Abstract: Background: Lumefantrine, a commonly used antimalarial drug, inhibits hemozoin formation in parasites. Several other antimalarial substances counteract parasitemia by triggering suicidal death or eryptosis of infected erythrocytes. Eryptosis is characterized by cell shrinkage and cell membrane scrambling leading to phosphatidylserine-exposure at the erythrocyte surface. Signaling involved in eryptosis include increase of cytosolic Ca2+-activity ([Ca2+]i), formation of ceramide, oxidative stress and/or activation of p38 kinase, protein kinase C (PKC), or caspases. The present study explored, whether lumefantrine stimulates eryptosis. Methods: Cell volume has been estimated from forward scatter, phosphatidylserine-exposure from annexin V binding, [Ca2+]i from Fluo3-fluorescence, reactive oxygen species from 2',7'-dichlorodihydrofluorescein-diacetate fluorescence, content of reduced glutathione (GSH) from mercury orange fluorescence, and ceramide abundance from binding of fluorescent antibodies in flow cytometry. Results: A 48 h exposure to lumefantrine (3 µg/mL) was followed by a significant increase of annexin-V-binding without significantly altering forward scatter, [Ca2+]i, ROS formation, reduced GSH, or ceramide abundance. The annexin-V-binding following lumefantrine treatment was not significantly modified by p38 kinase inhibitors SB203580 (2 μM) and p38 Inh III (1 μM), PKC inhibitor staurosporine (1 µM) or pancaspase inhibitor zVAD (1 or 10 µM). Conclusions: Lumefantrine triggers cell membrane scrambling, an effect independent from entry of extracellular Ca2+, ceramide formation, ROS formation, glutathione content, p38 kinase, PKC or caspases.
Keywords: phosphatidylserine; lumefantrine; calcium; ceramide; cell volume; eryptosis
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Alzoubi, K.; Alktifan, B.; Oswald, G.; Fezai, M.; Abed, M.; Lang, F. Breakdown of Phosphatidylserine Asymmetry Following Treatment of Erythrocytes with Lumefantrine. Toxins 2014, 6, 650-664.
Alzoubi K, Alktifan B, Oswald G, Fezai M, Abed M, Lang F. Breakdown of Phosphatidylserine Asymmetry Following Treatment of Erythrocytes with Lumefantrine. Toxins. 2014; 6(2):650-664.
Alzoubi, Kousi; Alktifan, Bassel; Oswald, Gergely; Fezai, Myriam; Abed, Majed; Lang, Florian. 2014. "Breakdown of Phosphatidylserine Asymmetry Following Treatment of Erythrocytes with Lumefantrine." Toxins 6, no. 2: 650-664.