Enhanced Eryptosis Following Auranofin Exposure

Abstract

Background/Aims: The antiinflammatory, antimicrobial and anticancer drug auranofin has previously been shown to trigger apoptosis, the suicidal death of nucleated cells. Side effects of the drug include anaemia. At least in theory the anaemia could result from stimulation of suicidal death of erythrocytes or eryptosis, which involves cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Methods: Stimulators of eryptosis include oxidative stress and increase of cytosolic Ca²⁺-activity ([Ca²⁺]_i). In the present study, phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, hemolysis from hemoglobin release, reactive oxygen species (ROS) from 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, and [Ca²⁺]_i from Fluo3-fluorescence. Results: A 24 hours exposure of human erythrocytes to auranofin (≥5 µg/ml) significantly increased the percentage of annexin-V-binding cells (from 2.2 ± 0.5 to 17.4 ± 1.5%), significantly decreased forward scatter and significantly enhanced ROS. At higher concentrations (10 µg/ml) auranofin triggered slight hemolysis (from 2.1 ± 0.2 to 3.2 ± 0.3%). Conclusions: Auranofin stimulates cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least partially due to induction of oxidative stress.

Trifluoperazine-Induced Suicidal Erythrocyte Death and S-Nitrosylation Inhibition, Reversed by the Nitric Oxide Donor Sodium Nitroprusside

“…In analogy to nucleated cell apoptosis, erythrocytes may enter eryptosis [20, 21], the suicidal death of erythrocytes characterized by cell shrinkage [22] and cell membrane scrambling with phosphatidylserine translocation to the cell surface [20]. Eryptosis may be triggered by an increase in cytosolic Ca 2+ ([Ca 2+ ] i )[20].…”

“…Eryptosis may be triggered by an increase in cytosolic Ca 2+ ([Ca 2+ ] i )[20]. Further stimulators of eryptosis include ceramide [23, 24], oxidative stress [20], energy depletion [20], activated caspases [20, 25, 26], stimulated activity of casein kinase 1α, Janus-activated kinase JAK3, protein kinase Cα, p38 kinase and PAK2 kinase [20], impaired activity of AMP activated kinase AMPK, cGMP-dependent protein kinase, and sorafenib/sunitinib sensitive kinases [20] and/or exposure to a wide variety of xenobiotics [20, 27-41]. Inhibitors of eryptosis include erythropoietin [42] and nitric oxide [43].…”

Triggering of Suicidal Erythrocyte Death by Gefitinib

“…Eryptosis is stimulated by hyperosmotic shock [50], oxidative stress [50], energy depletion [50], or a myriad of xenobiotics [50, 57-115]. Augmented eryptosis is observed in several clinical conditions including iron deficiency [50], dehydration [116], hyperphosphatemia [117], chronic kidney disease (CKD) [118-121], hemolytic-uremic syndrome [122], diabetes [123], hepatic failure [57], malignancy [124, 125], arteriitis [126], sepsis [127], sickle-cell disease [50], beta-thalassemia [50], Hb-C and G6PD-deficiency [50], Wilsons disease [127], as well as advanced age [128]. Eryptosis further increases during storage of blood for transfusion [129].…”

Triggering of Suicidal Erythrocyte Death by Exemestane

“…The cell membrane scrambling is typically paralleled by cell shrinkage [41]. Triggers of eryptosis include hyperosmotic shock [40], oxidative stress [40], energy depletion [40], or exposure to a wide variety of xenobiotics [40, 42-105]. The stimulation of eryptosis may involve increase of cytosolic Ca 2+ activity ([Ca 2+ ] i ) [40], ceramide [40], caspases [40, 106, 107], casein kinase 1α [40], Janus-activated kinase JAK3 [40], protein kinase C [40], and p38 kinase [40].…”

“…Eryptosis is inhibited by AMP activated kinase AMPK, cGMP-dependent protein kinase, PAK2 kinase [40], and sorafenib/sunitinib sensitive kinases [40]. Enhanced eryptosis is observed in a variety of clinical conditions including fever [40], iron deficiency [40], dehydration [40], hyperphosphatemia [40], chronic kidney disease (CKD) [40], hemolytic-uremic syndrome [40], diabetes [40], hepatic failure [42], malignancy [40], sepsis [40], sickle-cell disease [40], beta-thalassemia [40], Hb-C and G6PD-deficiency [40], as well as Wilson’s disease [40]. …”