P. J., 1983, Histochemical alterations of acute and chronic doxorubicin cardiotoxicity, J. Mol. Cell Cardiol. 15(8):543–553.CrossRefPubMedGoogle Scholar
  5. Bachmann, E., and Zbinden, G., 1979, Effect of doxorubicin and rubidazone on respiratory function and Ca2+ transport in rat heart mitochondria, Toxicol. Lett. 3:29–34.CrossRefGoogle Scholar
  6. Bachmann, E., Weber, E., and Zbinden, G., 1987, Effects of mitoxantrone and doxorubicin on energy metabolism of the rat heart, Cancer Treat. Rep. 71(4):361–366.PubMedGoogle Scholar
  7. Bachur, N. R., and Gee, M., 1976, Microsomal reductive glycosidase, J. Pharmacol. Exp. Ther. 197(3):681–686.PubMedGoogle Scholar
  8. Bachur, N. R., Gee, M. V, and Friedman, R. D., 1982, Nuclear catalyzed antibiotic free radical formation, Cancer Res. 42(3):1078–1081.PubMedGoogle Scholar
  9. Bachur, N. R., Gordon, S. L., and Gee, M. V, 1977, Anthracycline antibiotic augmentation of microsomal electron transport and free radical formation, Mol. Pharmacol. 13(5):901–910.PubMedGoogle Scholar
  10. Bachur, N. R., Friedman, R. D., and Hollenbeck, R. G., 1984, Physicochemical characteristics of ferric Adriamycin complexes, Cancer Chemother. Pharmacol. 12(l):5–9.PubMedGoogle Scholar
  11. Bates, D. A., and Winterbourn, C. C., 1982, Reactions of Adriamycin with haemoglobin: Superoxide dismutase indirectly inhibits reactions of the Adriamycin semiquinone, Biochem. J. 203(1):155–160.PubMedGoogle Scholar
  12. Beraldo, H., Garnier-Suillerot, A., Tosi, L., and Lavelle, R, 1985, Iron(III)-adriamycin and Iron(III)-daunorubicin complexes: Physicochemical characteristics, interaction with DNA, and antitumor activity, Biochemistry 24(2):284–289.CrossRefPubMedGoogle Scholar
  13. Bernardi, P., and Petronilli, V, 1996, The permeability transition pore as a mitochondrial calcium release channel: A critical appraisal, J. Bioenerg. Biomembr. 28(2):131–138.CrossRefPubMedGoogle Scholar
  14. Bernardi, P., Broekemeier, K. M., and Pfeiffer, D. R., 1994, Recent progress on regulation of the mitochondrial permeability transition pore: A cyclosporin-sensitive pore in the inner mitochondrial membrane, J. Bioenerg. Biomembr. 26(5):509–517.CrossRefPubMedGoogle Scholar
  15. Berry, G., Billingham, M., Alderman, E., Richardson, P., Torti, F., Lum, B., Patek, A., and Martin, F. J., 1998, The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi’s sarcoma patients treated with pegylated liposomal doxorubicin, Ann. Oncol. 9(7):711–716.CrossRefPubMedGoogle Scholar
  16. Bertazzoli, C., Sala, L., Ballerini, L., Watanabe, T., and Folkers, K., 1976, Effect of Adriamycin on the activity of the succinate dehydrogenase-coenzyme Q10 reductase of the rabbit myocardium. Res. Commun. Chem. Pathol. Pharmacol. 15(4):797–800.PubMedGoogle Scholar
  17. Bianchi, C., Bagnato, A., Paggi, M. G., and Floridi, A., 1987, Effect of Adriamycin on electron transport in rat heart, liver, and tumor mitochondria, Exp. Mol. Pathol. 46(l):123–135.PubMedGoogle Scholar
  18. Billingham, M. E., Mason, J. W., Bristow, M. R., and Daniels J. R., 1978, Anthracycline cardiomyopathy monitored by morphologic changes, Cancer Treat. Rep. 62(6):865–872.PubMedGoogle Scholar
  19. Boucek, R. J., Jr., Dodd, D. A., Atkinson, J. B., Oquist, N., and Olson, R. D., 1997, Contractile failure in chronic doxorubicin-induced cardiomyopathy, J. Mol. Cell. Cardiol. 29(10):2631–2640.PubMedGoogle Scholar
  20. Boulay, G., and Debaene, B., 1998, Acute cardiogenic postoperative edema after doxorubicin (Adriamycin) chemotherapy, Ann. Fr. Anesth, Reanim. 17(l):43–46.Google Scholar
  21. Brady, L. J., and Brady, P. S., 1987, Hepatic and cardiac carnitine palmitoyltransferase activity: Effects of Adriamycin and galactosamine, Biochem. Pharmacol, 36(20):3419–3423.CrossRefPubMedGoogle Scholar
  22. Bristow, M. R., Billingham, M. E., Mason, J. W., and Daniels, J. R., 1978, Clinical spectrum of anthracycline antibiotic cardiotoxicity, Cancer Treat. Rep. 62(6):873–879.PubMedGoogle Scholar
  23. Bristow, M. R., Mason, J. W., Billingham, M. E., and Daniels, J. R., 1981, Dose-effect and structure-function relationships in doxorubicin cardiomyopathy, Am. Heart J. 102(4):709–718.CrossRefPubMedGoogle Scholar
  24. Calzas, J., Lianes, P., and Cortes-Funes, H., 1998, Heart pathology of extracardiac origin: VII. Heart and neoplasms, Rev. Esp. Cardiol., 51(4):314–331.PubMedGoogle Scholar
  25. Chacon, E., and Acosta, D., 1991, Mitochondrial regulation of superoxide by Ca2+: An alternate mechanism for the cardiotoxicity of doxorubicin, Toxicol. Appl. Pharmacol. 107(1):117–128.CrossRefPubMedGoogle Scholar
  26. Chacon, E., Ulrich, R., and Acosta, D., 1992, A digitised-fluorescence-imaging study of mitochondrial Ca2+ increase by doxorubicin in cardiac myocytes, Biochem. J. 281(Pt. 3):871–878.PubMedGoogle Scholar
  27. Chalcroft, S. C., Gavin, J. B., and Herdson, P. B., 1973, Fine structural changes in rat myocardium induced by daunorubicin, Pathology 5(2):99–105.PubMedGoogle Scholar
  28. Chatham, J. C., Cousins, J. P., and Glickson, J. D., 1990, The relationship between cardiac function and metabolism in acute Adriamycin-treated perfused rat hearts studied by 31P and 13C NMR spectroscopy, J. Mol. Cell. Cardiol. 22(10):1187–1197.CrossRefPubMedGoogle Scholar
  29. Cheneval, D., Muller M., and Carafoli, E., 1983, The mitochondrial phosphate carrier reconstituted in liposomes is inhibited by doxorubicin, FEBS. Lett. 159(1, 2):123–126.PubMedGoogle Scholar
  30. Cuellar, A., Escamilla, E., Ramirez, J., and Chavez, E., 1984, Adriamycin as an inhibitor of 11 beta-hydroxylase activity in adrenal cortex mitochondria, Arch. Biochem. Biophys. 235(2):538–543.CrossRefPubMedGoogle Scholar
  31. Davies, K. J., and Doroshow, J. H., 1986, Redox cycling of anthracyclines by cardiac mitochondria: I. Anthracycline radical formation by NADH dehydrogenase, J. Biol. Chem. 261(7):3060–3067.PubMedGoogle Scholar
  32. Davies, K. J., Doroshow, J. H., and Hochstein, P., 1983, Mitochondrial NADH dehydrogenase-catalyzed oxygen radical production by Adriamycin and the relative inactivity of 5-iminodaunorubicin, FEBS. Lett. 153(1):227–230.CrossRefPubMedGoogle Scholar
  33. Dekker, T., van Echteld, C. J., Kirkels, J. H., Ruigrok, T. J., van Hoesel, Q. G., de Jong, W. H., and Schornagel, J. H., 1991, Chronic cardiotoxicity of Adriamycin studied in a rat model by 31P NMR, NMR Biomed. 4(l):16–24.PubMedGoogle Scholar
  34. Demant, E. J., 1991, Inactivation of cytochrome c oxidase activity in mitochondrial membranes during redox cycling of doxorubicin, Biochem. Pharmacol. 41(4):543–552.CrossRefPubMedGoogle Scholar
  35. Demant, E. J., and Jensen, P. K., 1983, Destruction of phospholipids and respiratory-chain activity in pig-heart submitochondrial particles induced by an Adriamycin-iron complex, Eur. J. Biochem. 132(3):551–556.PubMedGoogle Scholar
  36. Doroshow, J. H., and Davies, K. J., 1986, Redox cycling of anthracyclines by cardiac mitochondria: II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical, J. Biol. Chem. 261(7):3068–3074.PubMedGoogle Scholar
  37. Doroshow, J. H., 1983a, Anthracycline antibiotic-stimulated superoxide, hydrogen peroxide, and hydroxyl radical production by NADH dehydrogenase, Cancer Res. 43(10):4543–4551.PubMedGoogle Scholar
  38. Doroshow, J. H., 1983b, Effect of anthracycline antibiotics on oxygen radical formation in rat heart, Cancer Res. 43(2):460–472.PubMedGoogle Scholar
  39. Dutta, P. K., and Hurt, J. A., 1986, Resonance Raman spectroscopic studies of Adriamycin and copper(II)-Adriamycin and copper(II)-Adriamycin-DNA complexes, Biochemistry 25(3):691–695.CrossRefPubMedGoogle Scholar
  40. Eilers, M, Endo, T., and Schatz, G., 1989, Adriamycin, a drug interacting with acidic phospholipids, blocks import of precursor proteins by isolated yeast mitochondria, J. Biol. Chem. 264(5):2945–2950.PubMedGoogle Scholar
  41. Ferrans, V. )., 1978, Overview of cardiac pathology in relation to anthracycline cardiotoxicity, Cancer Treat. Rep. 62(6):955–961.PubMedGoogle Scholar
  42. Ferrans, V. J., Clark, J. R., Zhang, J., Yu, Z. X., and Herman, E. H., 1997, Pathogenesis and prevention of doxorubicin Cardiomyopathy, Tsitologiia 39(10):928–937.PubMedGoogle Scholar
  43. Ferrero, M. E., Ferrero, E., Gaja, G., and Bernelli-Zazzera, A., 1976, Adriamycin: Energy metabolism and mitochondrial oxidations in the heart of treated rabbits, Biochem. Pharmacol. 25(2):125–130.CrossRefPubMedGoogle Scholar
  44. Floridi, A., Pulselli, R., Gentile, F. P., Barbieri, R., and Benassi, M., 1994, Rhein enhances the effect of Adriamycin on mitochondrial respiration by increasing antibiotic-membrane interaction, Biochem. Pharmacol. 47(10):1781–1788.CrossRefPubMedGoogle Scholar
  45. Friedman, M. A., Bozdech, M. J., Billingham, M. E., and Rider, A. K., 1978, Doxorubicin cardiotoxicity: Serial endomyocardial biopsies and systolic time intervals, JAMA 240(15):1603–1606.CrossRefPubMedGoogle Scholar
  46. Geetha, A., 1993, Influence of alpha-tocopherol on doxorubicin-induced lipid peroxidation, swelling, and thiol depletion in rat heart mitochondria, Indian J. Exp. Biol. 31(3):297–298.PubMedGoogle Scholar
  47. Geetha, A., Devi, C.S., 1992, Effect of doxorubicin on heart mitochondrial enzymes in rats: A protective role for alpha-tocopherol, Indian J. Exp. Biol. 30(7):615–618.PubMedGoogle Scholar
  48. Gervasi, P. G., Agrillo, M. R., Citti, L., Danesi, R., and Del Tacca, M., 1986, Superoxide anion production by adriamycinol from cardiac sarcosomes and by mitochondrial NADH dehydrogenase, Anticancer Res. 6(5):1231–1235.PubMedGoogle Scholar
  49. Gervasi, P. G., Agrillo, M. R., Lippi, A., Bernardini, N., Danesi, R., and Del Tacca, M., 1990, Superoxide anion production by doxorubicin analogs in heart sarcosomes and by mitochondrial NADH dehydrogenase, Res. Commun. Chem. Pathol. Pharmacol. 67(1):101–115.PubMedGoogle Scholar
  50. Gianni, L., 1998, Paclitaxel plus doxorubicin in metastatic breast Ca: The Milan experience, Oncology (Hunting!.) 12(1) (Suppl. 1):13–15.Google Scholar
  51. Gille, L., and Nohl, H., 1997, Analyses of the molecular mechanism of Adriamycin-induced cardiotoxicity, Free Radical Biol. Med. 23(5):775–782.CrossRefGoogle Scholar
  52. Goormaghtigh, E., Brasseur, R., and Ruysschaert, J. M., 1982, Adriamycin inactivates cytochrome c oxidase by exclusion of the enzyme from its cardiolipin essential environment, Biochem. Biophys. Res. Commun. 104(1):314–320.CrossRefPubMedGoogle Scholar
  53. Goormaghtigh, E., Huart, P., Brasseur, R., and Ruysschaert, J. M., 1986, Mechanism of inhibition of mitochondrial enzymatic complex I–III by Adriamycin derivatives, Biochem. Biophys. Acta 861(l):83–94.PubMedGoogle Scholar
  54. Goormaghtigh, E., Huart, P., Praet, M., Brasseur, R., and Ruysschaert, J. M., 1990, Structure of the Adriamycin-cardiolipin complex: Role in mitochondrial toxicity, Biophys. Chem. 35(2, 3):247–257.PubMedGoogle Scholar
  55. Gorodetskaya, E. A., Dugin, S. F., Golikov, M. A., Kapelko, V. I., and Medvedev, O. S., 1990, The cardiac contractile function and hemodynamic control in rats after chronic Adriamycin treatment, Can. J. Physiol. Pharmacol. 68(2):211–215.PubMedGoogle Scholar
  56. Griffin-Green, E. A., Zaleska, M. M., Erecinska, M., 1988, Adriamycin-induced lipid peroxidation in mitochondria and microsomes, Biochem. Pharmacol. 37(16):3071–3077.CrossRefPubMedGoogle Scholar
  57. Gunter, T. E., Wingrove, D. E., Banerjee, S., and Gunter, K. K., 1988, Mechanisms of mitochondrial calcium transport, Adv. Exp. Med. Biol. 232:1–14.PubMedGoogle Scholar
  58. Gutierrez, P. L., Gee, M. V, and Bachur, N. R., 1983, Kinetics of anthracycline antibiotic free radical formation and reductive glycosidase activity, Arch. Biochem. Biophys. 223(1):68–75.CrossRefPubMedGoogle Scholar
  59. Hasinoff, B. B., 1990a, Inhibition and inactivation of NADH-cytochrome c reductase activity of bovine heart submitochondrial particles by the iron(III)-Adriamycin complex, Biochem. J. 265(3):865–870.PubMedGoogle Scholar
  60. Hasinoff, B. B., 1990b, Oxyradical production results from the Fe3+-doxorubicin complex undergoing self-reduction by its alpha-ketol group, Biochem. Cell Biol 68(12):1331–1336.PubMedGoogle Scholar
  61. Herman, E. H., Zhang, J., and Ferrans, V. J., 1994, Comparison of the protective effects of desferrioxamine and ICRF-187 against doxorubicin-induced toxicity in spontaneously hypertensive rats. Cancer Chemother. Pharmacol. 35(2):93–100.CrossRefPubMedGoogle Scholar
  62. Hirsch, T., Marzo, I., and Kroemer, G., 1997, Role of the mitochondrial permeability transition pore in apoptosis, Biosci. Rep. 17(1):67–76.CrossRefPubMedGoogle Scholar
  63. Hirsch, T., Susin, S. A., Marzo, I., Marchetti, P., Zamzami, N., and Kroemer, G., 1998, Mitochondrial permeability transition in apoptosis and necrosis, Cell Biol. Toxicol. 14(2):141–145.CrossRefPubMedGoogle Scholar
  64. Hofling, B., Zahringer, J., and Bolte, H. D., 1982, Adriamycin-induced decrease of myocardial contraction reserve in rats treated with dobutamine, Eur. J. Cancer Clin. Oncol. 18(1):75–80.CrossRefPubMedGoogle Scholar
  65. Huart, R, Brasseur, R.. Goormaghtigh, E., and Ruysschaert, J. M., 1984, Antimitotics induce cardiolipin cluster formation: Possible role in mitochondrial enzyme inactivation, Biochim. Biophys. Acta 799(2):199–202.PubMedGoogle Scholar
  66. Jensen, R. A., Acton, E. M., and Peters, J. H., 1984, Doxorubicin cardiotoxicity in the rat: Comparison of electrocardiogram, transmembrane potential, and structural effects, J. Cardiovasc. Pharmacol. 6(1):186–200.PubMedGoogle Scholar
  67. Ji, L. L., and Mitchell, E. W., 1994, Effects of Adriamycin on heart mitochondrial function in rested and exercised rats, Biochem. Pharmacol. 47(5):877–885.PubMedGoogle Scholar
  68. Kang, Y. J., Chen, Y., and Epstein, P. N., 1996, Suppression of doxorubicin cardiotoxicity by overexpression of catalase in the heart of transgenic mice, J. Biol. Chem. 271(21):12610–12616.PubMedGoogle Scholar
  69. Kang, Y. J., Chen, Y, Yu, A., Voss-McCowan, M., and Epstein, P. N., 1997, Overexpression of metallothionein in the heart of transgenic mice suppresses doxorubicin in cardiotoxicity, J. Clin. Invest. 100(6):1501–1506.PubMedGoogle Scholar
  70. Kashfi, K., Israel, M., Sweatman, T. W., Seshadri, R., and Cook, G. A., 1990, Inhibition of mitochondrial carnitine palmitoyltransferases by Adriamycin and Adriamycin analogues, Biochem. Pharmacol. 40(70):1441–1448.PubMedGoogle Scholar
  71. Kawasaki, N., Lee, J. D., Shimizu, H., Ishii, Y., and Ueda, T., 1996, Cardiac energy metabolism at several stages of Adriamycin-induced heart failure in rats. Int. J. Cardiol. 55(3):217–225.CrossRefPubMedGoogle Scholar
  72. Keizer, H. G., Pinedo, H. M., Schuurhuis, G. J., and Joenje, H., 1990, Doxorubucin (Adriamycin): A critical review of free radical-dependent mechanisms of cytotoxicity, Pharmacol. Ther. 47(2):219–231.CrossRefPubMedGoogle Scholar
  73. Lee, V, Randhawa, A. K., and Singal, P. K., 1991, Adriamycin-induced myocardial dysfunction in vitro is mediated by free radicals, Am. J. Physiol. 261(4) (Pt 2):H989–995.PubMedGoogle Scholar
  74. Lefrak, E. A., Pitha, J., Rosenheim, S., and Gottlieb, J. A., 1973, A clinicopathologic analysis of Adriamycin cardiotoxicity, Cancer 32(2):302–314.PubMedGoogle Scholar
  75. Lemasters, J. J., 1998, The mitochondrial permeability transition: From biochemical curiosity to pathophysiological mechanism [editorial; comment], Gastroenterology 115(3):783–786.CrossRefPubMedGoogle Scholar
  76. Lemasters, J. J., Nieminen, A. L., Qian, T., Trost, L. C., Elmore, S. P., Nishimura, Y, Crowe, R. A., Cascio, W. E., Bradham, C. A., Brenner, D. A., and Herman, B., 1998, The mitochondrial permeability transition in cell death: A common mechanism in necrosis, apoptosis, and autophagy, Biochim. Biophys. Acta 1366(1, 2): 177–196.PubMedGoogle Scholar
  77. Lin, T. J., Liu, G. T., Pan, Y, Liu, Y, and Xu, G. Z., 1991, Protection by schisahenol against Adriamycin toxicity in rat heart mitochondria, Biochem. Pharmacol. 42(9):1805–1810.PubMedGoogle Scholar
  78. Lin, T. J., Liu, G. T., Liu, Y, and Xu, G. Z., 1992, Protection by salvianolic acid A against Adriamycin toxicity on rat heart mitochondria, Free Radical Biol. Med. 12(5):347–351.CrossRefGoogle Scholar
  79. Link, G., Tirosh, R., Pinson, A., and Hershko, C., 1996, Role of iron in the potentiation of anthracycline cardiotoxicity: Identification of heart cell mitochondria as a major site of iron-anthracycline interaction, J. Lab. Clin. Med. 127(3):272–278.CrossRefPubMedGoogle Scholar
  80. Lown, J. W., Chen, H. H., Plambeck, J. A., and Acton, E. M., 1982, Further studies on the generation of reactive oxygen species from activated anthracyclines and the relationship to cytotoxic action and cardiotoxic effects, Biochem. Pharmacol. 31(4):575–581.PubMedGoogle Scholar
  81. Malatesta, V, Morazzoni, E, Gervasini, A., and Arcamone, F., 1985, Chelation of copper(II) ions by doxorubicin and 4′-epidoxorubicin: An e.s.r. study, Anticancer Drug Des. 1(l):53–57.PubMedGoogle Scholar
  82. Malisza, K. L., and Hasinoff, B. B., 1995, Production of hydroxyl radical by iron(III)-anthraquinone complexes through self-reduction and through reductive activation by the xanthine oxidase/hypoxanthine system, Arch. Biochem. Biophys. 321(1):51–60.CrossRefPubMedGoogle Scholar
  83. Marcillat, O., Zhang, Y., Davies, K. J., 1989, Oxidative and non-oxidative mechanisms in the inactivation of cardiac mitochondrial electron transport chain components by doxorubicin, Biochem. J. 259(1):181–189.PubMedGoogle Scholar
  84. Matsumura, M., Nishioka, K.., Fujii, T., Yoshibayashi, M., Nozaki, K., Nakata, Y., Temma, S., Ueda, T., and Mikawa, H., 1994, Age-related acute Adriamycin cardiotoxicity in mice, J. Mol. Cell Cardiol 26(7):899–905.CrossRefPubMedGoogle Scholar
  85. McKillop, J. H., Bristow, M. R., Goris, M. L., Billingham, M. E., and Bockemuehl, K., 1983, Sensitivity and specificity of radionuclide ejection fractions in doxorubicin cardiotoxicity, Am. Heart J. 106(5) (Pt. 1):1048–1056.CrossRefPubMedGoogle Scholar
  86. Meredith, M. J., and Reed, D. J., 1983, Depletion in vitro of mitochondrial glutathione in rat hepatocytes and enhancement of lipid peroxidation by Adriamycin and l,3-bis(2-chloroethyl)-l-nitrosourea (BCNU), Biochem. Pharmacol. 32(8):1383–1388.CrossRefPubMedGoogle Scholar
  87. Mimnaugh, E. G., Trush, M. A., Bhatnagar, M., and Gram, T. E., 1985, Enhancement of reactive oxygen-dependent mitochondrial membrane lipid peroxidation by the anticancer drug Adriamycin, Biochem. Pharmacol. 34(6):847–856.CrossRefPubMedGoogle Scholar
  88. Miura, T., Muraoka, S., Ogiso, T., 1994, Adriamycin-Fe3+-induced inactivation of rat heart mitochondrial creatine kinase: Sensitivity to lipid peroxidation, Biol. Pharm. Bull. 17(9):1220–1223.PubMedGoogle Scholar
  89. Montali, U, Del Tacca, M., Bernardini, C., Segnini, D., and Solaini, G., 1985, Cardiotoxic effects of Adriamycin and mitochondrial oxidation in rat cardiac tissue, Drug Exp. Clin. Res. 11(3):219–222.Google Scholar
  90. Monti, E., Paracchini, L., Perletti, G., and Piccinini, F., 1991, Protective effects of spin-trapping agents on Adriamycin-induced cardiotoxicity in isolated rat atria, Free Radical Res. Commun. 14(l):41–45.Google Scholar
  91. Monti, E., Prosperi, E., Supino, R., and Bottiroli, G., 1995, Free radical-dependent DNA lesions are involved in the delayed cardiotoxicity induced by Adriamycin in the rat, Anticancer Res. 15(1):193–197.PubMedGoogle Scholar
  92. Moore, L., Landon, E. J., Cooney, D. A., 1977, Inhibition of the cardiac mitochondrial calcium pump by Adriamycin in vitro, Biochem. Med. 18(2):131–138.CrossRefPubMedGoogle Scholar
  93. Mortensen, S. A., Olsen, H. S., and Baandrup, U., 1986, Chronic anthracycline cardiotoxicity: Haemodynamic and histopathological manifestations suggesting a restrictive endomyocardial disease, Br. Heart J. 55(3):274–282.PubMedGoogle Scholar
  94. Mott, M. G., 1997, Anthracycline cardiotoxicity and its prevention, Ann. NY Acad. Sci. 824:221–228.PubMedGoogle Scholar
  95. Muhammed, H., and Kurup, C. K., 1984, Influence of ubiquinone on the inhibitory effect of Adriamycin on mitochondrial oxidative phosphorylation, Biochem. J. 217(2):493–498.PubMedGoogle Scholar
  96. Muhammed, H., Ramasarma, T., and Kurup, C. K., 1983, Inhibition of mitochondrial oxidative phosphorylation by Adriamycin, Biochim. Biophys. Acta 722(1):43–50.PubMedGoogle Scholar
  97. Nicolay, K., and de Kruijff, B. 1987, Effects of Adriamycin on respiratory chain activities in mitochondria from rat liver, rat heart and bovine heart: Evidence for a preferential inhibition of complex III and IV, Biochim. Biophys. Acta 892(3):320–330.PubMedGoogle Scholar
  98. Nicolay, K., Timmers, R. J., Spoelstra, E., Van der Neut, R., Fok, J. J., Huigen, Y. M., Verkleij, A. J., and De Kruijff, B., 1984, The interaction of Adriamycin with cardiolipin in model and rat liver mitochondrial membranes, Biochim. Biophys. Acta 778(2):359–371.PubMedGoogle Scholar
  99. Nohl, H., and Jordan, W., 1983, OH-generation by Adriamycin semiquinone and H2O2: An explanation for the cardiotoxicity of anthracycline antibiotics, Biochem. Biophys. Res. Commun. 114(1):197–205.CrossRefPubMedGoogle Scholar
  100. Ogura, R., Sugiyama, M., Haramaki, N., and Hidaka, T., 1991, Electron spin resonance studies on the mechanism of Adriamycin-induced heart mitochondrial damages, Cancer Res. 51(13):3555–3558.PubMedGoogle Scholar
  101. Olson, H. M., and Capen, C. C., 1978, Chronic cardiotoxicity of doxorubicin (Adriamycin) in the rat: Morphologic and biochemical investigations, Toxicol. Appl. Pharmacol. 44(3):605–616.CrossRefPubMedGoogle Scholar
  102. Olson, R. D., and Mushlin, P. S., 1990, Doxorubicin cardiotoxicity: Analysis of prevailing hypotheses [see comments], FASEB J. 4(13):3076–3086.PubMedGoogle Scholar
  103. Olson, R. D., MacDonald, J. S., van Boxtel, C. J., Boerth, R. C., Harbison, R. D., Slonim, A. E., Freeman, R. W., and Oates, J. A., 1980, Regulatory role of glutathione and soluble sulfhydryl groups in the toxicity of Adriamycin, J. Pharmacol. Exp. Ther. 215:450–454.PubMedGoogle Scholar
  104. Olson, R. D., Boerth, R. C., Gerger, J. G., and Nies, A. S., 1981, Mechanism of Adriamycin cardiotoxicity: Evidence for oxidative stress, Life Sci. 29(14):1393–1401.CrossRefPubMedGoogle Scholar
  105. Pan, S. S., and Bachur, N. R., 1980, Xanthine oxidase catalyzed reductive cleavage of anthracycline antibiotics and free radical formation, Mol. Pharmacol. 17(1):95–99.PubMedGoogle Scholar
  106. Paradies, G., and Ruggiero, F. M, 1988, The effect of doxorubicin on the transport of pyruvate in rat-heart mitochondria, Biochem. Biophys. Res. Commun. 156(3):1302–1307.CrossRefPubMedGoogle Scholar
  107. Petronilli, V, Costantini, P., Scorrano, L., Colonna, R., Passamonti, S., and Bernardi, P., 1994, The voltage sensor of the mitochondrial permeability transition pore is tuned by the oxidation-reduction state of vicinal thiols: Increase of the gating potential by oxidants and its reversal by reducing agents, J. Biol. Chem. 269(24):16638–16642.PubMedGoogle Scholar
  108. Piccinini, F., Monti, E., Paracchini, L., and Perlettei, G., 1990, Are oxygen radicals responsible for the acute cardiotoxicity of doxorubicin? Adv. Exp. Med. Biol. 264:349–352.PubMedGoogle Scholar
  109. Pollakis, G., Goormaghtigh, E., Delmelle, M., Lion, Y., and Ruysschaert, J. M., 1984, Adriamycin and derivatives interaction with the mitochondrial membrane: O2 consumption and free radical formation, Res. Commun. Chem. Pathol. Pharmacol. 44(3):445–459.PubMedGoogle Scholar
  110. Praet, M., Laghmiche, M., Pollakis, G., Goormaghtigh, E., and Ruysschaert, J. M., 1986, In vivo and in vitro modifications of the mitochondrial membrane induced by 4′-Epi-Adriamycin, Biochem. Pharmacol. 35(17):2923–2928.CrossRefPubMedGoogle Scholar
  111. Praet, M., Calderon, P. B., Pollakis, G., Roberfroid, M., and Ruysschaert, J. M., 1988, A new class of free radical scavengers reducing Adriamycin mitochondrial toxicity, Biochem. Pharmacol. 37(24):4617–4622.CrossRefPubMedGoogle Scholar
  112. Praga, C., Beretta, G., et al., 1979, Adriamycin cardiotoxicity: A survey of 1273 patients, Cancer Treat. Rep. 63(5):827–834.PubMedGoogle Scholar
  113. Revis, N., Marusic, N., 1979, Sequestration of 45Ca2+ by mitochondria from rabbit heart, liver, and kidney after doxorubicin or digoxin/doxorubicin treatment, Exp. Mol. Pathol. 31(3):440–451.CrossRefPubMedGoogle Scholar
  114. Revis, N. W., Marusic, N., 1979, Effects of doxorubicin and its aglycone metabolite on calcium sequestration by rabbit heart, liver, and kidney mitochondria, Life Sci., 25(12):1055–1063.CrossRefPubMedGoogle Scholar
  115. Rhoden, W., Hasleton, P., and Brooks, N., 1993, Anthracyclines and the heart [see comments], Br. Heart J. 70(6):499–502.PubMedGoogle Scholar
  116. Rosenoff, S. H., Olson, H. M., Young, D. M., Bostick, F., and Young, R. C., 1975, Adriamycin-induced cardiac damage in the mouse: A small-animal model of cardiotoxicity, J. Natl. Cancer Inst. 55(1):191–194.PubMedGoogle Scholar
  117. Saltiel, E., McGuire, W, 1983, Doxorubicin (Adriamycin) cardiomyopathy, West. J. Med. 139(3):332–341.PubMedGoogle Scholar
  118. Scheulen, M. E., and Kappus, H., 1981, Metabolic activation of Adriamycin by NADPH-cytochrome P-450 reductase, rat liver, and heart microsomes and covalent protein binding of metabolites, Adv. Exp. Mol. Biol. 136(Pt. A):471–485.Google Scholar
  119. Scheulen, M. E., Kappus, H., Nienhaus, A., and Schmidt, C. G., 1982, Covalent protein binding of reactive Adriamycin metabolites in rat liver and rat heart microsomes, J. Cancer Res. Clin. Oncol. 103(1):39–48.CrossRefPubMedGoogle Scholar
  120. Shinozawa, S., Fukuda, T., Araki, Y, and Oda, T, 1985, Effect of dextran sulfate on the survival time and mitochondrial function of Adriamycin-(doxorubicin)-treated mice, Toxicol. Appl. Pharmacol. 79(2):353–357.CrossRefPubMedGoogle Scholar
  121. Singal, P. K., Iliskovic, N., Li, T., and Kumar, D., 1997, Adriamycin cardiomyopathy: Pathophysiology and prevention, FASEB J. 11(12):931–936.PubMedGoogle Scholar
  122. Singal, P. K., and Iliskovic, N., 1998, Doxorubicin-induced cardiomyopathy, N. Engl. J. Med. 339(13):900–905.CrossRefPubMedGoogle Scholar
  123. Singal, P. K., Forbes, M. S., and Sperelakis, N., 1984, Occurrence of intramitochondrial Ca2+ granules in a hypertrophied heart exposed to Adriamycin, Can. J. Physiol. Pharmacol. 62(9):1239–1244.PubMedGoogle Scholar
  124. Singal, P. K., Deally, C. M., and Weinberg, L. E., 1987, Subcellular effects of Adriamycin in the heart: A concise review, J. Mol. Cell Cardiol. 19(8):817–828.PubMedGoogle Scholar
  125. Sokolove, P. M., 1988, Mitochondrial sulfhydryl group modification by Adriamycin aglycones, FEBS Lett. 234(1):199–202.CrossRefPubMedGoogle Scholar
  126. Sokolove, P. M., 1990, Inhibition by cyclosporin A and butylated hydroxytoluene of the inner mitochondrial membrane permeability transition induced by Adriamycin and aglycones, Biochem. Pharmacol. 40(12):2733–2736.CrossRefPubMedGoogle Scholar
  127. Sokolove, P. M., 1991, Oxidation of mitochondrial pyridine nucleotides by aglycone derivatives of adriamycin, Arch. Biochem. Biophys. 284(2):292–297.CrossRefPubMedGoogle Scholar
  128. Sokolove, P. M., and Shinaberry, R. G., 1988, Na1-independent release of Ca2+ from rat heart mitochondria: Induction by Adriamycin aglycone, Biochem. Pharmacol. 37(5):803–812.CrossRefPubMedGoogle Scholar
  129. Solaini, G., Ronca, G., and Bertelli, A., 1985, Studies on the effects of anthracyclines on mitochondrial respiration in vitro, Drugs Exp. Clin. Res. 11(2):115–121.PubMedGoogle Scholar
  130. Solaini, G., Landi, L., Pasquali, P., and Rossi, C. A., 1987, Protective effect of endogenous coenzyme Q on both lipid peroxidation and respiratory chain inactivation induced by an Adriamycin-iron complex, Biochem. Biophys. Res. Commun. 147(2):572–580.CrossRefPubMedGoogle Scholar
  131. Solem, L. E., and Wallace, K. B., 1993, Selective activation of the sodium-independent, cyclosporin A-sensitive calcium pore of cardiac mitochondria by doxorubicin, Toxicol. Appl. Pharmacol. 121(1):50–57.CrossRefPubMedGoogle Scholar
  132. Solem, L. E., Henry, T. R., and Wallace, K. B., 1994, Disruption of mitochondrial calcium homeostasis following chronic doxorubicin administration, Toxicol. Appl. Pharmacol. 129(2):214–222.CrossRefPubMedGoogle Scholar
  133. Solem, L. E., Heller, L. J., and Wallace, K.. B., 1996, Dose-dependent increase in sensitivity to calcium-induced mito-chondrial dysfunction and cardiomyocete cell injury by doxorubicin, J. Mol. Cell Cardiol. 28(5): 1023–1032.CrossRefPubMedGoogle Scholar
  134. Steinherz, L., and Steinherz, P., 1991, Delayed cardiac toxicity from anthracycline therapy, Paediatrician 18(1):49–52.Google Scholar
  135. Steinherz, L. J., Stenherz, P. G., Tan, C. J., Heller, G., and Murphy, M. L., 1991, Cardiac toxicity 4 to 20 years after completing anthracycline therapy, JAMA 266(12):1672–1677.CrossRefPubMedGoogle Scholar
  136. Steinherz, L. J., Steinherz, P. G., and Tan, C., 1995, Cardiac failure and dysrhythmias 6–19 years after anthracycline therapy: A series of 15 patients, Med. Pediat. Oncol. 24(6):352–361.Google Scholar
  137. Sugiyama, S., Yamada, K., Hayakawa, M., and Ozawa, T., 1995, Approaches that mitigate doxorubicin-induced delayed adverse effects on mitochondrial function in rat hearts: Liposome-encapsulated doxorubicin or combination therapy with antioxidant, Biochem. Mol. Biol. Int. 36(5):1001–1007.PubMedGoogle Scholar
  138. Suzuki, T., Kanda, H., Kawai, Y., Tominaga, K., and Murata, K., 1979, Cardiotoxicity of anthracycline antineoplastic drugs: Clinicopathological and experimental studies, Jpn. Circ. J. 43(11):100–1008.Google Scholar
  139. Thayer, W. S., 1977, Adriamycin stimulated superoxide formation in submitochondrial particles, Chem. Biol. Int. 19(3):265–278.Google Scholar
  140. Trost, L. C., and Wallace, K. B., 1994a, Adriamycin-induced oxidation of myoglobin, Biochem. Biophys. Res. Commun. 204(1):30–37.PubMedGoogle Scholar
  141. Trost, L. C., and Wallace, K. B., 1994b, Stimulation of myoglobin-dependent lipid peroxidation by Adriamycin, Biochem. Biophys. Res. Commun. 204(1):23–29.PubMedGoogle Scholar
  142. Vails, V, Castelluccio, C., Fato, R., Genova, M. L., Bovina, C., Saez, G., Marchetti, M., Parenti Castelli, G., and Lenaz, G., 1994, Protective effect of exogenous coenzyme Q against damage by Adriamycin in perfused rat liver, Biochem. Mol. Bio. Int. 33(4):633–642.Google Scholar
  143. Van Vleet, J. F., and Ferrans, V. J., 1980, Clinical observations, cutaneous lesions, and hematologic alterations in chronic Adriamycin intoxication in dogs with and without vitamin E and selenium supplementation, Am. J. Vet. Res. 41(5):691–699.PubMedGoogle Scholar
  144. Vile, G. F., Winterbourn, C. C., Sutton, H. C., 1987, Radical-driven Fenton reactions: Studies with paraquat, Adriamycin, and anthraquinone 6-sulfonate and citrate, ATP, ADP, and pyrophosphate iron chelates, Arch. Biochem. Biophys. 259(2):6l6–626.CrossRefGoogle Scholar
  145. Villani, F, Favalli, L., Lanza, E., Rozza-Dionigi, A., and Poggi, P., 1987, Anthracycline cardiotoxicity in the rat: Relationship between ECG changes and morphologic effects induced by different analogues, Chemioterapia 6(2) (Suppl):688–690.PubMedGoogle Scholar
  146. Voelker, D. R., 1991, Adriamycin disrupts phosphatidylserine import into the mitochondria of permeabilized CHO-K1 cells, J. Biol. Chem. 266(19):12185–12188.PubMedGoogle Scholar
  147. Wallace, K. B., 1986a, Aglycosylation and disposition of doxorubicin in isolated rat liver nuclei and microsomes, Drug Metab. Dis. 14(4):399–404.Google Scholar
  148. Wallace, K. B., 1986b, Nonenzymatic oxygen activation and stimulation of lipid peroxidation by doxorubicin-copper, Toxicol. Appl. Pharmacol. 86(1):69–79.CrossRefPubMedGoogle Scholar
  149. Wallace, K. B., and Johnson, J. A., 1987, Oxygen-dependent effect of microsomes on the binding of doxorubicin to rat hepatic nuclear DNA, Mol. Pharmacol. 31(3):307–311.PubMedGoogle Scholar
  150. Yamada, K., Sugiyama, S., Kosaka, K., Hayakawa, M., and Ozawa, T., 1995, Early appearance of age-associated deterioration in mitochondrial function of diaphragm and heart in rats treated with doxorubicin, Exp. Gerontol. 30(6):581–593.CrossRefPubMedGoogle Scholar
  151. Yen, H. C., Oberley, T. D., Vichitbandha, S., Ho, Y. S., and St Clair, D. K., 1996, The protective role of manganese superoxide dismutase against Adriamycin-induced acute cardiac toxicity in transgenic mice [erratum appears in 1997, J. Clin. Invest. 99 (5):1141], J. Clin. Invest. 98(5):1253–1260.PubMedGoogle Scholar
  152. Zidenberg-Cherr, S., and Keen, C. L., 1986, Influence of dietary manganese and vitamin E on Adriamycin toxicity in mice, Toxicol. Lett. 30(1):79–87.CrossRefPubMedGoogle Scholar
  153. Zoratti, M., and Szabò, I., 1995, The mitochondrial permeability transition, Biochim. Biophys. Acta 1241(2): 139–176.PubMedGoogle Scholar
  154. Zunino, F., and Capranico, G., 1990, DNA topoisomerase II as the primary target of anti-tumor anthracyclines, Anticancer Drug Des. 5(4):307–317.PubMedGoogle Scholar
  155. Zweier, J. L., 1984, Reduction of O2 by iron-Adriamycin, J. Biol. Chem. 259(10):6056–6058.PubMedGoogle Scholar
  156. Zweier, J. L., 1985, Iron-mediated formation of an oxidized Adriamycin free radical, Biochim. Biophys. Acta 829(2):209–213.Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Kendall B. Wallace
    • 1
  1. 1.Department of Biochemistry and Molecular BiologyUniversity of Minnesota School of MedicineDuluth

Personalised recommendations