Skip to main content

Advertisement

SpringerLink
Log in

Role of mtDNA lesions in anthracycline cardiotoxicity

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

Doxorubicin (adriamycin) is an effective drug in the treatment of many malignancies. Its prolonged use is, however, limited by an irreversible, dose-dependent and progressive cardiomyopathy, which may become evident even years after completion of therapy. Data from rats and humans show that oxidative phosphorylation is impaired rapidly after acute doxorubicin-exposure. Such respiratory chain dysfunction is known to enhance the production of reactive oxygen species and may lead to quantitative and qualitative injury of mitochondrial DNA (mtDNA) and its encoded respiratory chain subunits. MtDNA depletion, mtDNA mutations and respiratory defects then accumulate with time also in the absence of continued anthracycline exposure. Chronic cardiotoxicity then manifests, when the bioenergetic capacity of the organelles is severely impaired. The mitochondrial damage in late-onset doxorubicin cardiomyopathy is heart specific and not found in skeletal muscle. DOXO-EMCH, a 6-maleimidocaproyl hydrazone derivative of doxorubicin has evolved from the search for less cardiotoxic anthracyclines. At equieffective antitumor doses, DOXO-EMCH has a substantially lower heart toxicity than free doxorubicin.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Buzdar, A. U., Marcus, C., Smith, T. L., & Blumenschein, G. R. (1985). Early and delayed clinical cardiotoxicity of doxorubicin. Cancer, 55, 2761–2765.

    Article  PubMed  CAS  Google Scholar 

  2. Steinherz, L. J., Steinherz, P. G., Tan, C. T., Heller, G., & Murphy, M. L. (1991). Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA, 266, 1672–1677.

    Article  PubMed  CAS  Google Scholar 

  3. Minow, R. A., Benjamin, R. S., & Gottlieb, J. A. (1975). Adriamycin (NSC-123127) cardiomyopathy – an overview with determination of risk factors. Cancer Chemotheraphy Reports, 6, 195–201.

    Google Scholar 

  4. Ferrans, V. J. (1978). Overview of cardiac pathology in relation to anthracycline cardiotoxicity. Cancer Treatment Reports, 62, 955–961.

    PubMed  CAS  Google Scholar 

  5. Davies, K. J. A., & Doroshow, J. H. (1986). Redox cycling of anthracyclines by cardiac mitochondria. I. Anthracycline radical formation by NADH dehydrogenase. Journal of Biological Chemistry, 261, 3060–3967.

    PubMed  CAS  Google Scholar 

  6. Marcillat, O., Zhang, Y., Lin, S. W., & Davies, K. J. (1988). Mitochondria contain a proteolytic system which can recognize and degrade oxidatively-denatured proteins. Biochemical Journal, 254, 677–683.

    PubMed  CAS  Google Scholar 

  7. Miura, T., Muraoka, S., & Ogiso, T. (1994). Adriamycin-fe(3+)-induced inactivation of rat heart mitochondrial creatine kinase: sensitivity to lipid peroxidation. Biological Pharmaceutical Bulletin, 17, 1220–1223.

    PubMed  CAS  Google Scholar 

  8. Hasinoff, B. B., Schnabl, K. L., Marusak, R. A., Patel, D., & Huebner, E. (2003). Dexrazoxane (ICRF-187) protects cardiac myocytes against doxorubicin by preventing damage to mitochondria. Cardiovascular Toxicology, 3, 89–100.

    Article  PubMed  CAS  Google Scholar 

  9. Hasinoff, B. B. (1990). Inhibition and inactivation of NADH-cytochrome c reductase activity of bovine heart submitochondrial particles by the iron(III)-adriamycin complex. Biochemical Journal, 265, 865–870.

    PubMed  CAS  Google Scholar 

  10. 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, 247–257.

    Article  PubMed  CAS  Google Scholar 

  11. Keizer, H. G., Pinedo, H. M., Schuurhuis, G. J., & Joenje, H. (1990). Doxorubicin (adriamycin): A critical review of free radical-dependent mechanisms of cytotoxicity. Pharmacology & Therapeutics, 47, 219–231.

    Article  CAS  Google Scholar 

  12. Goormaghtigh, E., Huart, P., Brasseur, R., & Ruysschaert, J. M. (1986). Mechanism of inhibition of mitochondrial complex I-III by adriamycin derivatives. Biochimica Et Biophysica Acta, 861, 83–94.

    PubMed  CAS  Google Scholar 

  13. Nicolay, K., & DeKruijff, B. (1987). Effects of adriamycin on respiratory chain activities in mitochondria from rat liver, rat heart and bovine heart. Evidence of preferential inhibition of complex III and IV. Biochimica Et Biophysica Acta, 892, 320–330.

    Article  PubMed  CAS  Google Scholar 

  14. Anderson, S., Bankier, A. T., Barell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., Schreier, P. H., Smith, A. J. H., Staden, R., & Young, I. G. (1981). Sequence and organization of the human mitochondrial genome. Nature, 9, 457–465.

    Article  Google Scholar 

  15. 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, 201–205.

    Article  PubMed  CAS  Google Scholar 

  16. Adachi, K., Fujiura, Y., Mayumi, F., Nozuhara, A., Sugiu, Y., Sakanashi, T., Hidaka, T., & Toshima, H. (1993). A deletion of mitochondrial DNA in murine doxorubicin-induced cardiotoxicity. Biochemical and Biophysical Research Communications, 195, 945–951.

    Article  PubMed  CAS  Google Scholar 

  17. Hixon, S. C., Ellis, C. N., & Daugherty, J. P. (1981). Heart mitochondrial DNA synthesis: Preferential inhibition by adriamycin. Journal of Molecular and Cellular Cardiology, 13, 855–860.

    Article  PubMed  CAS  Google Scholar 

  18. Wiseman, A., & Attardi, G. (1978). Reversible tenfold reduction in mitochondria DNA content of human cells treated with ethidium bromide. Molecular & General Genetics, 167, 51–63.

    CAS  Google Scholar 

  19. Abdella, B. R., & Fisher, J. (1985). A chemical perspective on the anthracycline antitumor antibiotics. Environmental Health Perspectives, 64, 4–18.

    Article  PubMed  CAS  Google Scholar 

  20. Nohl, H. (1987). Demonstration of the existence of an organo-specific NADH dehydrogenase in heart mitochondria. European Journal of Biochemistry, 169, 585–591.

    Article  PubMed  CAS  Google Scholar 

  21. Tsai-Pflugfelder, M., Liu, L. F., Liu, A. A., Tewey, K. M., Whang-Peng, J., Knutsen, T., Huebner, K., Croce, C. M., & Wang, J. C. (1988). Cloning and sequencing of cDNA encoding human DNA topoisomerase II and localization of the gene to chromosome region 17q21–22. Proceedings of National Academy Science of the United States of America, 85, 7177–7181.

    Article  CAS  Google Scholar 

  22. Tewey, K. M., Rowe, T. C., Yang, L., Halligan, B. D., & Liu, L. F. (1984). Adriamycin induced DNA damage mediated by mammalian DNA topoisomerase II. Science, 226, 466–468.

    Article  PubMed  CAS  Google Scholar 

  23. Lawrence, J. W., Darkin-Rattray, S., Xie, F., Neims, A. H., & Rowe, T. C. (1993). 4-Quinolones cause a selective loss of mitochondrial DNA from mouse L1210 leukemia cells. Journal of Cellular Biochemistry, 51, 165–174.

    Article  PubMed  CAS  Google Scholar 

  24. Lebrecht, D., Setzer, B., Ketelsen, U. P., Haberstroh, J., & Walker, U. A. (2003). Time-dependent and tissue-specific accumulation of mtDNA and respiratory chain defects in chronic doxorubicin cardiomyopathy. Circulation, 108, 2423–2429.

    Article  PubMed  CAS  Google Scholar 

  25. Richter, C. (1992). Reactive oxygen and DNA damage in mitochondria. Mutation Research, 275, 249–255.

    Article  PubMed  CAS  Google Scholar 

  26. Corral-Debrinski, M., Stepien, G., Shoffner, J. M., Lott, M. T., Kanter, K., & Wallace, D. C. (1991). Hypoxemia is associated with mitochondrial DNA damage and gene induction. Implications for cardiac disease. JAMA, 266, 1812–1816.

    Article  PubMed  CAS  Google Scholar 

  27. Zhou, S., Palmeira, C. M., & Wallace, K. B. (2001). Doxorubicin-induced persistent oxidative stress to cardiac myocytes. Toxicology Letters, 121, 151–157.

    Article  PubMed  CAS  Google Scholar 

  28. Attardi, G., Yoneda, M., & Chomyn, A. (1995). Complementation and segregation behavior of disease-causing mitochondrial DNA mutations in cellular model systems. Biochimica Et Biophysica Acta, 1271, 241–248.

    PubMed  Google Scholar 

  29. Yoneda, M., Chomyn, A., Martinuzzi, A., Hurko, O., & Attardi, G. (1992). Marked replicative advantage of human mtDNA carrying a point mutation that causes the MELAS encephalomyopathy. Proceedings of National Academy Science of the United States of America, 89, 11164–11168.

    Article  CAS  Google Scholar 

  30. Schon, E. A., Rizzuto, R., Moraes, C. T., Nakase, H., Zeviani, M., & DiMauro, S. (1989). A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA. Science, 244, 346–349.

    Article  PubMed  CAS  Google Scholar 

  31. Corral-Debrinski, M., Shoffner, J. M., Lott, M. T., & Wallace, D. C. (1992). Association of mitochondrial DNA damage with aging and coronary atherosclerotic heart disease. Mutation Research, 275, 169–180.

    Article  PubMed  CAS  Google Scholar 

  32. Kajander, O. A., Karhunen, P. J., & Jacobs, H. T. (2002). The relationship between somatic mtDNA rearrangements, human heart disease and aging. Human Molecular Genetics, 11, 317–324.

    Article  PubMed  CAS  Google Scholar 

  33. Trounce, I., Byrne, E., & Marzuki, S. (1989). Decline in skeletal muscle mitochondrial respiratory chain function: Possible factor in aging. Lancet I, 637–639.

    Article  Google Scholar 

  34. Singal, P. K., & Iliskovic, N. (1998). Doxorubicin-induced cardiomyopathy. New England Journal of Medicine, 339, 900–905.

    Article  PubMed  CAS  Google Scholar 

  35. Hensley, M. L., Schuchter, L. M., Lindley, C., Meropol, N. J., Cohen, G. I., Broder, G., Gradishar, W. J., Green, D. M., Langdon, R. J., Jr. Mitchell, R. B., Negrin, R., Szatrowski, T. P., Thigpen, J. T., Von Hoff, D., Wasserman, T. H., Winer, E. P., & Pfister, D. G. (1999). American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. Journal of Clinical Oncology, 17, 3333–3355.

    PubMed  CAS  Google Scholar 

  36. Robert, J. (1993). Epirubicin. Clinical pharmacology and dose-effect relationship. Drugs, 45(Suppl 2), 20–30.

    Article  PubMed  Google Scholar 

  37. Torti, F. M., Bristow, M. M., Lum, B. L., Carter, S. K., Howes, A. E., Aston, D. A., Brown, B. W., Jr. Hannigan, J. F., Jr. Meyers, F. J., & Mitchell, E. P. (1986). Cardiotoxicity of epirubicin and doxorubicin: assessment by endomyocardial biopsy. Cancer Research, 46, 3722–3727.

    PubMed  CAS  Google Scholar 

  38. Borchmann, P., Hubel, K., Schnell, R., & Engert, A. (1997). Idarubicin: A brief overview on pharmacology and clinical use. International Journal of Clinical Pharmacology and Therapeutics, 35, 80–83.

    PubMed  CAS  Google Scholar 

  39. Estorch, M., Carrio, I., Martinez-Duncker, D., Berna, L., Torres, G., Alonso, C., & Ojeda, B. (1993). Myocyte cell damage after administration of doxorubicin or mitoxantrone in breast cancer patients assessed by indium 111 antimyosin monoclonal antibody studies. Journal of Clinical Oncology, 11, 1264–1268.

    PubMed  CAS  Google Scholar 

  40. Buschini, A., Poli, P., & Rossi, C. (2003). Saccharomyces cerevisiae as an eukaryotic cell model to assess cytotoxicity and genotoxicity of three anticancer anthraquinones. Mutagenesis, 18, 25–36.

    Article  PubMed  CAS  Google Scholar 

  41. Stipani, I., Capalbo, M. I., & Zara, V. (1989). Effect of anthracycline antibiotics on the reconstituted mitochondrial tricarboxylate carrier. Biochemical and Biophysical Research Communications, 164, 1281–1287.

    Article  PubMed  CAS  Google Scholar 

  42. Sweatman, T. W., & Israel, M. (1987). Comparative metabolism and elimination of adriamycin and 4’-epiadriamycin in the rat. Cancer Chemotheraphy and Pharmacology, 19, 201–206.

    CAS  Google Scholar 

  43. Camaggi, C. M., Comparsi, R., Strocchi, E., Testoni, F., Angelelli, B., & Pannuti, F. (1988). Epirubicin and doxorubicin comparative metabolism and pharmacokinetics. A cross-over study Cancer Chemotheraphy and Pharmacology, 21, 221–228.

    CAS  Google Scholar 

  44. Salvatorelli, E., Guarnieri, S., Menna, P., Liberi, G., Calafiore, A. M., Mariggio, M. A., Mordente, A., Gianni, L., & Minotti, G. (2006). Defective one- or two-electron reduction of the anticancer anthracycline epirubicin in human heart. Relative importance of vesicular sequestration and impaired efficiency of electron addition. Journal of Biological Chemistry, 281, 10990–11001.

    Article  PubMed  CAS  Google Scholar 

  45. 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.

    Article  PubMed  CAS  Google Scholar 

  46. Kratz, F., Warnecke, A., Scheuermann, K., Stockmar, C., Schwab, J., Lazar, P., Druckes, P., Esser, N., Drevs, J., Rognan, D., Bissantz, C., Hinderling, C., Folkers, G., Fichtner, I., & Unger, C. (2002). Probing the cysteine-34 position of endogenous serum albumin with thiol-binding doxorubicin derivatives. Improved efficacy of an acid-sensitive doxorubicin derivative with specific albumin-binding properties compared to that of the parent compound. Journal of Medicinal Chemisty, 45, 5523–5533.

    Article  CAS  Google Scholar 

  47. Lebrecht, D., Geist, D., Ketelsen, U. P., Haberstroh, J., Setzer, B., Kratz, F., & Walker, U. A. (2006). The 6-maleimidocaproyl hydrazone derivative of doxorubicin (DOXO-EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage. International Journal of Cancer, 120, 927–934.

    Article  CAS  Google Scholar 

  48. Maeda, H., Wu, J., Sawa, T., Matsumura, Y., & Hori, K. (2000). Tumor vascular permeability and the EPR effect in macromolecular therapeutics: A review. Journal of Controlled Release, 65, 271–284.

    Article  PubMed  CAS  Google Scholar 

  49. Kratz, F., Warnecke, A., Schmid, B., Chung, D. E., & Gitzel, M. (2006). Prodrugs of anthracyclines in cancer chemotherapy. Current Medicinal Chemistry, 13, 477–523.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Rheumatology and Clinical Immunology, Albert-Ludwigs University, Medizinische Universitätsklinik, Hugstetterstr. 55, 79106, Freiburg, Germany

    Dirk Lebrecht & Ulrich A. Walker

Authors
  1. Dirk Lebrecht
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ulrich A. Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ulrich A. Walker.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lebrecht, D., Walker, U.A. Role of mtDNA lesions in anthracycline cardiotoxicity. Cardiovasc Toxicol 7, 108–113 (2007). https://doi.org/10.1007/s12012-007-0009-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-007-0009-1

Keywords

Search

Navigation