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The Effect of the Iron(III) Chelator, Desferrioxamine, on Iron and Transferrin Uptake by the Human Malignant Melanoma Cell¹

Lady Davis Institute for Medical Research of the Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec H3T 1E2[D. R., P. P.], Canada, and Department of Physiology, University of Western Australia, Nedlands, Perth[E. B.] Australia

The mechanism of action of the clinically used iron(III) chelator, desferrioxamine (DFO), on preventing iron (Fe) uptake from transferrin (Tf) has been investigated using the human melanoma cell line SK-MEL-28. This investigation was initiated due to the paucity of information on the mechanisms of action of DFO in neoplastic cells and because recent studies have suggested that DFO may be a useful antitumor agent. The effect of DFO was dependent on incubation time. After a 2-h incubation, DFO acted like the extracellular chelators, EDTA and diethylenetriaminepentaacetic acid, because there was little inhibition of ⁵⁹Fe uptake from Tf. In contrast, after a 24-h incubation, DFO (0.5 mM) efficiently reduced internalized ⁵⁹Fe uptake from Tf to 18% of the control value. These observations suggested the existence of a kinetic block to the entry of the apochelator to intracellular Fe pools and/or to the exit of the DFO-⁵⁹Fe complex. Indeed, cellular fractionation demonstrated that, in contrast to the decrease in the percentage of ⁵⁹Fe in the ferritin and membrane fractions, a marked increase in the percentage of ⁵⁹Fe present in the ferritin-free cytosol occurred. These observations suggested an accumulation of the DFO-⁵⁹Fe complex within the cell. The highly lipophilic Fe chelator, pyridoxal isonicotinoyl hydrazone, was far more effective than DFO at preventing ⁵⁹Fe uptake from Tf, illustrating the importance of membrane permeability for effective Fe chelation. Desferrioxamine at a concentration of 1 mM decreased internalized ¹²⁵I-Tf uptake to 70% of the control. However, the decrease in ⁵⁹Fe uptake observed could only be partially accounted for by a decrease in Tf uptake, and it appeared that DFO was chelating ⁵⁹Fe at an intracellular site consistent with the transit Fe pool. The results are discussed in the context of the use of Fe chelators as effective antineoplastic agents.

¹ Supported by Grant 880524 (to E. B.) and a Biomedical Postgraduate Scholarship (to D. R. R.) from the National Health and Medical Research Council of Australia.

² To whom requests for reprints should be addressed, at Lady Davis Institute for Medical Research, 3755 Chemin de la Cote-Ste-Catherine, Montreal, Quebec H3T 1E2, Canada.

Received 7/23/93. Accepted 11/29/93.

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