Dasatinib improves insulin sensitivity and affects lipid metabolism in a patient with chronic myeloid leukaemia

Iizuka, Katsumi; Niwa, Hiroyuki; Kato, Takehiro; Takeda, Jun

doi:10.1136/bcr-2015-214284

Cited by 12 publications

(14 citation statements)

References 14 publications

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“…A previous retrospective cohort study found that dasatinib treatment lowers mean serum glucose values by 52 mg/dL regardless of T2DM status, 9 whereas prior case reports have found improvements including remission of preexisting T2DM. 5,6,8,17,18 Our finding of an absolute improvement of serum glucose values by 31.4 mg/dL, including 2 of 4 patients who no longer required insulin within 12 months of dasatinib initiation, is consistent with prior literature on the antidiabetic properties of dasatinib. Retrospective cohort studies are conflicting about the impact of imatinib on glycemic control, with some reporting a modest improvement in serum glucose concentration (9 mg/dL) 9 and other studies reporting no improvement.…”

Section: Discussionsupporting

confidence: 89%

“…Sporadic case reports suggested that TKIs, primarily imatinib, may improve glycemic control or even result in complete remission of T2DM. [3][4][5][6][7][8] A subsequent retrospective cohort study of patients with (n¼17) and without (n¼61) T2DM found that treatment with various TKIs (sunitinib, sorafenib, dasatinib, and imatinib) was associated with lower serum glucose levels. This finding was limited by a small T2DM cohort, heterogeneous malignant neoplasms, and possible confounding by progression of the malignant disease and weight changes.…”

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confidence: 99%

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Antidiabetic Effects of the Senolytic Agent Dasatinib

Salaami

Kuo

Drake

et al. 2021

Mayo Clinic Proceedings

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Objective: To evaluate the antidiabetic effects of the senolytic agent dasatinib in older patients with type 2 diabetes mellitus. Methods: This retrospective cohort study included enterprise-wide Mayo Clinic patients using Informatics for Integrating Biology at the Bedside from January 1994 through December 2019. The antidiabetic outcomes (change in hemoglobin A 1c value, serum glucose concentration, and diabetic medications) after 1 year of a strongly senolytic tyrosine kinase inhibitor, dasatinib (n¼16), was compared with a weakly senolytic tyrosine kinase inhibitor, imatinib (n¼32). Results: Relative to imatinib, patients treated with dasatinib had a mean reduction of 43.7 mg/dL (P¼.005) in serum glucose concentration (to convert glucose values to mmol/L, multiply by 0.0555) and required 28.8 fewer total daily insulin units (P¼.08) in the setting of a 4.8-kg relative weight loss (5.3% of total body weight; P¼.045). Linear regression analysis suggests that the relative difference in weight accounts for 8.4 mg/dL of the 43.7 mg/dL blood glucose value decrease, or 19.2%. Relative to imatinib, patients treated with dasatinib had a mean 0.80 absolute point (P¼.05) reduction in hemoglobin A 1c and required 18.2 fewer total daily insulin units (P¼.16) in the setting of a 5.9-kg relative weight loss (6.3% of total body weight; P¼.06). Conclusion: Dasatinib may have antidiabetic effects comparable to contemporary diabetic treatments and may be considered for use as a novel diabetic therapy. Future studies are needed to determine whether these results are translatable to patients with type 2 diabetes mellitus without underlying malignant diseases and to determine whether the antidiabetic effects of dasatinib are due to its senolytic properties.

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Antidiabetic Effects of the Senolytic Agent Dasatinib

Salaami

Kuo

Drake

et al. 2021

Mayo Clinic Proceedings

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“…In both imatinib- and dasatinib-treated patients, increased circulating adiponectin e level correlates with decreased insulin resistance. 57 58 This correlation might be explained by the translocation of the glucose transporter GLUT4 f from the cytoplasm to the cell membrane following adiponectin signaling. 59 Additionally, adiponectin has been related to decreased hepatic glucose production which could be an additional mechanism by which imatinib and dasatinib improve glucose metabolism.…”

Section: Metabolic Dysregulationmentioning

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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“…It has been found that dasatinib might have positive as well as negative effects on the metabolism of glucose and lipids. 33 All these correlations were significant (P < 0.01). The drug-ME correlation matrix was provided in Tables S4 and S5.…”

Section: Dovepressmentioning

confidence: 87%

Gene Network Analysis of Hepatocellular Carcinoma Identifies Modules Associated with Disease Progression, Survival, and Chemo Drug Resistance

Ye¹,

Sun²,

Huang³

et al. 2021

IJGM

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Background: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. HCC transcriptome has been extensively studied; however, the progress in disease mechanisms, prognosis, and treatment is still slow. Methods: A rank-based module-centric workflow was introduced to analyze important modules associated with HCC development, prognosis, and drug resistance. The currently largest HCC cell line RNA-Seq dataset from the LIMORE database was used to construct the reference modules by weighted gene co-expression network analysis. Results: Thirteen reference modules were identified with validated reproducibility. These modules were all associated with specific biological functions. Differentially expressed module analysis revealed the crucial modules during HCC development. Modules and hub genes are indicative of patient survival. Modules can differentiate patients in different HCC stages. Furthermore, drug resistance was revealed by drug-module association analysis. Based on differentially expressed modules and hub genes, six candidate drugs were screened. The hub genes of those modules merit further investigation. Conclusion:We proposed a reference module-based analysis of the HCC transcriptome. The identified modules are associated with HCC development, survival, and drug resistance. M3 and M6 may play important roles during HCV to HCC development. M1, M3, M5, and M7 are associated with HCC survival. High M4, high M9, low M1, and low M3 may be associated with dasatinib, doxorubicin, CD532, and simvastatin resistance. Our analysis provides useful information for HCC diagnosis and treatment.

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Dasatinib improves insulin sensitivity and affects lipid metabolism in a patient with chronic myeloid leukaemia

Cited by 12 publications

References 14 publications

Antidiabetic Effects of the Senolytic Agent Dasatinib

Antidiabetic Effects of the Senolytic Agent Dasatinib

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

Gene Network Analysis of Hepatocellular Carcinoma Identifies Modules Associated with Disease Progression, Survival, and Chemo Drug Resistance

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