title: Stimulation of Suicidal Erythrocyte Death  by the Antimalarial Drug Mefloquine.
abstract: BACKGROUND
  The antimalarial drug mefloquine has previously been shown to stimulate apoptosis of nucleated cells. Similar to apoptosis, erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include oxidative stress, increase of cytosolic Ca2+-activity ([Ca2+]i), and ceramide.
  
  
  METHODS
  Phosphatidylserine abundance at the cell surface was estimated from annexin V binding, cell volume from forward scatter, reactive oxidant species (ROS) from 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, [Ca2+]i from Fluo3- fluorescence, and ceramide abundance from specific antibody binding.
  
  
  RESULTS
  A 48 h treatment of human erythrocytes with mefloquine significantly increased the percentage of annexin-V-binding cells (≥5 μg/ml), significantly decreased forward scatter (≥5 μg/ml), significantly increased ROS abundance (5 μg/ml), significantly increased [Ca2+]i (7.5 μg/ml) and significantly increased ceramide abundance (10 μg/ml). The up-regulation of annexin- V-binding following mefloquine treatment was significantly blunted but not abolished by removal of extracellular Ca2+. Even in the absence of extracellular Ca2+, mefloquine significantly increased annexin-V-binding.
  
  
  CONCLUSIONS
  Mefloquine treatment leads to erythrocyte shrinkage and erythrocyte membrane scrambling, effects at least partially due to induction of oxidative stress, increase of [Ca2+]i and up-regulation of ceramide abundance.
authors.forename: Rosi
authors.initials: R
authors.lastname: Bissinger
authors.forename: Susanne
authors.initials: S
authors.lastname: Barking
authors.forename: Kousi
authors.initials: K
authors.lastname: Alzoubi
authors.forename: Guilai
authors.initials: G
authors.lastname: Liu
authors.forename: Guoxing
authors.initials: G
authors.lastname: Liu
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000378:metabolism; D015767:Mefloquine / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000962:Antimalarials; D002518:Ceramides; D017382:Reactive Oxygen Species; D002118:Calcium; D015767:Mefloquine