Cardiovascular Toxicology

, Volume 7, Issue 2, pp 145–150 | Cite as

New iron chelators in anthracycline-induced cardiotoxicity

  • Helena Kaiserová
  • Tomáš Šimůnek
  • Martin Štěrba
  • Gertjan J. M. den Hartog
  • Ladislava Schröterová
  • Olga Popelová
  • Vladimír Geršl
  • Eva Kvasničková
  • Aalt Bast
Original Paper
First Online:

Abstract

The use of anthracycline anticancer drugs is limited by a cumulative, dose-dependent cardiac toxicity. Iron chelation has long been considered as a promising strategy to limit this unfavorable side effect, either by restoring the disturbed cellular iron homeostasis or by removing redox-active iron, which may promote anthracycline-induced oxidative stress. Aroylhydrazone lipophilic iron chelators have shown promising results in the rabbit model of daunorubicin-induced cardiomyopathy as well as in cellular models. The lack of interference with the antiproliferative effects of the anthracyclines also favors their use in clinical settings. The dose, however, should be carefully titrated to prevent iron depletion, which apparently also applies for other strong iron chelators. We have shown that a mere ability of a compound to chelate iron is not the sole determinant of a good cardioprotector and the protective potential does not directly correlate with the ability of the chelators to prevent hydroxyl radical formation. These findings, however, do not weaken the role of iron in doxorubicin cardiotoxicity as such, they rather appeal for further investigations into the molecular mechanisms how anthracyclines interact with iron and how iron chelation may interfere with these processes.

Keywords

Doxorubicin Daunorubicin Iron homeostasis Aroylhydrazone chelators Oxidative stress 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

The authors were supported by grants GAUK 97/2005, GAČR 305/05/P156, and a Research Project MSM0021620820.

References

  1. 1.
    Mladenka, P., Simunek, T., Hubl, M., & Hrdina, R. (2006). The role of reactive oxygen and nitrogen species in cellular iron metabolism. Free Radical Research, 40(3), 263–272.PubMedCrossRefGoogle Scholar
  2. 2.
    Walter, P. B., Knutson, M. D., Paler-Martinez, A., Lee, S., Xu, Y., Viteri, F. E., & Ames, B. N. (2002). Iron deficiency and iron excess damage mitochondria and mitochondrial DNA in rats. Proceedings of the National Academy of Sciences of the United States of America, 99(4), 2264–2269.PubMedCrossRefGoogle Scholar
  3. 3.
    Minotti, G., Ronchi, R., Salvatorelli, E., Menna, P., & Cairo, G. (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 Research, 61, 8422–8428.PubMedGoogle Scholar
  4. 4.
    Hrdina, R., Gersl, V., Klimtova, I., Simunek, T., Machackova, J., & Adamcova, M. (2000). Anthracycline-induced cardiotoxicity. Acta Medica (Hradec Kralove), 43(3), 75–82.Google Scholar
  5. 5.
    Kwok, J. C., & Richardson, D. R. (2003). Anthracyclines induce accumulation of iron in ferritin in myocardial and neoplastic cells: Inhibition of the ferritin iron mobilization pathway. Molecular Pharmacology, 63, 849–861.PubMedCrossRefGoogle Scholar
  6. 6.
    Simunek, T., Sterba, M., Holeckova, M., Kaplanova, J., Klimtova, I., Adamcova, M., Gersl, V., & Hrdina, R. (2005). Myocardial content of selected elements in experimental anthracycline-induced cardiomyopathy in rabbits. Biometals, 18(2), 163–169.PubMedCrossRefGoogle Scholar
  7. 7.
    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(2), 89–99.PubMedCrossRefGoogle Scholar
  8. 8.
    Voest, E. E., van Acker, S. A., van der Vijgh, W. J., van Asbeck, B. S., & Bast, A. (1994). Comparison of different iron chelators as protective agents against acute doxorubicin-induced cardiotoxicity. Journal of Molecular and Cellular Cardiology, 26(9), 1179–1185.PubMedCrossRefGoogle Scholar
  9. 9.
    Barnabe, N., Zastre, J. A., Venkataram, S., & Hasinoff, B. B. (2002). Deferiprone protects against doxorubicin-induced myocyte cytotoxicity. Free Radical and Biology Medicine, 33(2), 266–275.CrossRefGoogle Scholar
  10. 10.
    Link, G., Tirosh, R., Pinson, A., & 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. The Journal of Laboratory and Clinical Medicine, 127(3), 272–278.PubMedCrossRefGoogle Scholar
  11. 11.
    Hasinoff, B. B., Patel, D., & Wu, X. (2003). The oral iron chelator ICL670A (deferasirox) does not protect myocytes against doxorubicin. Free Radical and Biology Medicine, 35(11), 1469–1479.CrossRefGoogle Scholar
  12. 12.
    Simunek, T., Klimtova, I., Kaplanova, J., Mazurova, Y., Adamcova, M., Sterba, M., Hrdina, R., & Gersl, V. (2004). Rabbit model for in vivo study of anthracycline-induced heart failure and for the evaluation of protective agents. European Journal of Heart Failure, 6(4), 377–387.PubMedCrossRefGoogle Scholar
  13. 13.
    Richardson, D. R., Tran, E. H., & Ponka, P. (1995). The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents. Blood, 86, 4295–4306.PubMedGoogle Scholar
  14. 14.
    Kovarikova, P., Klimes, J., Sterba, M., Popelova, O., Gersl, V., & Ponka, P. (2006). HPLC determination of novel aroylhydrazone iron chelator (o-108) in rabbit plasma and its application to a pilot pharmacokinetic study. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, 838, 107–112.PubMedCrossRefGoogle Scholar
  15. 15.
    Kovarikova, P., Klimes, J., Sterba, M., Popelova, O., Mokry, M., Gersl, V., & Ponka, P. (2005). Development of high-performance liquid chromatographic determination of salicylaldehyde isonicotinoyl hydrazone in rabbit plasma and application of this method to an in vivo study. Journal of Seperation Science, 28, 1300–1306.CrossRefGoogle Scholar
  16. 16.
    Charkoudian, L. K., Pham, D. M., & Franz, K. J. (2006). A pro-chelator triggered by hydrogen peroxide inhibits iron-promoted hydroxyl radical formation. Journal of the American Chemical Society, 128(38), 12424–12425.PubMedCrossRefGoogle Scholar
  17. 17.
    Simunek, T., Boer, C., Bouwman, R. A., Vlasblom, R., Versteilen, A. M., Sterba, M., Gersl, V., Hrdina, R., Ponka, P., de Lange, J. J., Paulus, W. J., & Musters, R. J. (2005). SIH–––a novel lipophilic iron chelator–protects H9c2 cardiomyoblasts from oxidative stress-induced mitochondrial injury and cell death. Journal of Molecular and Cellular Cardiology, 39(2), 345–354.PubMedCrossRefGoogle Scholar
  18. 18.
    Schroterova, L., Kaiserova, H., Baliharova, V., Velik, J., Gersl, V., & Kvasnickova, E. (2004). The effect of new lipophilic chelators on the activities of cytosolic reductases and P450 cytochromes involved in the metabolism of anthracycline antibiotics: studies in vitro. Physiological Research, 53(6), 683–691.PubMedGoogle Scholar
  19. 19.
    Kaiserova, H., den Hartog, G. J., Simunek, T., Schroterova, L., Kvasnickova, E., & Bast, A. (2006). Iron is not involved in oxidative stress-mediated cytotoxicity of doxorubicin and bleomycin. British Journal of Pharmacology, 149(7), 920–930.PubMedCrossRefGoogle Scholar
  20. 20.
    Sterba, M., Popelova, O., Simunek, T., Mazurova, Y., Potacova, A., Adamcova, M., Kaiserova, H., Ponka, P., & Gersl, V. (2006). Cardioprotective effects of a novel iron chelator, pyridoxal 2-chlorobenzoyl hydrazone, in the rabbit model of daunorubicin-induced cardiotoxicity. The Journal of Pharmacology and Experimental Therapeutics, 319(3), 1336–1337.PubMedCrossRefGoogle Scholar
  21. 21.
    Simunek, T., Klimtova, I., Kaplanova, J., Sterba, M., Mazurova, Y., Adamcova, M., Hrdina, R., Gersl, V., & Ponka, P. (2005). Study of daunorubicin cardiotoxicity prevention with pyridoxal isonicotinoyl hydrazone in rabbits. Pharmacology Research, 51(3), 223–231.CrossRefGoogle Scholar
  22. 22.
    Bast, A., Kaiserova, H., den Hartog, G. J., Haenen, G. R., van der Vijgh1, W. J. (2007). Protectors against doxorubicin-induced cardiotoxicity: Flavonoids. Cell Biology and Toxicology, 23(1), 39–47.PubMedCrossRefGoogle Scholar
  23. 23.
    Hershko, C., Link, G., Tzahor, M., Kaltwasser, J. P., Athias, P., Grynberg, A., & Pinson, A. (1993). Anthracycline toxicity is potentiated by iron and inhibited by deferoxamine: Studies in rat heart cells in culture. The Journal of Laboratory and Clinical Medicine, 122(3), 245–251.PubMedGoogle Scholar
  24. 24.
    Herman, E. H., Zhang, J., & Ferrans, V. J. (1994). Comparison of the protective effects of desferrioxamine and ICRF-187 against doxorubicin-induced toxicity in spontaneously hypertensive rats. Cancer Chemotherapy and Pharmacology, 35(2), 93–100.PubMedCrossRefGoogle Scholar
  25. 25.
    Saad, S. Y., Najjar, T. A., & Al-Rikabi, A. C. (2001). The preventive role of deferoxamine against acute doxorubicin-induced cardiac, renal and hepatic toxicity in rats. Pharmacology Research, 43(3), 211–218.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Helena Kaiserová
    • 1
    • 5
  • Tomáš Šimůnek
    • 1
  • Martin Štěrba
    • 2
  • Gertjan J. M. den Hartog
    • 4
  • Ladislava Schröterová
    • 3
  • Olga Popelová
    • 2
  • Vladimír Geršl
    • 2
  • Eva Kvasničková
    • 1
  • Aalt Bast
    • 4
  1. 1.Department of Biochemical Sciences, Faculty of Pharmacy in Hradec KrálovéCharles University in PragueHradec KrálovéCzech Republic
  2. 2.Department of Pharmacology, Faculty of Medicine in Hradec KrálovéCharles University in PragueHradec KrálovéCzech Republic
  3. 3.Department of Medical Biology and Genetics, Faculty of Medicine in Hradec KrálovéCharles University in Prague Hradec KrálovéCzech Republic
  4. 4.Department of Pharmacology and Toxicology, Faculty of MedicineUniversity of MaastrichtMaastrichtThe Netherlands
  5. 5.Institute of Organic Chemistry and BiochemistryAcademy of Sciences of the Czech RepublicPrague 6Czech Republic

Personalised recommendations