Differential effects of 4-aminoquinoline-containing antimalarial drugs on hemoglobin digestion in Plasmodium falciparum-infected erythrocytes

Famin, Oleg; Ginsburg, Hagaï

doi:10.1016/s0006-2952(01)00878-4

Cited by 75 publications

(69 citation statements)

References 31 publications

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“…Artemisinin treatment also reproducibly increased the hemoglobin levels, although to a much lesser extent than chloroquine. By contrast, mefloquine appeared to decrease parasite hemoglobin levels compared to those in the controls, which is in agreement with previously published results (8).…”

Section: Effect Of Drug Treatment On Hemoglobin Levels In Parasitessupporting

confidence: 93%

“…Previous reports have suggested that chloroquine blocks hemoglobin degradation and should therefore produce an accumulation of undigested hemoglobin in treated parasites and, moreover, that quinoline antimalarials may differ in this regard (8,52). To determine the effects of antimalarial drugs on the hemoglobin levels in the D10 strain of P. falciparum, parasites were incubated with chloroquine, mefloquine, and artemisinin for 12 h; released from the RBCs by saponin treatment, and washed extensively to remove extraneous hemoglobin.…”

Section: Effect Of Drug Treatment On Hemoglobin Levels In Parasitesmentioning

confidence: 99%

“…By sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (PAGE) analysis it has been found that artemisinin leads to hemoglobin accumulation in the murine malaria species Plasmodium yoelii, possibly due to inhibition of vacuolar proteases by artemisinin-heme complexes (34). Similarly, chloroquine also leads to hemoglobin buildup in the murine species Plasmodium berghei and the FCR3 strain of Plasmodium falciparum (8,9,52). This effect has been ascribed to an inhibition of vacuolar hydrolases responsible for removing the inner membrane of endocytic vesicles following their fusion with the vacuole: there appears to be a buildup of hemoglobin-filled vesicles surrounded by a single membrane inside the vacuole of treated parasites when viewed by electron microscopy (51).…”

mentioning

confidence: 99%

“…In addition, a chloroquine-induced swelling of the vacuole has been reported (20), an effect that is also found in mammalian cells. Finally, a reduction in the hemoglobin content in parasites treated with mefloquine compared with that in controls and the fact that this drug antagonizes chloroquine toxicity in the FCR3 strain of P. falciparum have led to the proposal that mefloquine inhibits the actual endocytosis of hemoglobin by the parasite (8).…”

mentioning

confidence: 99%

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Antimalarial Quinolines and Artemisinin Inhibit Endocytosis in Plasmodium falciparum

Hoppe

Schalkwyk²,

Wiehart³

et al. 2004

Antimicrob Agents Chemother

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Endocytosis is a fundamental process of eukaryotic cells and fulfills numerous functions, most notably, that of macromolecular nutrient uptake. Malaria parasites invade red blood cells and during their intracellular development endocytose large amounts of host cytoplasm for digestion in a specialized lysosomal compartment, the food vacuole. In the present study we have examined the effects of artemisinin and the quinoline drugs chloroquine and mefloquine on endocytosis in Plasmodium falciparum. By using novel assays we found that mefloquine and artemisinin inhibit endocytosis of macromolecular tracers by up to 85%, while the latter drug also leads to an accumulation of undigested hemoglobin in the parasite. During 5-h incubations, chloroquine inhibited hemoglobin digestion but had no other significant effect on the endocytic pathway of the parasite, as assessed by electron microscopy, the immunofluorescence localization of hemoglobin, and the distribution of fluorescent and biotinylated dextran tracers. By contrast, when chloroquine was added to late ring stage parasites, followed by a 12-h incubation, macromolecule endocytosis was inhibited by more than 40%. Moreover, there is an accumulation of transport vesicles in the parasite cytosol, possibly due to a disruption in vacuole-vesicle fusion. This fusion block is not observed with mefloquine, artemisinin, quinine, or primaquine but is mimicked by the vacuole alkalinizing agents ammonium chloride and monensin. These results are discussed in the light of present theories regarding the mechanisms of action of the antimalarials and highlight the potential use of drugs in manipulating and studying the endocytic pathway of malaria parasites.

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Section: Effect Of Drug Treatment On Hemoglobin Levels In Parasitessupporting

confidence: 93%

Section: Effect Of Drug Treatment On Hemoglobin Levels In Parasitesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Antimalarial Quinolines and Artemisinin Inhibit Endocytosis in Plasmodium falciparum

Hoppe

Schalkwyk²,

Wiehart³

et al. 2004

Antimicrob Agents Chemother

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“…Arylaminoalcohols (Fig. 4) seem to interfere with the heme digestion [35,36]. Amplification of the pfmdr1 gene appears to be the main factor in arylaminoalcohol resistance [37 -42].…”

Section: Arylaminoalcoholsmentioning

confidence: 99%

Antimalarial Drugs – What is in Use and What is in the Pipeline

Schlitzer¹

2008

Archiv der Pharmazie

131

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Malaria continues to be a potentially fatal threat to almost half of the world's population. In light of this threat, the armory to fight this disease is rather limited. Resistance against the most common and affordable antimalarials is widespread. Only few new drugs are in clinical development, most of them belong to long used classes of antimalarial drugs. This review will concisely cover the drugs which are currently in use, and describe the drug candidates which are in clinical evaluation.

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Neue Antimalaria‐Wirkstoffe

et al. 2003

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Etwa 40 % der Weltbevölkerung leben in Malariagebieten. Jährlich erkranken 300 bis 500 Millionen Menschen an Malaria, bis zu 2.5 Millionen sterben an den Krankheitsfolgen. Obwohl Malaria in vielen Teilen der Welt bereits als ausgerottet galt, nimmt die Zahl der Fälle auch in diesen Gebieten wieder zu. Der wichtigste Grund für diese bedrohliche Entwicklung ist die zunehmende Verbreitung von Resistenzen gegen Antimalaria‐Wirkstoffe, insbesondere gegen das am häufigsten verwendete Chloroquin. Seit Mitte der siebziger Jahre wurde die Entwicklung neuer Wirkstoffe vernachlässigt. Dafür ist neben dem Wegfall kolonialer und militärischer Interessen auch das beschränkte Marktpotenzial verantwortlich. Unterstützt durch öffentliche Förderprogramme werden erst seit kurzem wieder intensivere Forschungsaktivitäten unternommen. Fortschritte verspricht man sich vor allem von der Sequenzierung des Genoms von Plasmodium falciparum, dem Malaria‐Erreger, sowie von modernem Wirkstoff‐Design.

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Differential effects of 4-aminoquinoline-containing antimalarial drugs on hemoglobin digestion in Plasmodium falciparum-infected erythrocytes

Cited by 75 publications

References 31 publications

Antimalarial Quinolines and Artemisinin Inhibit Endocytosis in Plasmodium falciparum

Antimalarial Quinolines and Artemisinin Inhibit Endocytosis in Plasmodium falciparum

Antimalarial Drugs – What is in Use and What is in the Pipeline

Neue Antimalaria‐Wirkstoffe

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