Suicidal erythrocyte death triggered by cisplatin

Abstract

Cisplatin, a cytotoxic drug for the treatment of cancer, induces suicidal death or apoptosis of nucleated cells. Side effects of cisplatin include anemia, which, at least in theory, could similarly result from suicidal cell death. Erythrocyte suicidal death or eryptosis is characterized by cell shrinkage and cell membrane scrambling, the latter leading to exposure of phosphatidylserine (PS) at the cell surface. PS-exposing cells are rapidly cleared from circulating blood. The present experiments explored whether cisplatin could trigger eryptosis. According to forward scatter in FACS analysis, a 48 h exposure to cisplatin (≥1 μM) indeed decreased cell volume and, according to annexin V-binding, cisplatin (≥1 μM, 48 h) indeed increased PS exposure at the cell surface. Cisplatin did not induce hemolysis. According to Fluo3 fluorescence, cisplatin increased cytosolic Ca 2+ activity, a known stimulator of eryptosis. In the absence of extracellular Ca 2+, the effect of cisplatin on annexin V-binding was blunted. Cisplatin did not significantly modify the formation of ceramide, another stimulator of eryptosis. Cisplatin moderately decreased the cellular concentration of ATP, which is known to favour eryptosis. In conclusion, cisplatin triggers suicidal erythrocyte death at least partially by increasing cytosolic Ca 2+ activity. The effect contributes to or even accounts for the development of anemia during cisplatin treatment.