Control of Transplasma Membrane Diferric Transferrin Reductase by Antitumor Drugs

  • I. L. Sun
  • F. L. Crane
Part of the NATO ASI Series book series (NSSA, volume 7)


It is well known that anthracycline antibiotics have been used successfully in the treatment of human cancer. It has long been thought that DNA is the primary target for the cytotoxic action of these drugs on susceptible cells (Chandra, 1987; DiMarco, 1975; Kanter et al., 1979; Ross et al., 1970). The DNA receptor hypothesis is attractive due to a reasonably high affinity between some of these drugs and nucleic acid. However, this hypothesis does not fully explain the antimitogenic effect of these drugs, since significant mitotic inhibition by daunomycin and adriamycin are observed under conditions in which DNA synthesis is unaffected (Silvetrini, 1970,1973). The N-substituted derivatives, such as N-acetyl daunomycin and N-trifluoro-acetyl adriamycin-l4-valerate (AD32) have very low affinity toward DNA, yet they are capable of inhibiting cell mitosis (DiMarco et al., 1965; DiMarco, 1975; Kanter et al., 1979). Similarly, bleomycin and its chelate, Cu-bleomycin, inhibit mitosis equally well although selective strong DNA binding affinity is shown only by bleomycin (Sun and Crane, 1985a; Gutteridge and Chang, 1981). Furthermore, both cis and trans diammine dichloroplatinum II bind equally well with DNA, yet the trans analog is not effective as an antitumor agent (Macquet and Butour, 1985; Salles et al., 1983) and is much less cytotoxic than the cis analog (Pascoe and Roberts, 1974). Therefore, there are reasons to suspect that additional targets other than DNA are involved in killing cancer cells with these drugs.


HeLa Cell BeLa Cell Ferricyanide Reduction Diferric Transferrin Transmembrane Electron Transport 
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  1. Bachur, N. R., Gordon, S. L., Gee, M. V., and Kon, H., 1979, NADPH cytochrome P-450 reductase activation of quinine anticancer agents to free radicals, Proc. Natl. Acad. Sci., 76: 954.PubMedCrossRefGoogle Scholar
  2. Burger, R. M., Peisach, J., and Horwitz, S. B., 1982, Effect of O2 on the reactions of activated bleomycin, J. Biol. Chem., 257: 3372.PubMedGoogle Scholar
  3. Buettner, G. R. and Oberley, L. W., 1979, The production of hydroxyl radical by tallysomycin and copper (II), FEBS Lett., 101: 333.PubMedCrossRefGoogle Scholar
  4. Chandra, P., 1975, Role of chemical structure in biochemical activity of daunorubicin, adriamycin and some structure analogs: macromolecular interactions and their biological consequences, Cancer Res. Rep., 59: 115.Google Scholar
  5. Chou, J. W. and Schlegel-Haueter, S. E., 1981, Study of liver differentiation in vitro, J. Cell. Biol., 89: 216.PubMedCrossRefGoogle Scholar
  6. Clark, M. G., Partick, E. J., Patten, G. S., Crane, F. L., Löw, H., and Grebing, C., 1981, Evidence for the extracellular reduction of ferri-cyanide by rat liver; a transplasma membrane redox system, Biochem. J, 200: 565.PubMedGoogle Scholar
  7. Cole, E. S. and Glass, J., 1983, Transferrin binding and iron uptake in mouse hepatocytes, Biochim. Biophys. Acta, 762: 102.PubMedCrossRefGoogle Scholar
  8. Crane, F. L. and Löw, H., 1976, NADH oxidation in liver and fat cell plasma membranes, FEBS Lett., 68: 153.PubMedCrossRefGoogle Scholar
  9. Crane, F. L., Crane, H. E., Sun, I. L., Mackellar, W. C., Grebing, C., and Löw, H., 1982, Insulin control of a transplasma membrane NADH dehydrogenase in erythrocyte membranes, J. Bioenerg. Biomemb., 14: 425.CrossRefGoogle Scholar
  10. DiMarco, A., Silvetrini, R., DiMarco, S., and Dasdia, T., 1965, Inhibiting effect of the new cytotoxic antibiotic daunomycin on nucleic acids and mitotic activity of HeLa cells. J. Cell. Biol., 27: 545.CrossRefGoogle Scholar
  11. DiMarco, A., 1975, Adriamycin (NSC - 123, 127): Mode and mechanism of action, Cancer Chem. Rep., 59: 91.Google Scholar
  12. Ellem, K. A. O. and Kay, G. F., 1983, Ferricyanide can replace pyruvate to stimulate growth and attachment of serum restricted human melanoma cells, Biochem. Biophys. Res. Commun., 112: 183.PubMedCrossRefGoogle Scholar
  13. Gutteridge, J. M. C. and Chang, F. X., 1981, Protection of iron-catalyzed free radical damage to DNA and lipids by copper (II) - bleomycin. Biochem. Biophys. Res. Commun., 99: 1354.PubMedCrossRefGoogle Scholar
  14. Israel, M., Modest, E. J., and Frei, E., 1975, N-trifluoracetyl-adriamycin-l4-valerate, and analog with greater experimental antitumor activity and less toxicity than adriamycin. Cancer Res., 38: 365.Google Scholar
  15. Kanter, P. M. and Schwartz, H. S., 1979, Quantitative models for growth inhibition of human leukemia cells by antitumor anthracycline derivatives. Cancer Res., 39: 3661.PubMedGoogle Scholar
  16. Löw, H., Grebing, C., Navas, P., Sun, I. L., Crane, F. L., and Morré, D. J., 1986, Transplasmalemma electron transport from cells is part of a diferric transferrin reductase system, Biochem. Biophys, Res. Commun., 139: 1117.CrossRefGoogle Scholar
  17. Maquet, J. P. and Butour, J. L., 1985, Avian erythroblastosis virus isolated from chick erythroblastosis induced by lymphatic leukemia virus subgroup A, J. Nat. Cancer Inst., 70: 899.Google Scholar
  18. Matsumara, M. and Miyachi, S., 1980, Cycling assay for nicotinamide adenine dinucleotides, Meth. Enzymol., 69: 465.CrossRefGoogle Scholar
  19. Mishell, B. B. and Shrigi, S. M., 1980, Determination of viability by eosin y exclusion, In: “Selected Methods in Cellular Immunology,” W. H. Freeman Company, San Francisco.Google Scholar
  20. Morley, C. D. G., Revers, K. and Bezkorvainy, A., 1982, “Biochemistry and Physiology of Iron,” (P. Saltman and Hagenauer, Eds.), Elsevier/North Holland, Amsterdam.Google Scholar
  21. Murphree, S. A., Cunningham, L. S., Hwang, K. M., and Sartorelli, A. C., 1976, Effect of adriamycin on surface properties of sarcoma 180 ascites cells, Biochem. Pharmacol., 25: 1227.PubMedCrossRefGoogle Scholar
  22. Na, C. and Timasheff, S. N., 1977, Physical-chemical study of daunomycintubulin interactions, Arch. Biochem. Biophys., 182: 147.PubMedCrossRefGoogle Scholar
  23. Navas, P., Sun, I. L., Morré, D. J., and Crane, F. L., 1986, Decrease of NADH in HeLa cells in the presence of transferrin and ferricyanide, Biochem. Biophys. Res. Commun., 135: 110.PubMedCrossRefGoogle Scholar
  24. Pascoe, J. N. and Roberts, J. J., 1974, Interactions between mammalian cell DNA and inorganic platinum compounds -I, Biochem. Pharmacol., 23: 1345.PubMedCrossRefGoogle Scholar
  25. Ross, W. E., Glaubiger, D., and Kohn, K. W., 1979, Qualitative and quantitative aspects of intercalator-induced DNA strand breaks, Biochim. Biophys. Acta, 562: 41.PubMedCrossRefGoogle Scholar
  26. Salles, B., Butour, J. L., Lesca, C., and Macquet, J. P., 1983, Cis-pt (NH3)2 Cl2 and trans-pt (NH3)2 Cl2 inhibit DNA synthesis in cultured L1210 leukemia cells, Biochem. Biophys. Res. Commun., 112: 555.PubMedCrossRefGoogle Scholar
  27. Silvetrini, R., DiMarco, A., and Dasdia, T., 1970, Interference of daunomycin with metabolic events of the cell cycle in synchronized cultures of rat fibroblasts, Cancer Res., 60: 603.Google Scholar
  28. Silvetrini, R., Lenaz, L., and DiFronzo, C., 1973, Correlations between cytotoxicity, biochemical effects, drug levels, and therapeutic effectiveness of daunomycin and adriamycin on Sarcoma 180 ascites in mice, Cancer Res., 33: 2954.Google Scholar
  29. Sims, P. J., Waggoner, A. S., Wang, C. H., and Hoffman, J. F., 1974, Studies on the mechanism by which cyanine dyes measure membrane potential in red blood cells and phosphatidylcholine vesicles. Biochemistry, 13: 3315.PubMedCrossRefGoogle Scholar
  30. Sun, I. L. and Crane, F. L., 1981, Evidence that a transplasma membrane redox system is coupled to membrane potentials in HeLa cells, Abst. Am. Soc. Microbiology, 81: 165.Google Scholar
  31. Sun, I. L., Crane, F. L., Chou, J. Y., Löw, H., and Grebing, G., 1983, Transformed liver cells have modified transplasma membrane redox activity which is sensitive to adriamycin, Biochem. Biophys. Res. Commun., 112: 183.CrossRefGoogle Scholar
  32. Sun, I. L and Crane, F. L., 1984a, The antitumor drug, cis-diaminedichloro-platinum, inhibits transplasmalemma electron transport in HeLa cells, Biochem. Intern., 9: 299.Google Scholar
  33. Sun, I. L., Crane, F. L., Löw, H., and Grebing, C., 1984b, Transplasma membrane redox stimulates HeLa cell growth, Biochem. Biophys. Res. Commun., 125: 649.PubMedCrossRefGoogle Scholar
  34. Sun, I. L., Crane, F. L., Löw, H., and Grebing, C., 1984c, Inhibition of plasma membrane NADH dehydrogenase by adriamycin and related anthracycline antibiotics, J. Bioenerg. Biomemb., 14: 425.Google Scholar
  35. Sun, I. L. and Crane, F. L., 1985, Bleomycin control of transplasma membrane redox activity and proton movement in HeLa cells, Biochem. Pharmacol., 34: 617.PubMedCrossRefGoogle Scholar
  36. Sun, I. L., Crane, F. L., Grebing, C., and Löw, H., 1985, Transmembrane redox in control of cell growth: Stimulation of HeLa cell growth by ferricyanide and insulin, Exp. Cell. Res., 156: 528.PubMedCrossRefGoogle Scholar
  37. Thorstensen, K. and Romslo, I., 1984, Uptake of iron from transferrin by isolated hepatocytes, Biochim. Biophys. Acta, 804: 200.PubMedCrossRefGoogle Scholar
  38. Tokes, Z. A., Rogers, K. E., and Rembaum, A., 1982, Synthesis of adriamycin-coupled polyglutaraldehyde microspheres and evaluation of their cytostatic activity. Proc. Natl, Acad. Sci. U.S.A., 79: 2026.CrossRefGoogle Scholar
  39. Tritton, R. R. and Yee, G., 1982, The anticancer agent adriamycin can be actively cytotoxic without entering cells, Science, 217: 248.CrossRefGoogle Scholar
  40. Tritton, T. R., Yee, G., and Wingard, L. B. Jr., 1983, Immobilized adriamycin: a tool for separating cell surface from intracellular mechanisms, Fed. Proc., 42: 284.PubMedGoogle Scholar
  41. Waring, M. J., 1981, Annu. Rev. Biochem., 50: 159.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1988

Authors and Affiliations

  • I. L. Sun
    • 1
  • F. L. Crane
    • 1
  1. 1.Department of Biological SciencesPurdue UniversityWest LafayetteUSA

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