Abstract
The nitrosourea alkylating agent, carmustine, is used as chemotherapeutic drug in several malignancies. The substance triggers tumor cell apoptosis. Side effects of carmustine include myelotoxicity with anemia. At least in theory, anemia could partly be due to stimulation of eryptosis, the suicidal death of erythrocytes, characterized by cell shrinkage and breakdown of phosphatidylserine asymmetry of the cell membrane with phosphatidylserine exposure at the erythrocyte surface. Stimulators of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i). The present study tested whether carmustine triggers eryptosis. To this end [Ca2+]i was estimated from Fluo3 fluorescence, cell volume from forward scatter, phosphatidylserine exposure from annexin V binding, and hemolysis from hemoglobin release. As a result a 48 h exposure to carmustine (≥25 µM) significantly increased [Ca2+]i, decreased forward scatter and increased annexin V binding. The effect on annexin V binding was significantly blunted in the absence of extracellular Ca2+. In conclusion, carmustine stimulates eryptosis at least partially by increasing cytosolic Ca2+ activity.
Highlights
Carmustine (1,3-bis-(2-chloroethyl)-1-nitrosourea), a nitrosourea alkylating agent is widely used for the treatment of malignancies [1,2,3,4,5,6,7]
The present study was designed to explore whether carmustine stimulates eryptosis, the suicidal death of erythrocytes
The erythrocytes were incubated in Ringer solution without or with carmustine (10–100 μM), loaded with Fluo3 AM and Fluo3 fluorescence quantified by FACS analysis
Summary
Carmustine (1,3-bis-(2-chloroethyl)-1-nitrosourea), a nitrosourea alkylating agent is widely used for the treatment of malignancies [1,2,3,4,5,6,7]. Carmustine induced oxidative stress is at least partially effective by increasing Ca2+ entry from extracellular space [15]. Side effects of systemic carmustine administration include anemia [2,8], which may at least partially result from erythrocyte death. Stimulators of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), which may result from Ca2+ entry through Ca2+. The increase of [Ca2+]i results in cell shrinkage due to activation of. The increase of [Ca2+]i further leads to breakdown of PS asymmetry of the erythrocyte cell membrane with translocation of PS to the erythrocyte surface [22]. Carmustine increases [Ca2+]i, decreases erythrocyte volume and enhances the PS abundance at the erythrocyte surface
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