Cardiovascular Toxicology

, Volume 7, Issue 2, pp 101–107 | Cite as

Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis



Adriamycin (doxorubicin) is a potent and broad-spectrum antineoplastic agent, the clinical utility of which is limited by the development of a cumulative and irreversible cardiomyopathy. Although the drug affects numerous structures in different cell types, the mitochondrion appears to a principal subcellular target for the development of cardiomyopathy. This review describes evidence demonstrating that adriamycin redox cycles on complex I of the mitochondrial electron transport chain to liberate highly reactive free radical species of molecular oxygen. The primary effect of adriamycin on mitochondrial performance is the interference with oxidative phosphorylation and inhibition of ATP synthesis. Free radicals liberated from adriamycin redox cycling are thought to be responsible for many of the secondary effects of adriamycin, including lipid peroxidation, the oxidation of both proteins and DNA, and the depletion of glutathione and pyridine nucleotide reducing equivalents in the cell. It is this altered redox status that is believed to cause assorted changes in intracellular regulation, including the induction of the mitochondrial permeability transition and complete loss of mitochondrial integrity and function. Associated with this is the interference with mitochondrial-mediated cell calcium signaling, which is implicated as essential to the capacity of mitochondria to participate in bioenergetic regulation in response to external signals reflecting changes in metabolic demand. If taken to an extreme, this loss of mitochondrial plasticity may manifest in the liberation of signals mediating either oncotic or necrotic cell death, further perpetuating the cardiac failure associated with adriamycin-induced mitochondrial cardiomyopathy.


Adriamycin Doxorubicin Mitochondria Permeability transition Calcium 



Financial support by the National Institutes of Health (NIH HL 58016) is gratefully acknowledged.


  1. 1.
    Lefrak, E. A., Pitha, J., Rosenheim, S., & Gottlieb J. A. (1973). A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer, 32(2), 302–314.PubMedCrossRefGoogle Scholar
  2. 2.
    Gewirtz, D. A. (1999). A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochemical Pharmacology, 57(7), 727–741.PubMedCrossRefGoogle Scholar
  3. 3.
    Ferrans, V. J., Clark, J. R., Zhang, J., Yu, Z. X., & Herman, E. H. (1997). Pathogenesis and prevention of doxorubicin cardiomyopathy. Tsitologiia, 39(10), 928–937.PubMedGoogle Scholar
  4. 4.
    Olson, R. D., & Mushlin, P. S. (1990). Doxorubicin cardiotoxicity: Analysis of prevailing hypotheses [see comments]. FASEB Journal, 4(13), 3076–3086.PubMedGoogle Scholar
  5. 5.
    Singal, P. K., & Iliskovic N. (1998). Doxorubicin-induced cardiomyopathy [see comments]. New England Journal of Medicine, 339(13), 900–905.PubMedCrossRefGoogle Scholar
  6. 6.
    Lou, H., Kaur, K., Sharma, A. K., & Singal, P. K. (2006). Adriamycin-induced oxidative stress, activation of MAP kinases and apoptosis in isolated cardiomyocytes. Pathophysiology, 13, 103–109.PubMedCrossRefGoogle Scholar
  7. 7.
    Tokarska-Schlattner, M., Wallimann, T., & Schlattner, U. (2006). Alterations in myocardial energy metabolism induced by the anti-cancer drug doxorubicin. Comptes Rendus Biology, 329, 657–668.CrossRefGoogle Scholar
  8. 8.
    Mailer, K., & Petering, D. H. (1976). Inhibition of oxidative phosphorylation in tumor cells and mitochondria by daunomycin and adriamycin. Biochemical Pharmacology, 25(18), 2085–2089.PubMedCrossRefGoogle Scholar
  9. 9.
    Herman, E. H., el-Hage, A. N., Creighton, A. M., Witiak, D. T., & Ferrans, V. J. (1985). Comparison of the protective effect of ICRF-187 and structurally related analogues against acute daunorubicin toxicity in Syrian golden hamsters. Research Communications in Chemical Pathology and Pharmacology, 48(1), 39–55.PubMedGoogle Scholar
  10. 10.
    Lebrecht, D., Kokkori, A., Ketelsen, U. P., Setzer, B., & Walker, U. A. (2005). Tissue-specific mtDNA lesions and radical-associated mitochondrial dysfunction in human hearts exposed to doxorubicin. Journal of Pathology, 207, 436–444.PubMedCrossRefGoogle Scholar
  11. 11.
    Wallace, K. B. (2003). Doxorubicin-induced cardiac mitochondrionopathy. Pharmacology & Toxicology, 93, 105–115.CrossRefGoogle Scholar
  12. 12.
    Berthiaume, J. M., & Wallace K. B. (2007). Adriamycin-induced oxidative mitochondrial cardiotoxicity. Cell Biology and Toxicology, 23, 15–25.PubMedCrossRefGoogle Scholar
  13. 13.
    Brown, H. R., Ni, H., Benavides, G., Yoon, L., Hyder, K., Giridhar, J., Gardner, G., Tyler, R. D., & Morgan, K. T. (2002). Correlation of simultaneous differential gene expression in the blood and heart with known mechanisms of adriamycin-induced cardiomyopathy in the rat. Toxicologic Pathology, 30, 452–469.PubMedCrossRefGoogle Scholar
  14. 14.
    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. Biochemical Journal, 259, 181–189.PubMedGoogle Scholar
  15. 15.
    Neri, B., Cini-Neri, G., & D’Alterio, M. (1984). Effect of anthracyclines and mitoxantrone on oxygen uptake and ATP intracellular concentration in rat heart slices. Biochemical and Biophysical Research Communications, 125, 954–960.PubMedCrossRefGoogle Scholar
  16. 16.
    Aversano, R. C., & Boor, P. J. (1983). Histochemical alterations of acute and chronic doxorubicin cardiotoxicity. Journal of Molecular and Cellular Cardiology, 15(8), 543–553.PubMedCrossRefGoogle Scholar
  17. 17.
    Davies, K. J., & Doroshow, J. H. (1986). Redox cycling of anthracyclines by cardiac mitochondria. I. Anthracycline radical formation by NADH dehydrogenase. Journal of Biological Chemistry, 261(7), 3060–3067.PubMedGoogle Scholar
  18. 18.
    Doroshow, J. H., & Davies K. J. (1986). Redox cycling of anthracyclines by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical. Journal of Biological Chemistry, 261(7), 3068–3074.PubMedGoogle Scholar
  19. 19.
    Solem, L. E., Henry, T. R., & Wallace, K. B. (1994). Disruption of mitochondrial calcium homeostasis following chronic doxorubicin administration. Toxicology and Applied Pharmacology, 129(2), 214–222.PubMedCrossRefGoogle Scholar
  20. 20.
    Santos, D. L., Moreno, A. J. M. , Leino, R. L., Froberg, M. K., & Wallace, K. B. (2002). Carvedilol protects against doxorubicin-induced mitochondrial cardiomyopathy. Toxicology and Applied Pharmacology, 184, 218–227.CrossRefGoogle Scholar
  21. 21.
    Mimnaugh, E. G., Trush, M. A., Bhatnagar, M., & Gram T. E. (1985). Enhancement of reactive oxygen-dependent mitochondrial membrane lipid peroxidation by the anticancer drug adriamycin. Biochemical Pharmacology, 34(6), 847–856.PubMedCrossRefGoogle Scholar
  22. 22.
    Boucek, R. J. Jr., Olson, R. D., Brenner, D. E., Ogunbunmi, E. M., Inui, M., & Fleischer, S. (1987). The major metabolite of doxorubicin is a potent inhibitor of membrane-associated ion pumps. A correlative study of cardiac muscle with isolated membrane fractions. Journal of Biological Chemistry, 262(33), 15851–15856.PubMedGoogle Scholar
  23. 23.
    Goormaghtigh, E., Huart, P., Praet, M., Brasseur, R., & Ruysschaert, J. M. (1990). Structure of the adriamycin-cardiolipin complex. Role in mitochondrial toxicity. Biophysical Chemistry, 35(2–3), 247–257.PubMedCrossRefGoogle Scholar
  24. 24.
    Gosalvez, M., Blanco, M., Hunter, J., Miko, M., & Chance, B. (1974). Effects of anticancer agents on the respiration of isolated mitochondria and tumor cells. European Journal of Cancer, 10(9), 567–574.PubMedGoogle Scholar
  25. 25.
    Singal, P. K., Deally, C. M., & Weinberg, L. E. (1987). Subcellular effects of adriamycin in the heart: a concise review. Journal of Molecular and Cellular Cardiology, 19(8), 817–828.PubMedCrossRefGoogle Scholar
  26. 26.
    Ferrero, M. E., Ferrero, E., Gaja, G., & Bernelli-Zazzera, A. (1976). Adriamycin: Energy metabolism and mitochondrial oxidations in the heart of treated rabbits. Biochemical Pharmacology, 25(2), 125–130.PubMedCrossRefGoogle Scholar
  27. 27.
    Hoek, J. B., Farber, J. L., Thomas, A. P., & Wang, X. (1995). Calcium ion-dependent signalling and mitochondrial dysfunction: Mitochondrial calcium uptake during hormonal stimulation in intact liver cells and its implication for the mitochondrial permeability transition. Biochimica et Biophysica Acta, 1271(1), 93–102.PubMedGoogle Scholar
  28. 28.
    Miyata, H., Silverman, H. S., Sollott, S. J., Lakatta, E. G., Stern, M. D., & Hansford, R. G. (1991). Measurement of mitochondrial free Ca2+ concentration in living single rat cardiac myocytes. American Journal of Physiology, 261(4 Pt 2), H1123–H1134.PubMedGoogle Scholar
  29. 29.
    Sparagna, G. C., Gunter, K. K., Sheu, S. S., & Gunter, T. E. (1995). Mitochondrial calcium uptake from physiological-type pulses of calcium. A description of the rapid uptake mode. Journal of Biological Chemistry, 270(46), 27510–27515.PubMedCrossRefGoogle Scholar
  30. 30.
    Rudge, M. F., & Duncan, C. J. (1984). Comparative studies on the role of calcium in triggering subcellular damage in cardiac muscle. Comparative Biochemistry and Physiology A, 77(3), 459–468.CrossRefGoogle Scholar
  31. 31.
    Li, Q., Hohl, C. M., Altschuld, R. A., & Stokes, B. T. (1989). Energy depletion-repletion and calcium transients in single cardiomyocytes. American Journal of Physiology, 257(3 Pt 1), C427–C434.PubMedGoogle Scholar
  32. 32.
    Solem, L. E., Heller, L. J., & Wallace, K. B. (1996). Dose-dependent increase in sensitivity to calcium-induced mitochondrial dysfunction and cardiomyocyte cell injury by doxorubicin. Journal of Molecular and Cellular Cardiology, 28(5), 1023–1032.PubMedCrossRefGoogle Scholar
  33. 33.
    Solem, L. E., & Wallace, K. B. (1993). Selective activation of the sodium-independent, cyclosporine A-sensitive calcium pore of cardiac mitochondria by doxorubicin. Toxicology and Applied Pharmacology, 121(1), 50–57.PubMedCrossRefGoogle Scholar
  34. 34.
    Bachmann, E., & Zbinden, G. (1979). Effect of doxorubicin and rubidazone on respiratory function and Ca2+ transport in rat heart mitochondria. Toxicology Letters, 3, 29–34.CrossRefGoogle Scholar
  35. 35.
    Chacon, E., & Acosta, D. (1991). Mitochondrial regulation of superoxide by Ca2+: An alternate mechanism for the cardiotoxicity of doxorubicin. Toxicology and Applied Pharmacology, 107(1), 117–128.PubMedCrossRefGoogle Scholar
  36. 36.
    Sokolove, P. M., & Shinaberry, R. G. (1988). Na+-independent release of Ca2+ from rat heart mitochondria. Induction by adriamycin aglycone. Biochemical Pharmacology, 37(5), 803–812.PubMedCrossRefGoogle Scholar
  37. 37.
    Sokolove, P. M. (1990). Inhibition by cyclosporine A and butylated hydroxytoluene of the inner mitochondrial membrane permeability transition induced by adriamycin aglycones. Biochemical Pharmacology, 40(12), 2733–2736.PubMedCrossRefGoogle Scholar
  38. 38.
    Singal, P. K., Forbes, M. S., & Sperelakis, N. (1984). Occurrence of intramitochondrial Ca2+ granules in a hypertrophied heart exposed to adriamycin. Canadian Journal of Physiology and Pharmacology, 62, 1239–1244.PubMedGoogle Scholar
  39. 39.
    Gunter, K. K., & Gunter, T. E. (1994). Transport of calcium by mitochondria. Journal Of Bioenergetics and Biomembranes, 26(5), 471–485.PubMedCrossRefGoogle Scholar
  40. 40.
    Gunter, T. E., & Pfeiffer, D. R. (1990). Mechanisms by which mitochondria transport calcium. American Journal of Physiology, 258(5 Pt 1), C755–C786.PubMedGoogle Scholar
  41. 41.
    Denton, R. M., & McCormack, J. G. (1990). Ca2+ as a second messenger within mitochondria of the heart and other tissues. Annual Review of Physiology, 52, 451–466.PubMedCrossRefGoogle Scholar
  42. 42.
    Bernardi, P., Broekemeier, K. M., & Pfeiffer, D. R. (1994). Recent progress on regulation of the mitochondrial permeability transition pore; a sensitive-sensitive pore in the inner mitochondrial membrane. Journal Of Bioenergetics and Biomembranes, 26(5), 509–517.PubMedCrossRefGoogle Scholar
  43. 43.
    Al-Nasser, I. A. (1998). In vivo prevention of adriamycin cardiotoxicity by cyclosporine A or FK506. Toxicology, 131, 175–181.PubMedCrossRefGoogle Scholar
  44. 44.
    Zhou, S., Starkov, A., & Wallace, K. B. (2001). Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Research, 61, 771–777.PubMedGoogle Scholar
  45. 45.
    Bernardi, P. (1999). Mitochondrial transport of cations: Channels, exchangers, and permeability transition. Physiological Reviews, 79(4), 1127–1155.PubMedGoogle Scholar
  46. 46.
    Richter, C., & Schlegel, J. (1993). Mitochondrial calcium release induced by prooxidants. Toxicology Letters, 67(1–3), 119–127.PubMedCrossRefGoogle Scholar
  47. 47.
    Wallace, K. B., Eells, J. T., Madeira, V. M., Cortopassi, G., & Jones, D. P. (1997). Mitochondria-mediated cell injury. Symposium overview. Fundamental and Applied Toxicology, 38(1), 23–37.PubMedCrossRefGoogle Scholar
  48. 48.
    Imberti, R., Nieminen, A. L., Herman, B., & Lemasters, J. J. (1993). Mitochondrial and glycolytic dysfunction in lethal injury to hepatocytes by t-butylhydroperoxide: Protection by fructose, cyclosporine A and trifluoperazine. Journal of Pharmacology and Experimental Therapeutics, 265(1), 392–400.PubMedGoogle Scholar
  49. 49.
    Groskreutz, J. L., Bronk, S. F., & Gores, G. J. (1992). Ruthenium red delays the onset of cell death during oxidative stress of rat hepatocytes. Gastroenterology, 102(3), 1030–1038.PubMedGoogle Scholar
  50. 50.
    Pastorino, J. G., Snyder, J. W., Serroni, A., Hoek, J. B., & Farber, J. L. (1993). Cyclosporine and carnitine prevent the anoxic death of cultured hepatocytes by inhibiting the mitochondrial permeability transition. Journal of Biological Chemistry, 268(19), 13791–13798.PubMedGoogle Scholar
  51. 51.
    Henry, T. R., & Wallace, K. B. (1996). Differential mechanisms of cell killing by redox cycling and arylating quinones. Archives of Toxicology, 70(8), 482–489.PubMedCrossRefGoogle Scholar
  52. 52.
    Petronilli, V., Cola, C., Massari, S., Colonna, R., & Bernardi, P. (1993). Physiological effectors modify voltage sensing by the cyclosporine A- sensitive permeability transition pore of mitochondria. Journal of Biological Chemistry, 268(29), 21939–21945.PubMedGoogle Scholar
  53. 53.
    Petronilli, V., Cola, C., & Bernardi, P. (1993). Modulation of the mitochondrial cyclosporine A-sensitive permeability transition pore. II. The minimal requirements for pore induction underscore a key role for transmembrane electrical potential, matrix pH, and matrix Ca2+. Journal of Biological Chemistry, 268(2), 1011–1016.PubMedGoogle Scholar
  54. 54.
    Petronilli, V., Nicolli, A., Costantini, P., Colonna, R., & Bernardi, P. (1994). Regulation of the permeability transition pore, a voltage-dependent mitochondrial channel inhibited by cyclosporine A. Biochimica et Biophysica Acta, 1187(2), 255–259.PubMedCrossRefGoogle Scholar
  55. 55.
    Petronilli, V., Costantini, P., Scorrano, L., Colonna, R., Passamonti, S., & 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. Journal of Biological Chemistry, 269(24), 16638–16642.PubMedGoogle Scholar
  56. 56.
    Fagian, M. M., Pereira-da-Silva, L., Martins, I. S., & Vercesi, A. E. (1990). Membrane protein thiol cross-linking associated with the permeabilization of the inner mitochondrial membrane by Ca2+ plus prooxidants. Journal of Biological Chemistry, 265(32), 19955–19960.PubMedGoogle Scholar
  57. 57.
    Meredith, M. J., & Reed, D. J. (1983). Depletion in vitro of mitochondrial glutathione in rat hepatocytes and enhancement of lipid peroxidation by adriamycin and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Biochemical Pharmacology, 32(8), 1383–1388.PubMedCrossRefGoogle Scholar
  58. 58.
    Oliveira, P. J., & Wallace, K. B. (2006). Depletion of adenine nucleotide translocator protein in heart mitochodria from doxorubicin-treated rats—Relevance for mitochondrial dysfunction. Toxicology, 220, 160–168.PubMedCrossRefGoogle Scholar
  59. 59.
    Halestrap, A. P., Woodfield, K. Y., & Connern, C. P. (1997). Oxidative stress, thiol reagents, and membrane potential modulate the mitochondrial permeability transition by affecting nucleotide binding to the adenine nucleotide translocase. Journal of Biological Chemistry, 272(6), 3346–3354.PubMedCrossRefGoogle Scholar
  60. 60.
    Halestrap, A. P., Kerr, P. M., Javadov, S., & Woodfield, K. Y. (1998). Elucidating the molecular mechanism of the permeability transition pore and its role in reperfusion injury of the heart. Biochimica et Biophysica Acta, 1366(1–2), 79–94.PubMedCrossRefGoogle Scholar
  61. 61.
    Oliveira, P. J., Santos, M. S., & Wallace, K. B. (2005). Doxorubicin-induced thiol-dependent alteration of cardiac mitochondrial permeability transition and respiration. Biochemistry (Moscow), 71, 194–199.CrossRefGoogle Scholar
  62. 62.
    Serrano, J., Palmeira, C. M., Kuehl, D. W., & Wallace, K. B. (1999). Cardioselective and cumulative oxidation of mitochondrial DNA following subchronic doxorubicin administration. Biochimica et Biophysica Acta, 1411(1), 201–205.PubMedCrossRefGoogle Scholar
  63. 63.
    Palmeira, C. M., Serrano, J., Kuehl, D. W., & Wallace, K. B. (1997). Preferential oxidation of cardiac mitochondrial DNA following acute intoxication with doxorubicin. Biochimica et Biophysica Acta, 1321(2), 101–106.PubMedCrossRefGoogle Scholar
  64. 64.
    Zhou, S., Palmeira, C. M., & Wallace, K. B. (2001). Doxorubicin-induced persistent oxidative stress to cardiac myocytes. Toxicology Letters, 121, 151–157.PubMedCrossRefGoogle Scholar
  65. 65.
    Chacon, E., Ohata, H., Harper, I. S., Trollinger, D. R., Herman, B., & Lemasters, J. J. (1996). Mitochondrial free calcium transients during excitation-contraction coupling in rabbit cardiac myocytes. FEBS Letters, 382(1–2), 31–36.PubMedCrossRefGoogle Scholar
  66. 66.
    Herrington, J., Park, Y. B., Babcock, D. F., & Hille, B. (1996). Dominant role of mitochondria in clearance of large Ca2+ loads from rat adrenal chromaffin cells. Neuron, 16(1), 219–228.PubMedCrossRefGoogle Scholar
  67. 67.
    Isenberg, G., Han, S., Schiefer, A., & Wendt-Gallitelli, M. F. (1993). Changes in mitochondrial calcium concentration during the cardiac contraction cycle. Cardiovascular Research, 27(10), 1800–1809.PubMedCrossRefGoogle Scholar
  68. 68.
    Gillis, J. M. (1997). Inhibition of mitochondrial calcium uptake slows down relaxation in mitochondria-rich skeletal muscles. Journal of Muscle Research and Cell Motility, 18(4), 473–483.PubMedCrossRefGoogle Scholar
  69. 69.
    Loew, L. M., Carrington, W., Tuft, R. A., & Fay, F. S. (1994). Physiological cytosolic Ca2+ transients evoke concurrent mitochondrial depolarizations. Proceedings of the National Academy of Sciences of the United States of America, 91(26), 12579–12583.Google Scholar
  70. 70.
    Zhou, S., Heller, L. J., & Wallace, K. B. (2001). Interferences with calcium-dependent mitochondrial bioenergetics in cardiac myocytes isolated from doxorubicin-treated rats. Toxicology and Applied Pharmacology, 175, 60–67.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  1. 1.Department of Biochemistry & Molecular BiologyUniversity of Minnesota School of MedicineDuluthUSA

Personalised recommendations