Triggering of Suicidal Erythrocyte Death by Topotecan

Bissinger, Rosi; Bouguerra, Ghada; Stockinger, Katja; Abbès, Salem; Läng, Florian

doi:10.1159/000438527

Cited by 46 publications

(4 citation statements)

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“…Signaling contributing to stimulation of eryptosis includes activated caspases, stimulated activity of casein kinase 1 α , Janus‐activated kinase JAK3, protein kinase C, and p38 kinase, as well as impaired activity of AMP activated kinase AMPK, cGMP‐dependent protein kinase, mitogen‐activated kinase and stress‐activated kinase MSK, PAK2 kinase, and sorafenib/sunitinib sensitive kinases . Eryptosis is triggered by a wide variety of xenobiotics and enhanced eryptosis is observed in several clinical conditions including dehydration, hyperphosphatemia, chronic kidney disease (CKD), hemolytic‐uremic syndrome, diabetes, hepatic failure, malignancy, sepsis, sickle‐cell disease, beta‐thalassemia, Hb‐C and G6PD‐deficiency, as well as Wilsons disease …”

Section: Introductionmentioning

confidence: 99%

Ceranib‐2‐induced suicidal erythrocyte death

Signoretto

Zierle

Bhuyan

et al. 2016

Cell Biochemistry & Function

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Ceramide is known to trigger apoptosis of nucleated cells and eryptosis of erythrocytes. Eryptosis is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Besides ceramide, stimulators of eryptosis include increase of cytosolic Ca(2+) -activity ([Ca(2+) ]i ) and oxidative stress. Ceramide is degraded by acid ceramidase and inhibition of the enzyme similarly triggers apoptosis. The present study explored, whether ceramidase inhibitor Ceranib-2 induces eryptosis. 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) from DCF dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemolysis was estimated from hemoglobin concentration in the supernatant. A 48 h exposure of human erythrocytes to Ceranib-2 significantly increased the percentage of annexin-V-binding cells (≥50 μM) and the percentage of hemolytic cells (≥10 μM) without significantly modifying forward scatter. Ceranib-2 significantly increased Fluo3-fluorescence, DCF fluorescence and ceramide abundance. The effect of Ceranib-2 on annexin-V-binding was not significantly blunted by removal of extracellular Ca(2+) . Ceranib-2 triggers phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to increase of ceramide abundance and induction of oxidative stress, but not dependent on Ca(2+) entry. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Introductionmentioning

confidence: 99%

Ceranib‐2‐induced suicidal erythrocyte death

Signoretto

Zierle

Bhuyan

et al. 2016

Cell Biochemistry & Function

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“…Eryptosis could be triggered by a myriad of xenobiotics including several cytostatic drugs [ 29 – 43 ]. Interestingly, both topotecan and cisplatin used for cytostatic treatment of some patients included in this study, have been shown to trigger eryptosis in vitro [ 44 , 45 ]. Notably, patients under platinum-based chemotherapy were shown to have higher risk for anemia as compared to patients with non-platinum based chemotherapy [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Enhanced eryptosis contributes to anemia in lung cancer patients

et al. 2016

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ObjectivesAnemia is a common complication of malignancy, which could result from either compromised erythropoiesis or decreased lifespan of circulating erythrocytes. Premature suicidal erythrocyte death, characterized by cell shrinkage and phosphatidylserine (PS) externalization, decreases erythrocyte lifespan and could thus cause anemia. Here, we explored whether accelerated eryptosis participates in the pathophysiology of anemia associated with lung cancer (LC) and its treatment.MethodsErythrocytes were drawn from healthy volunteers and LC patients with and without cytostatic treatment. PS exposure (annexin V-binding), cell volume (forward scatter), cytosolic Ca2+ (Fluo3 fluorescence), reactive oxygen species (ROS) production (DCFDA fluorescence) and ceramide formation (anti-ceramide antibody) were determined by flow cytometry.ResultsHemoglobin concentration and hematocrit were significantly lower in LC patients as compared to healthy controls, even though reticulocyte number was higher in LC (3.0±0.6%) than in controls (1.4±0.2%). The percentage of PS-exposing erythrocytes was significantly higher in LC patients with (1.4±0.1%) and without (1.2±0.3%) cytostatic treatment as compared to healthy controls (0.6±0.1%). Erythrocyte ROS production and ceramide abundance, but not Fluo3 fluorescence, were significantly higher in freshly drawn erythrocytes from LC patients than in freshly drawn erythrocytes from healthy controls. PS exposure of erythrocytes drawn from healthy volunteers was significantly more pronounced following incubation in plasma from LC patients than following incubation in plasma from healthy controls.ConclusionAnemia in LC patients with and without cytostatic treatment is paralleled by increased eryptosis, which is triggered, at least in part, by increased oxidative stress and ceramide formation.

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“…Кроме того, в патогенезе злокачественных новообразований анемии могут вызвать неблагоприятные эффекты после применения цитостатиков [180]. Многочисленные исследования in vitro и in vivo показали, что применение многих химиотерапевтических агентов, включая клофазимин, митоксантрон, блебистатин, руксолитиниб, oксалоплатину, топотекан, регорафениб, оридонин, пицетанол и бипазопаниб, вызывают эриптоз и могут, таким образом, усилить анемию у раковых больных [35,57,73,92,147,182,230,268,269,309].…”

Section: эриптоз как элемент патогенеза анемииunclassified

Eryptosis (quasi-apoptosis) the human red blood cells. Its role in medicinal therapy

Vaschenko

Иванович²,

Vilyaninov

et al. 2019

Rev Clin Pharm Drug Ther

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In the course of circulation erythrocytes can test damages, which compromises their integrity and thus triggers suicidal erythrocyte death or eryptosis. This mechanism is characterised by cell shrinkage, cell membrane blebbing, and cell membrane phospholipid scrambling after phosphatidylserine exposure on the cell surface that is identified by macrophages, which engulf and degrade the eryptotic cells. The term eryptosis also includes typical mechanisms, which contribute to the triggering of this process, such as oxidative stress, Ca2+ entry with an increase in cytosolic Ca2+ activity and the activation of p38 kinase, which is a kinase expressed in human erythrocytes and activated after hyperosmotic shock. Enhanced eryptosis has been observed in several clinical conditions such as diabetes, renal insufficiency, haemolytic uremic syndrome, sepsis, mycoplasma infection, malaria, iron deficiency, sickle cell anaemia, beta-thalassemia, glucose-6-phosphate dehydrogenase (G6PD)-deficiency, hereditary spherocytosis, paroxysmal nocturnal haemoglobinuria, Wilson’s disease, myelodysplastic syndrome, and phosphate depletion. Therefore, eryptosis may be considered as a useful mechanism of removal of defective erythrocytes to prevent haemolysis. Moreover, the clearance of infected erythrocytes in diseases such as malaria may counteract parasitemia. Indeed it is known that sickle-cell trait, beta-thalassemia trait, G6PD-deficiency and iron deficiency confer some protection against a severe course of malaria. Importantly, strategies to control Plasmodium infection by inducing eryptosis are not expected to generate resistance of the pathogen, as the proteins involved in suicidal death of the host cell are not encoded by the pathogen and thus cannot be modified by mutations of its genes. However, excessive eryptosis could compromise microcirculation and lead to anemia. Besides, adhesion of eryptosis erythrocytes to a vascular wall also can lead to microcirculation infringement.Thus, modern representations about eryptosis expand our knowledge about the programmed death of blood cells and is more directed to create new therapeutic schemes of treatment of patients.

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Triggering of Suicidal Erythrocyte Death by Topotecan

Cited by 46 publications

References 108 publications

Ceranib‐2‐induced suicidal erythrocyte death

Ceranib‐2‐induced suicidal erythrocyte death

Enhanced eryptosis contributes to anemia in lung cancer patients

Eryptosis (quasi-apoptosis) the human red blood cells. Its role in medicinal therapy

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