The second generation tyrosine kinase inhibitor dasatinib induced eryptosis in human erythrocytes—An in vitro study

Chan, Wai Yin; Lau, Patrick S. Y.; Yeung, Ka Wing; Kong, Siu Kai

doi:10.1016/j.toxlet.2018.05.030

Cited by 9 publications

(6 citation statements)

References 40 publications

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“…Eryptosis might promote blood coagulation through PS externalization. The effect of dasatinib on circulation is complex, and the clinical outcome of bleeding might depend on which effect is ore pronounced, e.g, inhibition or promotion of PS expression on different types of cells [27,28].…”

Section: Discussionmentioning

confidence: 99%

Dasatinib Inhibits Procoagulant and Clot Retracting Activities of Human Platelets

Debreceni

Mezei

Batár

et al. 2019

IJMS

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Tyrosine kinase inhibitors (TKI) such as the BCR-ABL inhibitor dasatinib and nilotinib are highly effective therapies for chronic myeloid leukemia (CML). However, several lines of evidence suggest that dasatinib can induce bleeding which may be due to impaired collagen-induced platelet adhesion, aggregation, and secretion. Sarcoma family kinases (SFK) play central role in the GPVI-induced signaling pathway. We aimed to investigate whether and how dasatinib can modulate SFK-mediated platelet procoagulant activity in a purified system and in dasatinib/nilotinib treated CML patients. In platelet rich plasmas of healthy volunteers, dasatinib dose-dependently reduced convulxin-induced phosphatidylserine exposure and attenuated thrombin formation. Similarly to these changes, integrin activation and clot retraction were also significantly inhibited by 100 nM dasatinib. Platelets isolated from dasatinib treated patients showed a significantly lower phosphatidylserine expression upon convulxin activation compared to premedication levels. In these samples, thrombin generation was significantly slower, and the quantity of formed thrombin was less compared to the trough sample. Western blot analyses showed decreased phosphorylation levels of the C-terminal tail and the activation loop of SFKs upon dasatinib administration. Taken together, these results suggest that dasatinib inhibits the formation of procoagulant platelets via the GPVI receptor by inhibiting phosphorylation of SFKs.

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Section: Discussionmentioning

confidence: 99%

Dasatinib Inhibits Procoagulant and Clot Retracting Activities of Human Platelets

Debreceni

Mezei

Batár

et al. 2019

IJMS

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“…SRC kinases play an essential role in erythropoiesis and the survival of B cells and myeloid cells ( 20 – 22 ). In addition, dasatinib may induce eryptosis in human erythrocytes through Ca 2+ channel loading and membrane permeabilization ( 23 ).…”

Section: Clinical Characteristic Of Dasatinib Related Aes In Patients...mentioning

confidence: 99%

Adverse reactions after treatment with dasatinib in chronic myeloid leukemia: Characteristics, potential mechanisms, and clinical management strategies

Cheng

et al. 2023

Front. Oncol.

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Dasatinib, a second-generation tyrosine kinase inhibitor, is recommended as first-line treatment for patients newly diagnosed with chronic myeloid leukemia (CML) and second-line treatment for those who are resistant or intolerant to therapy with imatinib. Dasatinib is superior to imatinib in terms of clinical response; however, the potential pulmonary toxicities associated with dasatinib, such as pulmonary arterial hypertension and pleural effusion, may limit its clinical use. Appropriate management of dasatinib-related severe events is important for improving the quality of life and prognosis of patients with CML. This review summarizes current knowledge regarding the characteristics, potential mechanisms, and clinical management of adverse reactions occurring after treatment of CML with dasatinib.

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“…Eryptosis can also be induced by a mechanistic increase in intracellular Ca 2+ levels [61,62], oxidative stress, energy depletion [63], and exposure to undesirable substances such as ZEN [56]. However, the loss of extracellular Ca 2+ can also inhibit the eryptotic effect [64] due to anaemia and microcirculatory disorders. Microcirculatory disorders are observed in various tissues during exposure to ZEN, and they lead to numerous extravasations and vasodilation [65,66] in pre-pubertal female mammals, due to the relaxation of smooth muscle cells in vessel walls, in particular in large veins, large arteries, and smaller arterioles.…”

Section: Red Blood Cellsmentioning

confidence: 99%

The Effect of Low Doses of Zearalenone (ZEN) on the Bone Marrow Microenvironment and Haematological Parameters of Blood Plasma in Pre-Pubertal Gilts

Mroz

Gajęcka

Przybyłowicz

et al. 2022

Toxins

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The aim of this study was to determine whether low doses of zearalenone (ZEN) influence the carry-over of ZEN and its metabolites to the bone marrow microenvironment and, consequently, haematological parameters. Pre-pubertal gilts (with a body weight of up to 14.5 kg) were exposed to daily ZEN doses of 5 μg/kg BW (group ZEN5, n = 15), 10 μg/kg BW (group ZEN10, n = 15), 15 μg/kg BW (group ZEN15, n = 15), or were administered a placebo (group C, n = 15) throughout the entire experiment. Bone marrow was sampled on three dates (exposure dates 7, 21, and 42—after slaughter) and blood for haematological analyses was sampled on 10 dates. Significant differences in the analysed haematological parameters (WBC White Blood Cells, MONO—Monocytes, NEUT—Neutrophils, LYMPH—Lymphocytes, LUC—Large Unstained Cells, RBC—Red Blood Cells, HGB—Haemoglobin, HCT—Haematocrit, MCH—Mean Corpuscular Volume, MCHC—Mean Corpuscular Haemoglobin Concentrations, PLT—Platelet Count and MPV—Mean Platelet Volume) were observed between groups. The results of the experiment suggest that exposure to low ZEN doses triggered compensatory and adaptive mechanisms, stimulated the local immune system, promoted eryptosis, intensified mycotoxin biotransformation processes in the liver, and produced negative correlations between mycotoxin concentrations and selected haematological parameters.

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The second generation tyrosine kinase inhibitor dasatinib induced eryptosis in human erythrocytes—An in vitro study

Cited by 9 publications

References 40 publications

Dasatinib Inhibits Procoagulant and Clot Retracting Activities of Human Platelets

Dasatinib Inhibits Procoagulant and Clot Retracting Activities of Human Platelets

Adverse reactions after treatment with dasatinib in chronic myeloid leukemia: Characteristics, potential mechanisms, and clinical management strategies

The Effect of Low Doses of Zearalenone (ZEN) on the Bone Marrow Microenvironment and Haematological Parameters of Blood Plasma in Pre-Pubertal Gilts

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