Estramustine-Induced Suicidal Erythrocyte Death

Bissinger, Rosi; Modicano, Paola; Frauenfeld, Leonie; Lang, Elisabeth; Jacobi, Janin; Faggio, Caterina; Läng, Florian

doi:10.1159/000356580

Cited by 59 publications

(19 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Eryptosis is further triggered by a wide variety of xenobiotics and is enhanced in a variety of clinical disorders [9,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43]. …”

Section: Introductionmentioning

confidence: 99%

Stimulation of Suicidal Erythrocyte Death by Increased Extracellular Phosphate Concentrations

Voelkl

Alzoubi

Mamar

et al. 2013

Kidney Blood Press Res

Self Cite

109

101

View full text Add to dashboard Cite

Background/Aim: Anemia in renal insufficiency results in part from impaired erythrocyte formation due to erythropoietin and iron deficiency. Beyond that, renal insufficiency enhances eryptosis, the suicidal erythrocyte death characterized by phosphatidylserine-exposure at the erythrocyte surface. Eryptosis may be stimulated by increase of cytosolic Ca²⁺-activity ([Ca²⁺]_i). Several uremic toxins have previously been shown to stimulate eryptosis. Renal insufficiency is further paralleled by increase of plasma phosphate concentration. The present study thus explored the effect of phosphate on erythrocyte death. Methods: Cell volume was estimated from forward scatter, phosphatidylserine-exposure from annexin V binding, and [Ca²⁺]_i from Fluo3-fluorescence. Results: Following a 48 hours incubation, the percentage of phosphatidylserine exposing erythrocytes markedly increased as a function of extracellular phosphate concentration (from 0-5 mM). The exposure to 2 mM or 5 mM phosphate was followed by slight but significant hemolysis. [Ca²⁺]_i did not change significantly up to 2 mM phosphate but significantly decreased at 5 mM phosphate. The effect of 2 mM phosphate on phosphatidylserine exposure was significantly augmented by increase of extracellular Ca²⁺ to 1.7 mM, and significantly blunted by nominal absence of extracellular Ca²⁺, by additional presence of pyrophosphate as well as by presence of p38 inhibitor SB203580. Conclusion: Increasing phosphate concentration stimulates erythrocyte membrane scrambling, an effect depending on extracellular but not intracellular Ca²⁺ concentration. It is hypothesized that suicidal erythrocyte death is triggered by complexed CaHPO₄.

show abstract

Section: Introductionmentioning

confidence: 99%

Stimulation of Suicidal Erythrocyte Death by Increased Extracellular Phosphate Concentrations

Voelkl

Alzoubi

Mamar

et al. 2013

Kidney Blood Press Res

Self Cite

109

101

View full text Add to dashboard Cite

show abstract

“…PRIMA-1 tended to increase phosphatidylserine exposure at lower concentrations (10 µM), an effect, however, not reaching statistical significance. It must be kept in mind that erythrocytes may be sensitized to the effect of PRIMA-1 by other xenobiotics stimulating cell membrane scrambling [35,49,50,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82] or by diseases associated with enhanced cell membrane scrambling, such as sepsis, malaria, sickle cell disease, Wilson's disease, iron deficiency, malignancy, metabolic syndrome, diabetes, hepatic failure, renal insufficiency, hemolytic uremic syndrome, hyperphosphatemia and phosphate depletion [34,83,84]. …”

Section: Discussionmentioning

confidence: 99%

Stimulation of Suicidal Erythrocyte Death by PRIMA-1

Faggio

Alzoubi

Calabrò

et al. 2015

Cell Physiol Biochem

Self Cite

View full text Add to dashboard Cite

Background: The anticarcinogenic drug PRIMA-1 (p53 reactivation and induction of massive apoptosis 1) induces suicidal death of tumor cells, an effect in large part attributed to the up-regulation of the proapoptotic transcription factor p53. Erythrocytes are lacking gene transcription but are nevertheless able to enter eryptosis, a suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include increase of cytosolic Ca²⁺-activity ([Ca²⁺]_i) and ceramide formation. The present study tested whether PRIMA-1 stimulates eryptosis. Methods: Phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, [Ca²⁺]_i from Fluo3-fluorescence, ceramide abundance from binding of specific antibodies, and ROS formation from DCFDA fluorescence. Results: A 48 h exposure of human erythrocytes to PRIMA-1 (25 µM) significantly increased the percentage of annexin-V-binding cells without significantly influencing [Ca²⁺]_i or forward scatter. PRIMA-1 (100 µM) induced annexin-V-binding was not significantly blunted by removal of extracellular Ca²⁺ or by the caspase-3 inhibitor zVAD. PRIMA-1 (100 µM) further increased the ceramide abundance at the cell surface and ROS formation. Conclusions: PRIMA-1 stimulates phosphatidylserine translocation at the erythrocyte cell membrane, an effect at least partially due to up-regulation of ceramide abundance and ROS formation.

show abstract

“…Eryptosis is triggered by a myriad of xenobiotics [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63] and enhanced eryptosis contributes to the pathophysiology of several clinical conditions including fever, malaria, sepsis, iron deficiency, malignancy, metabolic syndrome, diabetes, hepatic and renal insufficiency, hemolytic uremic syndrome, dehydration, hyperphosphatemia, phosphate depletion, sickle cell disease, thalassemia, glucose phosphate dehydrogenase deficiency and Wilson's disease [12,63,64,65]. …”

Section: Introductionmentioning

confidence: 99%

Programmed Erythrocyte Death Following in Vitro Treosulfan Treatment

Peter

Bissinger

Enkel

et al. 2015

Cell Physiol Biochem

Self Cite

View full text Add to dashboard Cite

Background/Aims: The cytotoxic drug Treosulfan is clinically used for the treatment of malignancy. A common side effect of Treosulfan treatment is anemia. Treosulfan is at least partially effective by triggering apoptosis of tumor cells. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, a suicidal death characterized by cell shrinkage and translocation of phosphatidylserine from the inner to the outer leaflet of the plasma membrane. Triggers of eryptosis include oxidative stress, Ca²⁺-entry and increase of cytosolic Ca²⁺-activity ([Ca²⁺]_i). The present study explored whether Treosulfan stimulates eryptosis, which may contribute to development of anemia. Methods: Erythrocyte volume was estimated from forward scatter, phosphatidylserine abundance at the erythrocyte surface from Fluorescein isothiocyanate (FITC)-annexin-V-binding, [Ca²⁺]_i from Fluo3 fluorescence and reactive oxygen species (ROS) from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA)-fluorescence. Results: A 48 hours exposure of human erythrocytes to Treosulfan (800 µg/ml) significantly decreased erythrocyte forward scatter, increased the percentage of annexin-V-binding cells, increased [Ca²⁺]_i, and increased ROS. The effect of Treosulfan on annexin-V-binding was virtually abrogated by removal of extracellular Ca²⁺. Conclusion: Treosulfan stimulates suicidal erythrocyte death or eryptosis at least in part by inducing oxidative stress and stimulating Ca²⁺ entry.

show abstract

Estramustine-Induced Suicidal Erythrocyte Death

Cited by 59 publications

References 91 publications

Stimulation of Suicidal Erythrocyte Death by Increased Extracellular Phosphate Concentrations

Stimulation of Suicidal Erythrocyte Death by Increased Extracellular Phosphate Concentrations

Stimulation of Suicidal Erythrocyte Death by PRIMA-1

Programmed Erythrocyte Death Following in Vitro Treosulfan Treatment

Contact Info

Product

Resources

About