Growth inhibition of bloodstream forms of Trypanosoma brucei by the iron chelator deferoxamine.
Treatment of bloodstream forms of Trypanosoma brucei with the iron chelator deferoxamine inhibits the proliferation of the parasites. Compared with mammalian cells, bloodstream forms of Trypanosoma brucei are 10 times more sensitive to iron depletion. The primary target of the chelator is obviously the intracellular iron as the toxicity of deferoxamine is abolished by addition of holotransferrin, the exogenous source of iron for the parasite. To identify probable target sites, the effect of deferoxamine on ribonucleotide reductase, alternative oxidase and superoxide dismutase, three iron-dependent enzymes in bloodstream-form trypanosomes, was studied. Incubation of the parasites with the chelator leads to inhibition of DNA synthesis and lowers oxygen consumption indicating that deferoxamine may affect ribonucleotide reductase and alternative oxidase. The compound does not inhibit the holoenzymes directly but probably acts by chelating cellular iron thus preventing its incorporation into the newly synthesised apoproteins. Treatment of the parasites with deferoxamine for 24 h has no effect on the activity of superoxide dismutase. The results have implications for antitrypanosomal drug development based on specific intervention with the parasite's iron metabolism.
Breidbach
Tanja
T
Abteilung Parasitologie, Hygiene-Institut der Ruprecht-Karls Universität, Im Neuenheimer Feld 324, D-69120 Heidelberg, Germany.
Scory
Stefan
S
Krauth-Siegel
R Luise
RL
Steverding
Dietmar
D
D000818:Animals; D001769:Blood / Q000469:parasitology*; D003470:Culture Media; D016054:DNA, Protozoan / Q000187:drug effects / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology*; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D051379:Mice; D010101:Oxygen Consumption / Q000187:drug effects; D012264:Ribonucleotide Reductases / Q000187:drug effects / Q000378:metabolism; D013482:Superoxide Dismutase / Q000187:drug effects / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000254:growth & development*
D003470:Culture Media; D016054:DNA, Protozoan; D007502:Iron Chelating Agents; D007501:Iron; D013482:Superoxide Dismutase; D012264:Ribonucleotide Reductases; D003676:Deferoxamine