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Mode of action of iron (III) chelators as antimalarials: II. Evidence for
differential effects on parasite iron-dependent nucleic acid synthesis
SD Lytton, B Mester, J Libman, A Shanzer and ZI Cabantchik
Department of Biological Chemistry, Hebrew University, Jerusalem, Israel.
Iron chelation treatment of red blood cells infected with Plasmodium
falciparum selectively intervenes with iron-dependent metabolism of malaria
parasites and inhibits their development. Highly permeant hydroxamate iron
chelator RSFileum2 affects all parasite stages when cultures are
continuously exposed to drug, but affects primarily ring stages when
assessed for irreversible effects, ie, sustained inhibition remaining after
drug removal. On the other hand, the hydrophilic and poorly permeant
desferrioxamine (DFO) affects primarily trophozoite/schizont stages when
tested either in the continuous mode or irreversible mode. Unlike
parasites, mammalian cells subjected to similar drug treatment show
complete growth recovery once drugs are removed. Our studies indicate that
parasites display a limited capacity to recover from intracellular iron
depletion evoked by iron chelators. Based on these findings we provide a
working model in which the irreversible effects of RSFs on rings are
explained by the absence of pathways for iron acquisition/utilization by
early forms of parasites. Trophozoite/schizonts can partially recover from
RSFileum2 treatments, but show no DNA synthesis following DFO treatment
even after drug removal and iron replenishment by permeant iron carriers.
At trophozoite stage, the parasite uses a limited pathway for refurnishing
its iron-containing enzymes, thus overcoming iron deprivation caused by
permeant RSFileum2, but not by DFO because this latter drug is not easily
removable from parasites. Their DNA synthesis is blocked by the hydroxamate
iron chelators probably by affecting synthesis of ribonucleotide reductase
(RNRase). Presumably in parasites, prolonged repression of the enzyme leads
also to irreversible loss of activity. The action profiles of RSFileum2 and
DFO presented in this study have implications for improved chemotherapeutic
performance by combined drug treatment and future drug design based on
specific intervention at parasite DNA synthesis.
Volume 84,
Issue 3,
pp. 910-915,
08/01/1994
Copyright © 1994 by The American Society of Hematology
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