Stimulation of Eryptosis by Caspofungin

Peter, Thomas; Bissinger, Rosi; Läng, Florian

doi:10.1159/000447802

Cited by 20 publications

(4 citation statements)

References 92 publications

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“…Ãëèêîôîðèí Ãëèêîôîðèí По причине того, что молекулы фосфолипидов перемещаются с одной стороны мембраны на другую, происходит изменение свойств и функциональной активности эритроцитов [198]. Обстоятельными исследованиями установлено, что если фосфатидилсерин появляется в наружном слое мембраны, это приводит к усилению способности эритроцитов активировать функцию макрофагов по захвату старых и поврежденных клеток [145,153,239]. Наличие холестерина в мембране уменьшает подвижность жирных кислот, снижает латеральное смещение липидов и белков, изменяя тем самым функцию последних [95,196,198,229].…”

Section: ãëèêîôîðèíunclassified

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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Section: ãëèêîôîðèíunclassified

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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“…Erythrocytes from newborns are highly sensitive to oxidative stress leading to rapid eryptosis and subsequent clearance of those erythrocytes following birth . Eryptosis is triggered by complement, hyperosmotic shock, energy depletion, oxidative stress, cellular K + loss, hyperthermia and a wide variety of xenobiotics including diverse cytostatic drugs (see below).…”

Section: Introductionmentioning

confidence: 99%

Suicidal death of erythrocytes in cancer and its chemotherapy: A potential target in the treatment of tumor‐associated anemia

Lang

Bissinger

Qadri

et al. 2017

Intl Journal of Cancer

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In analogy to apoptosis of nucleated cells, erythrocytes may enter eryptosis characterized by cell shrinkage and cell membrane scrambling. Eryptotic erythrocytes are rapidly cleared from circulating blood and may adhere to the vascular wall. Stimulation of eryptosis thus impairs microcirculation and leads to anemia as soon as the loss of erythrocytes cannot be fully compensated by enhanced erythropoiesis. Signaling stimulating eryptosis includes increase of cytosolic Ca -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, and sorafenib- and sunitinib-sensitive tyrosine-kinases. Eryptosis is triggered by complement, hyperosmotic shock, energy-depletion, oxidative stress, multiple xenobiotics including diverse cytostatic drugs, diabetes, hepatic failure, iron-deficiency, chronic kidney disease, hemolytic-uremic-syndrome, fever, systemic lupus erythematosus, infections, sepsis, sickle cell anemia, thalassemia, glucose-6-phosphate-dehydrogenase deficiency, and Wilson´s disease. Compelling evidence points to a decisive role of eryptosis in anemia of malignancy. As shown for lung cancer, eryptosis inducing plasma components accumulate in cancer patients and trigger oxidative stress and ceramide. The tumor-induced eryptosis leads to anemia despite increased erythropoiesis. The stimulation of eryptosis in malignancy is compounded by cytostatic treatment, as a large number of cytostatic agents trigger eryptosis. Inhibiting eryptosis may be a useful strategy in reducing tumor-induced anemia and impaired microcirculation. Inhibitors of eryptosis may, however, be harmful, if they similarly interfere with death of tumor cells. Clearly, additional experimental effort is required to achieve killing of tumor cells with simultaneous avoidance of stimulated eryptosis.

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“…Eryptosis is suppressed by AMP activated kinase AMPK [73], cGMP-dependent protein kinase [74], mitogen and stress activated kinase MSK1/2 [75], PAK2 kinase [76] and sorafenib/sunitinib sensitive kinases [77, 78]. Eryptosis is triggered by a wide variety of conditions including hyperosmotic shock [61], oxidative stress [61], energy depletion [61], or exposure to diverse xenobiotics [61, 79‒137]. Several clinical disorders are associated with enhanced eryptosis, such as iron deficiency [61], dehydration [138], hyperphosphatemia [139], chronic kidney disease (CKD) [140‒143], hemolytic-uremic syndrome [144], diabetes [145], hepatic failure [79], malignancy [146, 147], arteriitis [148], sepsis [149], sickle-cell disease [61], beta-thalassemia [61], Hb-C and G6PD-deficiency [61], Wilsons disease [149], as well as advanced age [150].…”

Section: Introductionmentioning

confidence: 99%

Triggering of Eryptosis, the Suicidal Erythrocyte Death by Mammalian Target of Rapamycin (mTOR) inhibitor Temsirolimus

Bhuyan¹,

Cao²,

Läng³

2017

Cell Physiol Biochem

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Background/Aims: The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is utilized for the treatment of malignancy. Temsirolimus is at least in part effective by triggering suicidal tumor cell death. The most common side effect of temsirolimus treatment is anemia. At least in theory, the anemia following temsirolimus treatment could result from stimulation of eryptosis, the suicidal erythrocyte death. Hallmarks of eryptosis include cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling involved in the orchestration of eryptosis include increase of cytosolic Ca²⁺ activity ([Ca²⁺]_i), oxidative stress, ceramide, as well as activation of staurosporine and chelerythrine sensitive protein kinase C, SB203580 sensitive p38 kinase, D4476 sensitive casein kinase 1, and zVAD sensitive caspases. The purpose of the present study was to test whether temsirolimus influences eryptosis and, if so, to shed light on the signaling involved. Methods: Flow cytometry was employed to estimate cell volume from forward scatter, phosphatidylserine exposure at the cell surface from annexin-V-binding, [Ca²⁺]_i from Fluo3-fluorescence, reactive oxygen species (ROS) abundance from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemolysis was determined from hemoglobin concentration in the supernatant. Results: A 48 hours exposure of human erythrocytes to temsirolimus (5 – 20 µg/ml) significantly decreased forward scatter and significantly increased the percentage of annexin-V-binding cells. Temsirolimus significantly increased Fluo3-fluorescence, DCFDA fluorescence and ceramide abundance at the erythrocyte surface. The effect of temsirolimus on annexin-V-binding was significantly blunted but not abolished by removal of extracellular Ca²⁺ and by addition of staurosporine (1 µM) or chelerythrine (10 µM) but not significantly modified by addition of SB203580 (2 µM), D4476 (10 µM), or zVAD (10 µM). Chelerythrine (10 µM) further significantly blunted the effect of temsirolimus on DCFDA fluorescence but not ceramide formation. Removal of extracellular Ca²⁺ had no effect on temsirolimus induced ROS formation or ceramide abundance. Conclusions: Temsirolimus triggers eryptosis with cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca²⁺ entry, oxidative stress, ceramide and activation of staurosporine/Chelerythrine sensitive kinase(s).

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Stimulation of Eryptosis by Caspofungin

Cited by 20 publications

References 92 publications

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

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

Suicidal death of erythrocytes in cancer and its chemotherapy: A potential target in the treatment of tumor‐associated anemia

Triggering of Eryptosis, the Suicidal Erythrocyte Death by Mammalian Target of Rapamycin (mTOR) inhibitor Temsirolimus

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