Skip to main content
SpringerLink
Log in

Enhancement of adriamycin toxicity by iron chelates is not a free radical mechanism

  • Original Articles
  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

The possible involvement of metal ions and free radicals in the cytotoxic mechanism of Adriamycin (ADR) was investigated, using a model system ofEscherichia coli cells. It is shown thatE. coli mediated the production of free radicals under anaerobic (ADR-semiquinone) and aerobic (superoxide) conditions. ADR-induced loss of colony-forming ability was enhanced by the addition of iron (Fe) chelates. These observations suggested that a Fenton-type free radical mechanism was responsible for ADR toxicity. However, the mortality rate was essentially unchanged by the exclusion of oxygen. It was also unaffected by the addition of H2O2, catalase, or chelating agents. Cu(II), Zn(II) or Mg(II) had no effect on ADR toxicity. ADR and iron chelates did not induce measurable amounts of DNA strand-breaks. These observations suggest a mechanism of ADR-induced cell killing that is enhanced by Fe chelates, but does not directly involve oxygen-derived free radicals.

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

Similar content being viewed by others

References

  1. S. Sato, M. Iwaizumi, K. Handa, and Y. Tamura, Electron spin resonance study of the mode of generation of free radicals of daunomycin, adriamycin, and carboquone in NAD(P)H-microsome system,Gann 68, 603–608 (1977).

    PubMed  CAS  Google Scholar 

  2. B. Kalyanaraman, E. Perez-Reyes, and R. P. Mason, Spin-trapping and direct electron spin resonance investigations of the redox metabolism of quinone anticancer drugs,Biochim. Biophys. Acta 630, 119–130 (1980).

    PubMed  CAS  Google Scholar 

  3. V. Berlin and W. A. Haseltine, Reduction of adriamycin to a semiquinone-free radical by NADPH cytochrome P-450 reductase produces DNA cleavage in a reaction mediated by molecular oxygen.J. Biol. Chem. 256, 4747–4756 (1981).

    PubMed  CAS  Google Scholar 

  4. K. Handa, and S. Sato, Generation of free radicals of quinone group-containing anticancer chemicals in NADPH-microsome system as evidenced by initiation of sulfite oxidation.Gann 66, 43 (1975).

    PubMed  CAS  Google Scholar 

  5. J. W. Lown, S.-K. Sim, K. C. Majumdar, and R.-Y. Chang, Strand scission of DNA by bound adriamycin and daunorubicin in the presence of reducing agents.Biochem. Biophys. Res. Commun. 76 705–710 (1977).

    Article  PubMed  CAS  Google Scholar 

  6. N. R. Bachur, S. L. Gordon, M. V. Gee, and H. Kon, NADPH cytochrome P-450 reductase activation of quinone anticancer agents to free radicals,Proc. Natl. Acad. Sci. USA 76, 954–957 (1979).

    Article  PubMed  CAS  Google Scholar 

  7. J. Schreiber, C. Mottley, B. K. Sinha, B. Kalyanaraman, and R. P. Mason, One-electron reduction of daunomycin, daunomycinone, and 7-deoxydaunomycinone by the xanthine/xanthine oxidase system: detection of semiquinone free radicals by electron spin resonance.J. Am. Chem. Soc. 109, 348–351 (1987).

    Article  CAS  Google Scholar 

  8. W. S. Thayer, Adriamycin stimulated superoxide formation in submitochondrial particles,Chem. Biol. Interactions 19, 265–278 (1977).

    Article  CAS  Google Scholar 

  9. N. R. Bachur, M. V. Gee, and R. D. Friedman, Nuclear catalyzed antibiotic free radical formation,Cancer Res. 42, 1078–1081 (1982).

    PubMed  CAS  Google Scholar 

  10. G. Pollakis, E. Goormaghtigh, M. Delmelle, Y. Lion, and J.-M. Ruysschaert, Adriamycin and derivatives interaction with the mitochondrial membrane: O2 consumption and free radicals formation.Res. Commun. Chem. Pathol. Pharmacol. 44, 445–459 (1984).

    PubMed  CAS  Google Scholar 

  11. A. V. Peskin, A. A. Konstantinov, and I. B. Zbarsky, An unusual NAD(P)H-dependent O2 − generating redox system in hepatoma 22a nuclei.Free Rad. Res. Commun. 3, 47–55 (1987).

    Article  CAS  Google Scholar 

  12. C. A. Henderson, E. N. Metz, S. P. Balcerzak, and A. L. Sagone, Jr., Adriamycin and Daunomycin generate reactive oxygen compounds in erythrocytes,Blood 52, 878–885 (1978).

    PubMed  CAS  Google Scholar 

  13. J. H. Doroshow, Effect of doxorubicin (D) on oxygen radical metabolism in Ehrlich ascites tumor (EAT) cells,Proc. Am. Assoc. Cancer Res. 22, 805 (1981).

    Google Scholar 

  14. B. K. Sinha, A. G. Katki, G. Batist, K. H. Cowan, and C. E. Myers, Adriamycin-stimulated hydroxyl radical formation in human breast tumor cells,Biochem. Pharmacol. 36, 793–796 (1987).

    Article  PubMed  CAS  Google Scholar 

  15. A. E. Alegria, A. Samuni, J. B. Mitchell, P. Reisz, and A. Russo, Free radicals induced by adriamycin-sensitive and adriamycin-resistant cells: a spin-trapping study,Biochemistry 28, 8653–8658 (1989).

    Article  PubMed  CAS  Google Scholar 

  16. S. Rajagopalan, P. M. Politi, B. K. Sinha, and C. E. Myers, Adriamycin-induced free radical formation in the perfused rat heart: implications for cardiotoxicity,Cancer Res. 48, 4766–4769 (1988).

    PubMed  CAS  Google Scholar 

  17. J. Goodman and P. Hochstein, Generation of free radicals and lipid peroxidation by redox cycling of adriamycin and daunomycin.Biochem. Biophys. Res. Commun. 77, 797–803 (1977).

    Article  PubMed  CAS  Google Scholar 

  18. C. E. Myers, W. P. McGuire, R. H. Liss, I. Ifrim, K. Grotzinger, and R. C. Young, Adriamycin: The role of lipid peroxidation in cardiac toxicity and tumor response,Science 197, 165–167 (1977).

    Article  PubMed  CAS  Google Scholar 

  19. H. G. Keizer, H. M. Pinedo, G. J. Schuurhuis, and H. Joenje, Doxorubicin (adriamycin): a critical review of free radical-dependent mechanisms of cytotoxicity.Pharmacol. Ther. 47, 219–231 (1990).

    Article  PubMed  CAS  Google Scholar 

  20. Y. Iwamoto, I. L. Hansen, T. H. Porter, and K. Folkers, Inhibition of coenzyme Q10-enzymes, succinoxidase and NADH-oxidase, by adriamycin and other quinones having antitumor activity,Biochem. Biophys. Res. Commun. 58, 633–638 (1974).

    Article  PubMed  CAS  Google Scholar 

  21. K. J. Davies and J. H. Doroshow, Redox cycling of anthracyclines by cardiac mitochondria. I. Anthracycline radical formation by NADH dehydrogenase.J. Biol. Chem. 261, 3060–3067 (1986).

    PubMed  CAS  Google Scholar 

  22. S. A. Akman, J. H. Doroshow, T. G. Burke, and M. Dizdaroglu, DNA base modifications induced in isolated human chromatin by NADH dehydrogenase-catalyzed reduction of doxorubicin,Biochemistry 31, 3500–3506 (1992).

    Article  PubMed  CAS  Google Scholar 

  23. T. Komiyama, T. Oki, and T. J. Inui, A proposed reaction mechanism for the enzymatic reductive cleavage of glycosidic bond in anthracycline antibiotics,J. Antibiot. 32, 1219–1222 (1979).

    PubMed  CAS  Google Scholar 

  24. B. K. Sinha and J. L. Gregory, Role of one-electron and two-electron reduction products of adriamycin and daunomycin in deoxyribonucleic acid binding.Biochem. Pharmacol. 30, 2626–2629 (1981).

    Article  PubMed  CAS  Google Scholar 

  25. J. F. Van Vleet, L. Greenwood, V. J. Ferrans, and A. H. Rebar, Effect of selenium-vitamin E on adriamycin-induced cardiomyopathy in rabbits,Am. J. Vet. Res. 39, 997–1010 (1978).

    PubMed  Google Scholar 

  26. J. H. Doroshow, G. Y. Locker, I. Ifrim and C. E. Myers, Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine,J. Clin. Invest. 68, 1053–1064 (1981).

    Article  PubMed  CAS  Google Scholar 

  27. T. Usui, H. Ishikura, Y. Izumi, H. Konishi, N. Dohmae, H. Sawada, H. Uchino, H. Matsuda, and T. Konishi, Possible prevention from the progression of cardiotoxicity in adriamycin-treated rabbits by coenzyme Q10,Toxicol. Lett. 12, 75–82 (1982).

    Article  PubMed  CAS  Google Scholar 

  28. J. H. Doroshow, Prevention of doxorubicin-induced killing of MCF-7 human breast cancer cells by oxygen radical scavengers and iron chelating agents,Biochem. Biophys. Res. Commun. 135, 330–335 (1986).

    Article  PubMed  CAS  Google Scholar 

  29. E. Monti and B. K. Sinha, Potentiation of doxorubicin cytotoxicity by (+)-1,2-bis-(3,5-dioxopiperazinyl-1-yl) propane (ICRF-187) in human leukemic HL-60 cells,Cancer Commun. 2, 145–149 (1990).

    PubMed  CAS  Google Scholar 

  30. G. R. Fisher, and L. H. Patterson, Lack of involvement of reactive oxygen in the cytotoxicity of mitoxantrone, C1941 and ametantrone in MCF-7 cells: comparison with doxorubicin,Cancer Chemother. Pharmacol. 30, 451–458 (1992).

    Article  PubMed  CAS  Google Scholar 

  31. T. J. Lin, G. T. Liu, Y. Liu, and G. S. Xu, Protection by salvianolic acid A against adriamycin toxicity on rat heart mitochondria,Free Rad. Biol. Med. 12, 347–351 (1992).

    Article  PubMed  CAS  Google Scholar 

  32. M. N. Benchekroun, P. Catroux, D. Montaudon, and J. Robert, Development of mechanisms of protection against oxidative stress in doxorubicin-resistant rat tumoral cells in culture,Free Rad. Res. Commun. 11, 137–144 (1990).

    Article  CAS  Google Scholar 

  33. D. Gelvan and A. Samuni, Cellular targets of adriamycin-induced damage in Escherichia coli,Biochem. Pharmacol. 35, 3267–3275 (1986).

    Article  PubMed  CAS  Google Scholar 

  34. P. L. Gutierrez, M. V. Gee, and N. R. Bachur, Kinetics of anthracycline antibiotic free radical formation and reductive glycosidase activity,Arch. Biochem. Biophys. 223, 68–75 (1983).

    Article  PubMed  CAS  Google Scholar 

  35. A. Samuni, A. J. Carmichael, A. Russo, J. B. Mitchell, and P. Riesz, On the spintrapping and ESR detection of oxygen-derived radicals generated inside cells,Proc. Natl. Acad. Sci. USA 83, 7593–7597 (1986).

    Article  PubMed  CAS  Google Scholar 

  36. T. G. Spiro, S. E. Allerton, J. Renner, A. Terzis, R. Bils, and P. Saltman, The hydrolytic polymerization of iron(III),J. Am. Chem. Soc. 88, 2721–2726 (1966).

    Article  CAS  Google Scholar 

  37. J. Aronovitch, A. Samuni, D. Godinger, M. Greenbaum, and G. Czapski, Bactericidal effect of H2O2 and DNA damage in xthA mutants of E. coli, inSuperoxide and Superoxide Dismutase in Chemistry, Biology and Medicine, G. Rotilio, ed., Elsevier, Amsterdam, pp. 343–345 (1986).

    Google Scholar 

  38. J. Aronovitch, A. Samuni, D. Godinger, and G. Czapski, In vivo degradation of bacterial DNA by H2O2 and o-phenanthroline, inSuperoxide and Superoxide Dismutase in Chemistry, Biology and Medicine, G. Rotilio, ed., Elsevier, Amsterdam, pp. 346–348 (1986).

    Google Scholar 

  39. J. R. White and H. N. Yeowell, Iron enhances the bactericidal action of streptonigrin,Biochem. Biophys. Res. Commun. 106, 407–411 (1982).

    Article  PubMed  CAS  Google Scholar 

  40. J. H. Doroshow, Anthracycline antibiotic-stimulated superoxide, hydrogen peroxide, and hydroxyl radical production by NADH dehydrogenase.Cancer Res. 43, 4543–4551 (1983).

    PubMed  CAS  Google Scholar 

  41. M. J. Turner, D. B. Everman, S. P. Ellington, and C. E. Fields, Detection of free radicals during the cellular metabolism of adriamycin,Free Rad. Biol. Med. 9, 415–421 (1990).

    Article  PubMed  CAS  Google Scholar 

  42. A. Samuni and G. Czapski, Radiation-induced damage in Escherichia coli B: the effect of superoxide radicals and molecular oxygen.Radiat. Res. 76, 624–632 (1978).

    Article  PubMed  CAS  Google Scholar 

  43. J. Aronovitch, D. Godinger, A. Samuni, and G. Czapski, The effect of cell-bound copper on the toxicity of superoxide and vitamin C, inOxygen Radicals in Chemistry and Biology, W. Bors, M. Saran and D. Tait, eds., Berlin, Walter de Gruyter, pp. 219–223 (1984).

    Google Scholar 

  44. P. Korbashi, R. Kohen, J. Katzhendler, and, M. Chevion, Iron mediates paraquat toxicity in Escherichia coli,J. Biol. Chem. 261, 12472–12476 (1986).

    PubMed  CAS  Google Scholar 

  45. R. Kohen and M. Chevion, Transition metals potentiate paraquat toxicity.Free Rad. Res. Commun. 1, 78–88 (1985).

    Google Scholar 

  46. S. R. Powell and A. J. Tortolani, Recent advances in the role of reactive oxygen intermediates in ischemic injury,J. Surg. Res. 53, 417–429 (1992).

    Article  PubMed  CAS  Google Scholar 

  47. R. Kohen, M. Szyf, and M. Chevion, Quantitation of single and double-strand DNA breaks in vitro and in vivo.Anal. Biochem. 154, 485–491 (1986).

    Article  PubMed  CAS  Google Scholar 

  48. F. A. Fornari, J. K. Randolph, J. C. Yalowich, M. K. Ritke, and D. A. Gewirtz, Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells,Mol. Pharmacol. 45, 649–656 (1994).

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  50. G. Aubel-Sadron and D. Londos-Gagliardi, Daunorubicin and doxorubicin, anthracycline antibiotics, a physicochemical and biological review,Biochimie 66, 333–352 (1984).

    Article  PubMed  CAS  Google Scholar 

  51. J. R. Muindi, B. K. Sinha, L. Giani, and, C. E. Myers, Hydroxyl radical production and DNA damage induced by anthracycline-iron complex.FEBS Lett. 172, 226–230 (1984).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dept. of Human Nutrition and Metabolism, Hebrew University—Hadassah Medical School, PO Box 12272, 91120, Jerusalem, Israel

    Dan Gelvan

Authors
  1. Dan Gelvan
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gelvan, D. Enhancement of adriamycin toxicity by iron chelates is not a free radical mechanism. Biol Trace Elem Res 56, 295–309 (1997). https://doi.org/10.1007/BF02785301

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02785301

Index Entries

Search

Navigation