title: Antimalarial quinolines and artemisinin inhibit endocytosis in Plasmodium falciparum.
abstract: 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.
authors.affiliation: Division of Pharmacology, University of Cape Town Medical School, Groote Schuur Hospital Old Building, Observatory, Cape Town 7925, South Africa. hhoppe@uctgsh1.uct.ac.za
authors.forename: Heinrich C
authors.initials: HC
authors.lastname: Hoppe
authors.forename: Donelly A
authors.initials: DA
authors.lastname: van Schalkwyk
authors.forename: Ursula I M
authors.initials: UI
authors.lastname: Wiehart
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Meredith
authors.forename: Joanne
authors.initials: J
authors.lastname: Egan
authors.forename: Brandon W
authors.initials: BW
authors.lastname: Weber
mesh_terms: D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D001710:Biotin / Q000494:pharmacology; D015153:Blotting, Western; D002738:Chloroquine / Q000494:pharmacology; D003911:Dextrans / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects*; D016650:Fluorescein-5-isothiocyanate; D005455:Fluorescent Antibody Technique; D005456:Fluorescent Dyes; D006454:Hemoglobins / Q000378:metabolism; D015767:Mefloquine / Q000494:pharmacology; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008985:Monensin / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000648:ultrastructure; D015363:Quinolones / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology*; D022161:Transport Vesicles / Q000187:drug effects; D014617:Vacuoles / Q000187:drug effects / Q000648:ultrastructure
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D003911:Dextrans; D005456:Fluorescent Dyes; D006454:Hemoglobins; D015363:Quinolones; D012717:Sesquiterpenes; D000643:Ammonium Chloride; D001710:Biotin; D002738:Chloroquine; D008985:Monensin; C031327:artemisinin; D016650:Fluorescein-5-isothiocyanate; D015767:Mefloquine