Impact of Cyclin-Dependent Kinase CDK4 Inhibition on Eryptosis

Lang, Elisabeth; Zelenak, Christine; Eberhard, Matthias; Bissinger, Rosi; Rotte, Anand; Ghashghaeinia, Mehrdad; Lupescu, Adrian; Läng, Florian; Qadri, Syed M.

doi:10.1159/000430241

Cited by 44 publications

(26 citation statements)

References 52 publications

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“…Cellular mechanisms leading to eryptosis include increase of cytosolic Ca 2+ activity ([Ca 2+ ] i ) [56], ceramide [72], oxidative stress [56,73,74], energy depletion [56], caspases [56,75,76], casein kinase 1α, Janus-activated kinase JAK3, protein kinase C, and p38 kinase [56]. Cellular mechanisms counteracting eryptosis include AMP activated kinase AMPK, cGMP-dependent protein kinase, PAK2 kinase [56], cyclin-dependent kinase CDK4 [77], mitogen-and stress-activated kinase MSK1/2 [78], and sorafenib/ sunitinib sensitive kinases [56].…”

Section: Introductionmentioning

confidence: 99%

Enhanced Eryptosis Following Exposure to Dolutegravir

Bhuyan

Signoretto

Bissinger³

et al. 2016

Cell Physiol Biochem

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Background/Aims: The viral integrase enzyme inhibitor dolutegravir is utilized for the treatment of immunodeficiency virus (HIV) infection. Knowledge on cytotoxicity of dolutegravir is limited. The present study thus explored, whether dolutegravir is able to trigger suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Cellular mechanisms involved in the triggering of eryptosis include increase of cytosolic Ca²⁺ activity ([Ca²⁺]_i), oxidative stress, ceramide, and activation of protein kinase C, p38 kinase, casein kinase, and caspases. The present study explored, whether Dolutegravir induces eryptosis and, if so, to gain insight into cellular mechanisms involved. Methods: Utilizing flow cytometry, phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca²⁺]_i from Fluo3-fluorescence, ROS formation from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemolysis was quantified from haemoglobin concentration in the supernatant. Results: A 48 hours exposure of human erythrocytes to dolutegravir significantly increased the percentage of annexin-V-binding cells (≥ 4.8 µM), significantly increased hemolysis (19.1 µM), but did not significantly modify forward scatter. Dolutegravir significantly increased Fluo3-fluorescence (≥ 4.8 µM), DCFDA fluorescence (19.1 µM) and ceramide abundance (19.1 µM). The effect of dolutegravir on annexin-V-binding was significantly blunted by removal of extracellular Ca²⁺, but was not significantly modified by protein kinase C inhibitor staurosporine (1 µM), p38 kinase inhibitor SB203580 (2 µM), casein kinase inhibitor D4476 (10 µM) or pancaspase inhibitor zVAD (10 µM). Conclusions: Dolutegravir triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca²⁺ entry, ceramide formation and oxidative stress.

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Section: Introductionmentioning

confidence: 99%

Enhanced Eryptosis Following Exposure to Dolutegravir

Bhuyan

Signoretto

Bissinger³

et al. 2016

Cell Physiol Biochem

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“…Eryptosis is stimulated by protein kinase C [1], cyclin-dependent kinase 4 (CDK4) [1, 117], p38 mitogen activated kinase [1], casein kinase 1α (CK1α) [1], and Janus-activated kinase JAK3 [118]. Eryptosis is supressed by the energy sensing AMP-activated kinase (AMPK) [1], p21-activated kinase 2 (PAK2) [1], mitogen- and stress-activated kinase MSK1/2 [119], sorafenib and sunitinib sensitive tyrosine kinases [1], and the cGMP-dependent protein kinase (cGKI).…”

Section: Cellular Mechanisms Contributing To Orchestration Of Eryptosismentioning

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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“…Several substances inhibit eryptosis [113][114][115][116]. Enhanced eryptosis is observed in diverse clinical conditions including iron deficiency [58], vitamin D excess [117], chronic kidney disease (CKD) [118][119][120][121][122][123], hemolytic-uremic syndrome [124], autoimmune hemolytic anemia [125], diabetes [126], hypertension and dyslipidemia [127], hepatic failure [128], malignancy [129][130][131], arteritis [132], systemic lupus erythematosus [133], sepsis [134,135], malaria [58,136,137], sicklecell disease [58], beta-thalassemia [58], Hb-C and G6PD-deficiency [58], Wilsons disease [134], as well as advanced age [138]. Eryptosis further increases following storage for transfusion [67,68,83,139] and is enhanced in erythrocytes from newborns exposed to oxidative stress [58,140].…”

Section: Introductionmentioning

confidence: 99%

Stimulation of Eryptosis by Afatinib

Bhuyan

Läng

2018

Cell Physiol Biochem

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Background/Aims: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor afatinib is primarily utilized for the treatment of non-small cell lung carcinoma. The drug is at least partially effective by triggering suicidal tumor cell death. Side effects of afatinib treatment include anemia. At least in theory, afatinib induced anemia could be secondary to stimulation of suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling potentially stimulating eryptosis include increase of cytosolic Ca 2+ activity ([Ca 2+ ] i ), induction of oxidative stress, and increase of ceramide abundance. The present study explored, whether afatinib induces eryptosis and, if so, whether its effect involves Ca 2+ entry, oxidative stress, and/or ceramide. Methods: Flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca 2+ ] i from Fluo3-fluorescence, reactive oxygen species (ROS) abundance from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Results: A 48 hours exposure of human erythrocytes to afatinib (≥ 4 µg/ml) significantly increased the percentage of annexin-V-binding cells and significantly decreased forward scatter. Afatinib significantly increased Fluo3-fluorescence, DCFDA fluorescence and ceramide abundance. The effect of afatinib on annexin-V-binding and forward scatter was significantly blunted by removal of extracellular Ca 2+ . Conclusions: Afatinib triggers phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca 2+ entry, oxidative stress, and ceramide.

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Impact of Cyclin-Dependent Kinase CDK4 Inhibition on Eryptosis

Cited by 44 publications

References 52 publications

Enhanced Eryptosis Following Exposure to Dolutegravir

Enhanced Eryptosis Following Exposure to Dolutegravir

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

Stimulation of Eryptosis by Afatinib

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