Differential cytotoxicity of iron chelators on malaria-infected cells versus mammalian cells

Iron chelators of the hydroxamate class arrest in vitro proliferation of malaria parasites and of mammalian cells. The factors determining the biological activity of the chelators have classically been attributed to the chelators' capacity for binding iron and to their ability to traverse membranes as free chelators and as chelator-iron complexes. We show in this work that the nature of the chelatable pool of cell iron also contributes to the susceptibility of cells to iron chelators. A class of N-terminal (N(t)) derivatives of desferrioxamine (DFO), (N(t)-DFO), is shown here to differentially affect growth and replication of intraerythrocytic parasites (Plasmodium falciparum). Methyl-anthranilic DFO (MADFO), the relatively less hydrophilic member of the N(t)-DFOs series, reduced parasite proliferation (48 hour test) with an IC₅₀ of 4 ± 1 μmol/L and mammalian cell (K562 and HepG2) proliferation with an IC₅₀ > 100 μmol/L. On the other hand, the more hydrophilic N(t)-free DFO, displayed IC₅₀ values of 21 ± 5 μmol/L for parasites and 7 ± 1 μmol/L for mammalian cells. The selective antiparasitic activity of MA-DFO, as reflected in the speed of action and IC₅₀ values on cell proliferation, is attributed primarily to membrane permeation and iron(III) binding properties of the drug. In contrast, the relatively low antiproliferative activity of the more permeant MA-DFO on mammalian cells, resulted from MA-DFO's reduced capacity for scavenging intracellular iron. This is apparent from MA-DFO reduced effects on: (1) the chelatable iron(II) pool that is associated with the cell cytosol; (2) the call chelator-extractable iron, and (3) cell ferritin levels. The potent antimalarial efficacy and biological selectivity of MA-DFO relative to the parent DFO, is of importance for improved design of chemotherapeutic agents.