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Sunitinib-sensitive Suicidal Erythrocyte DeathShaik N. · Lupescu A. · Lang F.
Department of Physiology, University of Tuebingen, Tuebingen Corresponding Author
Prof. Dr. Florian Lang
Physiologisches Institut, der Universität Tübingen
Gmelinstr. 5, D-72076 Tübingen (Germany)
Tel. +49 7071 29 72194, Fax +49 7071 29 5618
Sunitinib, a multikinase inhibitor, stimulates apoptosis and is thus utilized for the treatment of malignancy. Even though lacking mitochondria and nuclei, critical elements in apoptosis of nucleated cells, erythrocytes may undergo eryptosis, an apoptosis-like suicidal death, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserineexposure at the cell surface. Triggers of eryptosis include activation of Ca2+ permeable cation channels with subsequent increase of cytosolic Ca2+-activity ([Ca2+]i), ceramide formation, ATP-depletion, stimulation of p38 kinase and caspase activation. The present study explored, whether sunitinib stimulates eryptosis. [Ca2+]i was estimated from Fluo-3-fluorescence, cell volume from forward scatter, phosphatidylserine-exposure from annexin-V-binding, hemolysis from hemoglobin release, ceramide abundance from anti-ceramide antibody binding, and cytosolic ATP from luciferin–luciferase activity. A 48 h exposure to sunitinib (10 µM) significantly decreased forward scatter and increased annexin-V-binding, effects paralleled by significant increase of [Ca2+]i. Sunitinib exposure was followed by a slight but significant increase of hemolysis. Sunitinib induced annexin-V-binding was slightly, but significantly blunted by removal of extracellular Ca2+, by p38 kinase inhibitor SB203580 (10 µM) and by the pancaspase inhibitor zVAD (10 µM). Sunitinib, however, did not significantly modify cytosolic ATP and ceramide abundance. The present observations reveal that sunitinib is able to trigger suicidal death in erythrocytes even in the absence of nuclei and mitochondria.
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