Triggering of Suicidal Erythrocyte Death by Bexarotene

Bhuyan, Abdulla Al Mamun; Bissinger, Rosi; Cao, Hang; Läng, Florian

doi:10.1159/000453178

Cited by 27 publications

(5 citation statements)

References 114 publications

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“…Eryptosis is a common clinical problem, as it is triggered by a myriad of xenobiotics as well as endogenous substances [1-3, 10-68] and accelerated eryptosis is observed in a variety of clinical disorders including iron deficiency [1-3], dehydration [69], hyper-cholesterolemia and enhanced oxysterol levels [70, 71], hyperphosphatemia [72], vitamin D excess [36], chronic kidney disease (CKD) [73-77], haemolytic-uremic syndrome [78], diabetes [79], hepatic failure [38, 80], malignancy [81, 82], arteritis [83], sepsis [84], fever [1-7], malaria [85], sickle-cell disease [1-3], beta-thalassemia [1-3], Hb-C and G6PD-deficiency [1-3], Wilsons disease [86], as well as advanced age [87]. Eryptosis further increases following erythrocyte storage for transfusion [88].…”

Section: Introductionmentioning

confidence: 99%

Methods Employed in Cytofluorometric Assessment of Eryptosis, the Suicidal Erythrocyte Death

Jèmaà¹,

Fezai²,

Bissinger³

et al. 2017

Cell Physiol Biochem

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Suicidal erythrocyte death or eryptosis contributes to or even accounts for anemia in a wide variety of clinical conditions, such as iron deficiency, dehydration, hyperphosphatemia, vitamin D excess, chronic kidney disease (CKD), hemolytic-uremic syndrome, diabetes, hepatic failure, malignancy, arteriitis, sepsis, fever, malaria, sickle-cell disease, beta-thalassemia, Hb-C and G6PD-deficiency, Wilsons disease, as well as advanced age. Moreover, eryptosis is triggered by a myriad of xenobiotics and endogenous substances including cytotoxic drugs and uremic toxins. Eryptosis is characterized by cell membrane scrambling with phosphatidylserine exposure to the erythrocyte surface. Triggers of eryptosis include oxidative stress, hyperosmotic shock, and energy depletion. Signalling involved in the regulation of eryptosis includes Ca²⁺ entry, ceramide, caspases, calpain, p38 kinase, protein kinase C, Janus-activated kinase 3, casein kinase 1α, cyclin-dependent kinase 4, AMP-activated kinase, p21-activated kinase 2, cGMP-dependent protein kinase, mitogen- and stress-activated kinase MSK1/2, and ill-defined tyrosine kinases. Inhibitors of eryptosis may prevent anaemia in clinical conditions associated with enhanced eryptosis and stimulators of eryptosis may favourably influence the clinical course of malaria. Additional experimentation is required to uncover further clinical conditions with enhanced eryptosis, as well as further signalling pathways, further stimulators, and further inhibitors of eryptosis. Thus, a detailed description of the methods employed in the analysis of eryptosis may help those, who enter this exciting research area. The present synopsis describes the experimental procedures required for the analysis of phosphatidylserine exposure at the cell surface with annexin-V, cell volume with forward scatter, cytosolic Ca²⁺ activity ([Ca²⁺]_i) with Fluo3, oxidative stress with 2′,7′-dichlorodihydrofuorescein diacetate (DCFDA), glutathione (GSH) with mercury orange 1(4-chloromercuryphenyl-azo-2-naphthol), lipid peroxidation with BODIPY 581/591 C11 fluorescence, and ceramide abundance with specific antibodies. The contribution of kinases and caspases is defined with the use of the respective inhibitors. It is hoped that the present detailed description of materials and methods required for the analysis of eryptosis encourages further scientists to enter this highly relevant research area.

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Section: Introductionmentioning

confidence: 99%

Methods Employed in Cytofluorometric Assessment of Eryptosis, the Suicidal Erythrocyte Death

Jèmaà¹,

Fezai²,

Bissinger³

et al. 2017

Cell Physiol Biochem

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“…Eryptosis is triggered by complement, hyperosmotic shock, energy depletion, oxidative stress, cellular K + loss, increase of temperature and a wide variety of xenobiotics [32, 43, 54, 64, 72-111]. …”

Section: Introductionmentioning

confidence: 99%

Eryptosis - the Neglected Cause of Anemia in End Stage Renal Disease

Läng

Bissinger

Abed

et al. 2017

Kidney Blood Press Res

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End stage renal disease (ESRD) invariably leads to anemia which has been mainly attributed to compromised release of erythropoietin from the defective kidneys with subsequent impairment of erythropoiesis. However, erythropoietin replacement only partially reverses anemia pointing to the involvement of additional mechanisms. As shown more recently, anemia of ESRD is indeed in large part a result of accelerated erythrocyte loss due to suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the cell surface. Phosphatidylserine exposing erythrocytes are bound to and engulfed by macrophages and are thus rapidly cleared from circulating blood. If the loss of erythrocytes cannot be fully compensated by enhanced erythropoiesis, stimulation of eryptosis leads to anemia. Eryptotic erythrocytes may further adhere to the vascular wall and thus impair microcirculation. Stimulators of eryptosis include complement, hyperosmotic shock, energy depletion, oxidative stress, and a wide variety of xenobiotics. Signaling involved in the stimulation of eryptosis includes increase of cytosolic Ca²⁺ activity, ceramide, caspases, calpain, p38 kinase, protein kinase C, Janus-activated kinase 3, casein kinase 1α, and cyclin-dependent kinase 4. Eryptosis is inhibited by AMP-activated kinase, p21-activated kinase 2, cGMP-dependent protein kinase, mitogen- and stress-activated kinase MSK1/2, and some illdefined tyrosine kinases. In ESRD eryptosis is stimulated at least in part by a plasma component, as it is triggered by exposure of erythrocytes from healthy individuals to plasma from ESRD patients. Several eryptosis-stimulating uremic toxins have been identified, such as vanadate, acrolein, methylglyoxal, indoxyl sulfate, indole-3-acetic acid and phosphate. Attempts to fully reverse anemia in ESRD with excessive stimulation of erythropoiesis enhances the number of circulating suicidal erythrocytes and bears the risk of interference with micocirculation, At least in theory, anemia in ESRD could preferably be treated with replacement of erythropoietin and additional inhibition of eryptosis thus avoiding eryptosis-induced impairment of microcirculation. A variety of eryptosis inhibitors have been identified, their efficacy in ESRD remains, however, to be shown.

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“…Inhibitors of eryptosis include AMP activated kinase AMPK [50], cGMP-dependent protein kinase [50], mitogen and stress activated kinase MSK1/2 [56], PAK2 kinase [50] and sorafenib/sunitinib sensitive kinases [50]. 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].…”

Section: Introductionmentioning

confidence: 99%

Triggering of Suicidal Erythrocyte Death by Gefitinib

Bhuyan

Wagner

Cao

et al. 2017

Cell Physiol Biochem

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Background/Aims: The epidermal growth factor receptor-tyrosine kinase inhibitor gefitinib is effective against several malignancies and is mainly utilized in the treatment of epidermal growth factor receptor mutation positive non-small cell lung cancer. The anti-cancer effect of the drug involves stimulation of apoptosis. Side effects of gefitinib include anemia. At least in theory, the development of anemia during gefitinib treatment could result from triggering of eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and by cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling potentially stimulating eryptosis include increase of cytosolic Ca²⁺ activity ([Ca²⁺]_i) and generation of oxidative stress. The present study explored, whether gefitinib stimulates eryptosis and, if so, whether its effect involves Ca²⁺ entry and/or oxidative stress. Methods: Flow cytometry was employed to quantify cell volume from forward scatter, phosphatidylserine exposure at the cell surface from annexin-V-binding, [Ca²⁺]_i from Fluo3-fluorescence, and reactive oxygen species (ROS) abundance from 2’,7’-dichlorodihydrofluorescein diacetate (DCFDA) dependent fluorescence. Results: A 48 hours exposure of human erythrocytes to gefitinib (≥ 2 µg/ml) significantly decreased forward scatter and significantly increased the percentage of annexin-V-binding cells. Gefitinib did not significantly increase Fluo3-fluorescence but the effect of gefitinib on annexin-V-binding was significantly blunted by removal of extracellular Ca²⁺. Gefitinib further significantly increased DCFDA fluorescence. Conclusions: Gefitinib triggers erythrocyte shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part dependent on extracellular Ca²⁺ and paralleled by oxidative stress.

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Triggering of Suicidal Erythrocyte Death by Bexarotene

Cited by 27 publications

References 114 publications

Methods Employed in Cytofluorometric Assessment of Eryptosis, the Suicidal Erythrocyte Death

Methods Employed in Cytofluorometric Assessment of Eryptosis, the Suicidal Erythrocyte Death

Eryptosis - the Neglected Cause of Anemia in End Stage Renal Disease

Triggering of Suicidal Erythrocyte Death by Gefitinib

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