title: Oxaliplatin Induced Suicidal Death of Human Erythrocytes.
abstract: OBJECTIVE
  The alkylating drug oxaliplatin is widely used for chemotherapy of malignancy. Oxaliplatin is effective by inducing both, necrosis and apoptosis. Similar to necrosis or apoptosis of nucleated cells, erythrocytes may enter hemolysis, which is apparent from hemoglobin release or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include oxidative stress and/or Ca2+ entry with increase of cytosolic Ca2+ activity ([Ca2+]i). The present study explored, whether and how oxaliplatin induces eryptosis.
  
  
  METHODS
  Phosphatidylserine exposure at the cell surface was quantified utilizing annexin-V-binding, cell volume estimated from forward scatter, hemolysis deduced from hemoglobin release, [Ca2+]i determined utilizing Fluo-3 fluorescence, and reactive oxygen species (ROS) abundance visualized using 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) dependent fluorescence.
  
  
  RESULTS
  A 48 hours exposure of human erythrocytes to oxaliplatin (10 µg/ml) significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter, significantly increased Fluo-3 fluorescence, and significantly increased DCFDA fluorescence. The effect of oxaliplatin on annexin-V-binding and forward scatter was rather augmented by removal of extracellular Ca2+, but was significantly blunted in the presence of the antioxidant N-acetyl-cysteine (1 mM).
  
  
  CONCLUSIONS
  Oxaliplatin triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect partially dependent on ROS formation.
authors.forename: Antonella
authors.initials: A
authors.lastname: Fazio
authors.forename: Marilena
authors.initials: M
authors.lastname: Briglia
authors.forename: Caterina
authors.initials: C
authors.lastname: Faggio
authors.forename: Kousi
authors.initials: K
authors.lastname: Alzoubi
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D017136:Ion Transport; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D017382:Reactive Oxygen Species; D000077150:Oxaliplatin; D002118:Calcium