Nilotinib Does Not Alter the Secretory Functions of Carotid Artery Endothelial Cells in a Prothrombotic or Antithrombotic Fashion

Katgi, Abdullah; Sevindik, Omur Gokmen; Gökbulut, Aysun Adan; Özsan, Güner Hayri; Yüksel, Faize; Solmaz, Şerife; Alacacıoğlu, İnci; Özcan, Mehmet Ali; Demırkan, Fatih; Baran, Yusuf; Pişkin, Özden

doi:10.1177/1076029614550817

Cited by 9 publications

(6 citation statements)

References 13 publications

(34 reference statements)

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“…Nilotinib and ponatinib reduce EC proliferation and might impaired endothelial regeneration. 39 82 89 90 Additionally, ponatinib induces EC apoptosis, although it is well recognized that high glucose concentration induces EC death, 91 suggesting that nilotinib might, by this intermediary, affect EC viability. Moreover, clinical data indicate that dasatinib induces pulmonary arterial hypertension, whereas imatinib is possibly beneficial in this disease.…”

Section: Effects On Atherosclerosismentioning

confidence: 99%

BCR-ABL Tyrosine Kinase Inhibitors: Which Mechanism(s) May Explain the Risk of Thrombosis?

Haguet

Douxfils

Chatelain

et al. 2018

TH Open

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Imatinib, the first-in-class BCR-ABL tyrosine kinase inhibitor (TKI), had been a revolution for the treatment of chronic myeloid leukemia (CML) and had greatly enhanced patient survival. Second- (dasatinib, nilotinib, and bosutinib) and third-generation (ponatinib) TKIs have been developed to be effective against BCR-ABL mutations making imatinib less effective. However, these treatments have been associated with arterial occlusive events. This review gathers clinical data and experiments about the pathophysiology of these arterial occlusive events with BCR-ABL TKIs. Imatinib is associated with very low rates of thrombosis, suggesting a potentially protecting cardiovascular effect of this treatment in patients with BCR-ABL CML. This protective effect might be mediated by decreased platelet secretion and activation, decreased leukocyte recruitment, and anti-inflammatory or antifibrotic effects. Clinical data have guided mechanistic studies toward alteration of platelet functions and atherosclerosis development, which might be secondary to metabolism impairment. Dasatinib, nilotinib, and ponatinib affect endothelial cells and might induce atherogenesis through increased vascular permeability. Nilotinib also impairs platelet functions and induces hyperglycemia and dyslipidemia that might contribute to atherosclerosis development. Description of the pathophysiology of arterial thrombotic events is necessary to implement risk minimization strategies.

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Section: Effects On Atherosclerosismentioning

confidence: 99%

BCR-ABL Tyrosine Kinase Inhibitors: Which Mechanism(s) May Explain the Risk of Thrombosis?

Haguet

Douxfils

Chatelain

et al. 2018

TH Open

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“…Katgi et al [55] further tested the effects of nilotinib on function and viability of human carotid artery endothelial cells (HCtAECs). Nilotinib reduced proliferation of the HCtAECs, in a mild, albeit statistically significant manner, with dose-dependence.…”

Section: Pathogenesis Of Vaementioning

confidence: 99%

Tyrosine kinase inhibitor associated vascular toxicity in chronic myeloid leukemia

et al. 2015

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Tyrosine kinase inhibitors (TKIs) have revolutionized the management and outcomes of chronic myeloid leukemia (CML) patients. Improved disease control and prolonged life expectancy now mandate focus on improving TKIs' safety profile. Recently, vascular adverse events (VAEs) have emerged as a serious consequence of some of the newer TKIs. In this review, we describe the clinical spectrum of TKI-associated VAE, and examine the unique vascular safety profile of the main TKIs currently used in the treatment of CML: imatinib, nilotinib, dasatinib, bosutinib and ponatinib. The issue of TKI-related platelet dysfunction is discussed as well. We describe the contemporary research findings regarding the possible pathogenesis of the VAE. Finally, the different aspects of TKI-associated VAE management are addressed, including prevention methods, monitoring strategies and treatment options.

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“…There is a lack of homogeneity in the in vitro studies performed to investigate the effects of nilotinib and ponatinib on endothelial cells. Overall, the methods, the tested concentrations and the cell line used often differed, making arduous the comparison between studies and resulting in conflicting reports ( Vrekoussis et al., 2006 ; Venalis et al., 2009 ; Katgi et al., 2015 ). Here, we aimed to provide a homogenous evaluation and comparison of the viability of endothelial cells exposed to each of the five commercially available BCR-ABL TKIs.…”

Section: Introductionmentioning

confidence: 99%

The Risk of Arterial Thrombosis in Patients With Chronic Myeloid Leukemia Treated With Second and Third Generation BCR-ABL Tyrosine Kinase Inhibitors May Be Explained by Their Impact on Endothelial Cells: An In-Vitro Study

Haguet

Bouvy²,

Delvigne³

et al. 2020

Front. Pharmacol.

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BCR-ABL tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia, inducing deep molecular responses, largely improving patient survival and rendering treatment-free remission possible. However, three of the five BCR-ABL TKIs, dasatinib, nilotinib, and ponatinib, increase the risk of developing arterial thrombosis. Prior investigations reported that nilotinib and ponatinib affect the endothelium, but the mechanisms by which they exert their toxic effects are still unclear. The impact of dasatinib and bosutinib on endothelial cells has been poorly investigated. Here, we aimed to provide an in vitro homogenous evaluation of the effects of BCR-ABL TKIs on the endothelium, with a special focus on the type of cell death to elucidate the mechanisms responsible for the potential cytotoxic effects of BCR-ABL TKIs nilotinib and ponatinib on endothelial cells. We tested the five BCR-ABL TKIs at three concentrations on human umbilical venous endothelial cells (HUVECs). This study highlights the endothelial toxicity of ponatinib and provides insights about the mechanisms by which it affects endothelial cell viability. Ponatinib induced apoptosis and necrosis of HUVECs after 72 h. Dasatinib affected endothelial cells in vitro by inhibiting their proliferation and decreased wound closure as soon as 24 h of treatment and even at infra-therapeutic dose (0.005 µM). Comparatively, imatinib, nilotinib, and bosutinib had little impact on endothelial cells at therapeutic concentrations. They did not induce apoptosis nor necrosis, even after 72 h of treatment but they inhibited HUVEC proliferation. Overall, this study reports various effects of BCR-ABL TKIs on endothelial cells and suggests that ponatinib and dasatinib induce arterial thrombosis through endothelial dysfunction.

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Nilotinib Does Not Alter the Secretory Functions of Carotid Artery Endothelial Cells in a Prothrombotic or Antithrombotic Fashion

Cited by 9 publications

References 13 publications

BCR-ABL Tyrosine Kinase Inhibitors: Which Mechanism(s) May Explain the Risk of Thrombosis?

BCR-ABL Tyrosine Kinase Inhibitors: Which Mechanism(s) May Explain the Risk of Thrombosis?

Tyrosine kinase inhibitor associated vascular toxicity in chronic myeloid leukemia

The Risk of Arterial Thrombosis in Patients With Chronic Myeloid Leukemia Treated With Second and Third Generation BCR-ABL Tyrosine Kinase Inhibitors May Be Explained by Their Impact on Endothelial Cells: An In-Vitro Study

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