Journal
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
Volume 34, Issue 5, Pages 1756-1767Publisher
KARGER
DOI: 10.1159/000366376
Keywords
Phosphatidylserine; Mitoxantrone; Calcium; Ceramide; Cell volume; Eryptosis
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Funding
- Deutsche Forschungsgemeinschaft
- Open Access Publishing Fund of Tuebingen University
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Background/Aims: Mitoxantrone, a cytotoxic drug used for the treatment of malignancy and multiple sclerosis, is at least in part effective by triggering apoptosis. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, a type of suicidal cell death. Hallmarks of eryptosis are cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signalling involved in eryptosis include Ca2+-entry, ceramide formation and oxidative stress. Methods: Cell volume was estimated from forward scatter, phosphatidylserine-exposure from annexin V binding, formation of reactive oxidant species (ROS) from 2',7'-dichlorodihydrofluorescein-diacetate fluorescence, and ceramide abundance from binding of fluorescent antibodies in flow cytometry. Results: A 48 hours exposure to mitoxantrone was followed by significant decrease of forward scatter (>= 5 mu g/ml mitoxantrone) and increase of annexin-V-binding (>= 10 mu g/ml mitoxantrone), effects paralleled by significant increases of ROS formation (25 mu g/ml mitoxantrone) and ceramide abundance (25 mu g/ml mitoxantrone). The effect of mitoxantrone was not significantly modified by nominal absence of extracellular Ca2+ but significantly blunted by the antioxidant N-acetylcysteine (1 mM). Conclusions: Mitoxantrone triggers cell membrane scrambling, an effect not requiring entry of extracellular Ca2+ but at least partially due to formation of ROS and ceramide. Copyright (C) 2014 S. Karger AG, Basel
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