Insulin resistance is an underlying mechanism of impaired glucose metabolism during nilotinib therapy

Ráčil, Zdeněk; Koriťáková, Eva; Sacha, Tomasz; Klamová, Hana; Bělohlávková, Petra; Faber, Edgar; Réa, Delphine; Malásková, Ludmila; Procházková, Jiřina; Žáčková, Daniela; Voglová, J; Wącław, Joanna; Cetkovský, Petr; Žák, Pavel; Mayer, Jiřı́

doi:10.1002/ajh.25232

Cited by 15 publications

(8 citation statements)

References 5 publications

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“…Molecular docking was performed to predict the binding of rosuvastatin and aspirin to the hub proteins and the targets enriched in the atherosclerosis signaling pathway. The three-dimensional structures of rosuvastatin and aspirin were obtained from the PubChem database, 8 and the three-dimensional structures of hub proteins were obtained from the RCSB Protein Data Bank (PDB) database. 9 Molecular docking simulations between rosuvastatin, aspirin and the target proteins were performed by using the AutoDock Tool (version 1.5.6) and AutoDock Vina 1.1.2 (Molecular Graphics Laboratory, Scripps Institute, 2011).…”

Section: Molecular Dockingmentioning

confidence: 99%

“…A total of 23.3% of patients have at least one arterial obstructive event, which suggests that cardiovascular toxicity remains a concern. Nilotinib (NILO) can cause accelerated atherosclerosis and arterial thrombotic events (myocardial ischemia, stroke, and peripheral artery obstructive disease), hyperglycemia and hyperlipidemia ( 7 , 8 ). The risk increases with the nilotinib administration duration ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

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Cardiovascular adverse events in chronic myeloid leukemia patients treated with nilotinib or imatinib: A systematic review, meta-analysis and integrative bioinformatics analysis

Zhang

et al. 2022

Front. Cardiovasc. Med.

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ObjectiveThe aim of this article is to assess the risk and potential mechanisms of cardiovascular adverse events in patients treated with nilotinib or imatinib by conducting a systematic review, meta-analysis and integrative bioinformatics analysis.Materials and methodsThree databases were systematically searched for studies published from inception to May 29, 2022. Differential expression analysis and weighted gene coexpression network analysis (WGCNA) were performed to search for modules of genes most associated with cardiotoxicity. Protein-protein interaction (PPI) network analysis was then performed to identify hub genes for the cardiotoxicity of nilotinib. Molecular docking was used to analyze the effects of rosuvastatin and aspirin on these targets.ResultsPatients treated with nilotinib as first-line treatment were associated with a higher risk of CAE (OR = 3.43 [95% CI 2.77–4.25]), CAD (OR = 5.30 [95% CI 3.85–7.29]), ACS (OR 2.7 [95% CI 1.60–4.54]), CVA (OR 5.76 [95% CI 2.84–11.28]), PAOD (OR 5.57 [95% CI 3.26–9.50]) and arrhythmia (OR 2.34 [1.17,4.67]) than those treated with imatinib, while no significant difference was found in the risk of HF (OR 1.40 [95% CI 0.42–4.69]) between the two groups. Patients who were treated with more than 600 mg daily dosage of nilotinib or followed up for more than 5 years had a higher risk of ACS and CVA. IL6, CXCL8, CCL2, SOD2, NFKBIA, and BIRC3 were identified as the top 6 hub genes in the magenta module (human cardiomyocyte samples) and were mainly enriched in the NOD-like receptor signaling pathway, IL-17 signaling pathway, TNF signaling pathway, lipid and atherosclerosis signaling pathway. TYROBP and CSF1R were identified as hub genes in the turquoise module (liver samples from Mus musculus). GSEA results showed that type II diabetes mellitus, B-cell receptor, apoptosis, insulin, natural killer cell mediated cytotoxicity,mTOR, chemokine, and T-cell receptor signaling pathways were related to the higher risk of atherosclerosis caused by nilotinib. Rosuvastatin can effectively bind to most of the hub targets and proteins enriched in the inflammatory pathways above.ConclusionCML patients who start with nilotinib have a higher risk of CAE than those with imatinib. Atherosclerosis caused by the inflammatory response and glycolipid metabolism disorder is the key mechanism of nilotinib cardiotoxicity. Rosuvastatin may be an effective treatment for the cardiotoxicity of nilotinib.

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Section: Molecular Dockingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cardiovascular adverse events in chronic myeloid leukemia patients treated with nilotinib or imatinib: A systematic review, meta-analysis and integrative bioinformatics analysis

Zhang

et al. 2022

Front. Cardiovasc. Med.

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“…[ 43 ] A prospective study on patients with CML who were treated with nilotinib for 12 months showed a significant increase in blood glucose levels. [ 44 ]…”

Section: Type 2 Diabetesmentioning

confidence: 99%

“…Interestingly, treatment of high-fat diet mice with nilotinib increases insulin sensitivity and decreases fat mass,[ 45 ] which contradicts the clinical data of the adverse effects of nilotinib on glucose impairment. One possible explanation is that clinical observations[ 42 , 44 ] have focused on insulin secretion rather than insulin action. Another probable reason is that nilotinib may have off-target effects that may include dual effects of insulin.…”

Section: Type 2 Diabetesmentioning

confidence: 99%

Tyrosine Kinase Targeting

Althubiti¹

2022

Saudi Journal of Medicine &Amp; Medical Sciences

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Tyrosine kinase inhibitors (TKIs) have been studied extensively in cancer research, ultimately resulting in the approval of many drugs for cancer therapy. Recent evidence from reported clinical cases and experimental studies have suggested that some of these drugs have a potential role in diabetes treatment. These TKIs include imatinib, sunitinib, dasatinib, erlotinib, nilotinib, neratinib, and ibrutinib. As a result of promising findings, imatinib has been used in a phase II clinical trial. In this review, studies that used TKIs in the treatment of both types of diabetes are critically discussed. In addition, the different molecular mechanisms of action of these drugs in diabetes models are also highlighted to understand their antidiabetic mode of action.

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“…Such events are clearly influenced by individual background, patients already at high or very high cardiovascular disease (CVD) risk being the most vulnerable [28], [21••]. Nilotinib also impairs glucose and cholesterol homeostasis through mechanisms that are not completely understood [29] [30]. These parameters need to be tightly monitored and controlled throughout treatment as diabetes and dyslipidemia are well-known risk factors for CVD.…”

Section: Safety Of First-line Tkis and Patient-related Factorsmentioning

confidence: 99%

Towards a Personalized Treatment of Patients with Chronic Myeloid Leukemia

Rabian

Lengliné

Réa

2019

Curr Hematol Malig Rep

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Purpose of Review Treatment goals and ambitions have even been upwardly revised since demonstration was made that under certain conditions, treatment-free remission was possible. Herein, we will discuss on how to try tailoring treatment choices to the unique characteristics of each patient. Recent Findings Since the first-generation ATP-competitive TKI imatinib was made available in the clinic in 2001, secondgeneration drugs such as dasatinib, nilotinib and bosutinib and the third-generation TKI ponatinib have broadened the therapeutic armamentarium, providing effective salvage against intolerance and different types of resistance, or as frontline options. Summary Management and outcomes of patients with chronic myeloid leukemia have been revolutionized by the discovery, development, and approval of BCR-ABL tyrosine kinase inhibitors (TKIs). Most patients can now expect a near-to normal life expectancy and acceptable quality of life on lifelong treatment, providing awareness and avoidance of harmful adverse events, which depend on each TKI safety profile and patient personal background. Keywords Chronic myeloid leukemia. Tyrosine kinase inhibitors. Personalized medicine This article is part of Topical Collection on Chronic Myeloid Leukemias

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Insulin resistance is an underlying mechanism of impaired glucose metabolism during nilotinib therapy

Abstract: TP and CG contributed equally to this work REFERENCES SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section at the end of the article.

Cited by 15 publications

References 5 publications

Cardiovascular adverse events in chronic myeloid leukemia patients treated with nilotinib or imatinib: A systematic review, meta-analysis and integrative bioinformatics analysis

Cardiovascular adverse events in chronic myeloid leukemia patients treated with nilotinib or imatinib: A systematic review, meta-analysis and integrative bioinformatics analysis

Tyrosine Kinase Targeting

Towards a Personalized Treatment of Patients with Chronic Myeloid Leukemia

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