Sulindac Sulfide – Induced Stimulation of Eryptosis

Abstract

Background: Sulindac sulfide, a non-steroidal anti-inflammatory drug (NSAID), stimulates apoptosis of tumor cells and is thus effective against malignancy. In analogy to apoptosis of nucleated cells, erythrocytes may undergo eryptosis, an apoptosis-like suicidal erythrocyte death, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine-exposure at the cell surface. Stimulators of eryptosis include increase of cytosolic Ca²⁺-activity ([Ca²⁺]_i) and ceramide formation. The present study explored, whether sulindac sulfide stimulates eryptosis. Methods: [Ca²⁺]_i was estimated from Fluo-3 fluorescence, cell volume from forward scatter, phosphatidylserine-exposure from binding of fluorescent annexin-V, hemolysis from hemoglobin release, and ceramide abundance utilizing fluorescent antibodies. Results: A 48 h exposure to sulindac sulfide (≤ 20 µM) was followed by significant increase of [Ca²⁺]_i, enhanced ceramide abundance, decreased forward scatter and increased percentage of annexin-V-binding erythrocytes. Sulindac sulfide triggered slight but significant hemolysis. Removal of extracellular Ca²⁺ significantly blunted, but did not abrogate the effect of sulindac sulfide (20 µM) on annexin-V-binding. Conclusion: Sulindac sulfide stimulates the suicidal death of erythrocytes or eryptosis, an effect paralleled by Ca²⁺-entry, ceramide formation, cell shrinkage and phosphatidylserine-exposure.

Hemocompatibility of dextran-graft-polyacrylamide/zinc oxide nanosystems: hemolysis or eryptosis?

“…Thus, it can be postulated that eryptosis should be triggered by lower concentrations of xenobiotics compared with hemolysis. Indeed, xenobiotics-induced eryptosis is shown to precede hemolysis in multiple studies [44,[73][74][75][76][77]. This hypothesis is also supported by some nanotoxicological studies for Fe 3 O 4 magnetic NPs [44] or polyvinylpyrrolidone-and citrate-coated silver NPs [43].…”

Stimulation of Erythrocyte Membrane Blebbing by Bifenthrin Induced Oxidative Stress

“… 38 Released hemoglobin by the ruptured erythrocytes is either filtered by the kidney or it gets precipitated in the acidic lumen of renal tubule. 12 The release of hemoglobin from erythrocytes lead to a decrease in NO bioavailability during hemolysis, which can promote vasomotor instability, systemic vasoconstriction, and endothelial dysfunction and contribute to serious clinical conditions such as high blood pressure, pulmonary complications, cardiovascular disorders, renal dysfunction, and inflammation. 39 Observed hemolytic activity was may be due to oxidative stress as high ROS generation was noticed during the episodes of hemolysis.…”

“…High calcium and ceramide levels promote membrane scrambling with phosphatidylserine exposure on outer face of membrane. 11 Erythrocytes with phosphatidylserine on outer side are rapidly removed from circulating blood 12 as such cells are primarily bound to the phosphatidylserine receptors of splenic macrophages and CD207 + dendritic cells 13 that are responsible for engulfment and destruction of apoptotic erythrocytes. 14 Similarly, Ca +2 influx activates the enzyme calpain which degrades cytoskeletal proteins leading to the blebbing of the cell membrane.…”