Control of Transplasma Membrane Diferric Transferrin Reductase by Antitumor Drugs
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.
KeywordsHeLa Cell BeLa Cell Ferricyanide Reduction Diferric Transferrin Transmembrane Electron Transport
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- 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
- DiMarco, A., 1975, Adriamycin (NSC - 123, 127): Mode and mechanism of action, Cancer Chem. Rep., 59: 91.Google Scholar
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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