Micafungin-Induced Suicidal Erythrocyte Death

Peter, Thomas; Bissinger, Rosi; Signoretto, Elena; Mack, Andreas F.; Läng, Florian

doi:10.1159/000445650

Cited by 27 publications

(7 citation statements)

References 94 publications

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“…7,9) Nonetheless, our data show that PSN-induced eryptosis is not mediated through oxidative stress (Fig. 6), unlike emodin, 21) but similar to micafungin, 15) triclosan, 25) and N,N-diethyl-3-methylbenzamide. 26) Therefore, counteracting eryptosis by antioxidants is unlikely to attenuate PSN-induced cell death.…”

Section: Discussionmentioning

confidence: 47%

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Physcion Induces Hemolysis and Premature Phosphatidylserine Externalization in Human Erythrocytes

Akiel

Alsughayyir

Basudan

et al. 2021

Biological & Pharmaceutical Bulletin

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The prevalence of cancer-associated anemia (CIA) is high, and the mechanisms governing its development remain poorly understood. Eryptosis, the suicidal cell death of red blood cells (RBCs), may account for CIA as it is triggered by clinically approved chemotherapeutics including cisplatin and paclitaxel. Physcion (PSN), an anthraquinone extracted from rhubarb and other plants, has shown great promise as an anticancer agent. However, the potential toxicity of PSN to RBCs remains elusive. RBCs were isolated from heparinized blood, and incubated with 10-100 µM of PSN for 24 h at 37 o C.Hemolysis was photometrically calculated from hemoglobin concentration in the medium at 405 nm, while flow cytometry was employed to investigate cardinal markers of eryptosis. Phosphatidylserine (PS) exposure was detected by Annexin-V-FITC, intracellular calcium by Fluo4/AM, cellular volume from forward scatter (FSC), and oxidative stress by 2',7'-dichlorodihydrofluorescein diacetate (H 2 DCFDA). PSN induced overt hemolysis at 50 and 100 µM which was not mediated through calcium influx, protein kinase C, casein kinase 1α, or receptor-interacting protein 1. Moreover, PSN caused significant increase in Annexin-V-FITC and Fluo4 fluorescence with no appreciable influence on FSC or DCF values. Accordingly, PSN stimulates premature eryptosis characterized by PS externalization and intracellular calcium overload without cell shrinkage or oxidative damage. In conclusion, this report shows, for the first time, that PSN is cytotoxic to RBCs by inducing hemolysis and programmed cell death which may limit its success as a chemotherapeutic agent.

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Section: Discussionmentioning

confidence: 47%

“…13) Circulating hemoglobin causes oxidative damage to vital organs, and aggravates renal disease. 15) Moreover, hemoglobin degradation products interfere with immune function and exacerbate inflammatory conditions. 16,17) PSN also induced significant loss of membrane asymmetry (Fig.…”

Section: Discussionmentioning

confidence: 99%

Physcion Induces Hemolysis and Premature Phosphatidylserine Externalization in Human Erythrocytes

Akiel

Alsughayyir

Basudan

et al. 2021

Biological & Pharmaceutical Bulletin

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“…50 Another recent report claimed that MCFG induces hemolysis by triggering cell shrinkage and cell membrane scrambling in human erythrocytes. 51 Although further investigations on the effects of MCFG to mouse blood are warranted, we suspect that this effect may be related to a similar mechanism as proposed in humans. We also observed spleen enlargement in the MCFG-treated mice; although the spleen expansion was only reduced by 0.5-fold compared with that of the DENV-infected group, it was significantly (p < 0.05) enlarged relative to that of untreated healthy mice.…”

Section: ■ Discussionmentioning

confidence: 78%

“…In humans, the drug label indicates that high dosing could induce hemolysis, which is supported by a clinical report . Another recent report claimed that MCFG induces hemolysis by triggering cell shrinkage and cell membrane scrambling in human erythrocytes . Although further investigations on the effects of MCFG to mouse blood are warranted, we suspect that this effect may be related to a similar mechanism as proposed in humans.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Direct-Acting Antiviral Agent Targeting RNA Helicase via a Graphene Oxide Nanobiosensor

Kim

Park

et al. 2021

ACS Appl. Mater. Interfaces

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Dengue virus (DENV), an arbovirus transmitted by mosquitoes, causes infectious diseases such as dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Despite the dangers posed by DENV, there are no approved antiviral drugs for treatment of DENV infection. Considering the potential for a global dengue outbreak, rapid development of antiviral agents against DENV infections is crucial as a preemptive measure; thus, the selection of apparent drug targets, such as the viral enzymes involved in the viral life cycle, is recommended. Helicase, a potential drug target in DENV, is a crucial viral enzyme that unwinds double-stranded viral RNA, releasing single-stranded RNA genomes during viral replication. Therefore, an inhibitor of helicase activity could serve as a direct-acting antiviral agent. Here, we introduce an RNA helicase assay based on graphene oxide, which enables fluorescence-based analysis of RNA substrate-specific helicase enzyme activity. This assay demonstrated high reliability and ability for high-throughput screening, identifying a new helicase inhibitor candidate, micafungin (MCFG), from an FDA-approved drug library. As a direct-acting antiviral agent targeting RNA helicase, MCFG inhibits DENV proliferation in cells and an animal model. Notably, in vivo, MCFG treatment reduced viremia, inflammatory cytokine levels, and viral loads in several tissues and improved survival rates by up to 40% in a lethal mouse model. Therefore, we suggest MCFG as a potential direct-acting antiviral drug candidate.

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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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Micafungin-Induced Suicidal Erythrocyte Death

Cited by 27 publications

References 94 publications

Physcion Induces Hemolysis and Premature Phosphatidylserine Externalization in Human Erythrocytes

Physcion Induces Hemolysis and Premature Phosphatidylserine Externalization in Human Erythrocytes

Identification of a Direct-Acting Antiviral Agent Targeting RNA Helicase via a Graphene Oxide Nanobiosensor

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

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