title: Disruption of Plasmodium falciparum-infected erythrocyte cytoadherence to human melanoma cells with inhibitors of glycoprotein processing.
abstract: Adherence of Plasmodium falciparum-infected erythrocytes (IE) to the venular endothelium in brain and other organs is characteristic of cerebral malaria, an often fatal complication in infected individuals. It has been shown that cytoadherence may be mediated through interaction of IE with glycoproteins on host target cell surfaces, including CD36 (GPIV), intercellular adhesion molecule-1 (ICAM-1), and thrombospondin. Inhibitors of glycoprotein synthesis and processing were tested for their abilities to decrease IE adherence to C32 human melanoma cells. The alpha-glucosidase inhibitor, castanospermine, was effective in disrupting cytoadherence in vitro when incubated with C32 cells (IC50 = 600-700 microM). Castanospermine-6-butyrate was even more effective than the parent compound (IC50 = 9 microM) in disrupting cytoadherence. The mannosidase inhibitors, swainsonine and deoxymannojirimycin, had no effect on cytoadherence at concentrations up to 2 mM. No effect on cytoadherence was observed when the glucosidase and mannosidase inhibitors were incubated with IE rather than the C32 cell cultures. The level of CD36 on the C32 cell surface was decreased as measured by fluorescence-activated cell sorting (FACS) analysis with the same inhibitors which inhibited cytoadherence. Cells labeled with fluorescein isothiocyanate (FITC) OKM5 monoclonal antibody, which recognizes CD36 and disrupts cytoadherence, showed decreased fluorescence when treated with tunicamycin and castanospermine-6-butyrate but not when treated with swainsonine or deoxymannojirimycin. ICAM-1 levels, as measured by surface labeling of C32 cells with FITC CD54 monoclonal antibody, were decreased in cells treated with tunicamycin. However, incubation of cells with castanospermine-6-butyrate or deoxymannojirimycin decreased cell surface ICAM-1 levels only slightly. These findings suggest that (1) in C32 cells, levels of cell surface CD36, and not ICAM-1, change proportionally to the level of cytoadherence; (2) drugs which can affect the carbohydrate moiety of cellular glycoproteins decrease cytoadherence of IE to C32 cells; and (3) protection against the development of cerebral malaria may be possible with inhibitors of glycoprotein biosynthesis.
authors.affiliation: Marion Merrell Dow Research Institute, Cincinnati, OH 45215-6300.
authors.forename: P S
authors.initials: PS
authors.lastname: Wright
authors.forename: D E
authors.initials: DE
authors.lastname: Cross-Doersen
authors.forename: K K
authors.initials: KK
authors.lastname: Schroeder
authors.forename: T L
authors.initials: TL
authors.lastname: Bowlin
authors.forename: P P
authors.initials: PP
authors.lastname: McCann
authors.forename: A J
authors.initials: AJ
authors.lastname: Bitonti
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D018955:CD36 Antigens; D002448:Cell Adhesion / Q000187:drug effects*; D002450:Cell Communication / Q000187:drug effects; D004912:Erythrocytes / Q000166:cytology / Q000469:parasitology*; D006023:Glycoproteins / Q000096:biosynthesis / Q000502:physiology; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D007212:Indolizines / Q000494:pharmacology; D008361:Mannosidases / Q000037:antagonists & inhibitors; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D010963:Plasmodium falciparum / Q000502:physiology*; D014407:Tumor Cells, Cultured; D054836:Indolizidines
chemical_list: D015703:Antigens, CD; D018955:CD36 Antigens; D006023:Glycoproteins; D065089:Glycoside Hydrolase Inhibitors; D007212:Indolizines; D008361:Mannosidases; C037806:castanospermine; D054836:Indolizidines