Pulmonary arterial hypertension and chronic heart failure as dasatinib cardiotoxicity. A case report

Макеева, Л. М.; Емелина, Е. И.; Gendlin, G. E.; Никитин, И. Г.; Vasyuk, Yu. A.; Nesvetov, V V

doi:10.18087/cardio.2428

Cited by 3 publications

(1 citation statement)

References 13 publications

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“…2 However, administration of DASA has been reported to cause serious adverse reactions that affect multiple organs. Among these side effects are hepatotoxicity, 3,4 cardiotoxicity, 5 and nephrotoxicity. 6 In fact, DASA is primarily metabolized in the liver by the CYP 3A4 pathway as a major route of drug clearance.…”

Section: Introductionmentioning

confidence: 99%

Hydroxychloroquine ameliorates dasatinib-induced liver injury via decrease in hepatic lymphocytes infiltration

Alhazzani,

Alrewily,

Aljerian

et al. 2023

Hum Exp Toxicol

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Dasatinib is an effective treatment for chronic myeloid leukemia. However, cases of idiosyncratic hepatotoxicity were reported. This study was conducted to investigate the chemopreventive effects of hydroxychloroquine against dasatinib-induced hepatotoxicity. Balb/c mice were randomly assigned into four groups; vehicle control (5% DMSO, i.p., n = 6), dasatinib (50 mg/kg; i.p., n = 6), hydroxychloroquine (10 mg/kg, i.p., n = 6), and hydroxychloroquine + dasatinib (10 mg/kg + 50 mg/kg; i.p., n = 6). Treatments were given once every 2 days for 14 days. Serum and histopathological assessments of liver architecture and fibrosis were performed using H&E, Masson’s trichrome, and reticulin staining. The infiltration of lymphocytes was assessed using immunohistochemistry. The gene expression of antioxidant enzymes (CAT, SOD-2, GPX-1) was assessed using real-time quantitative PCR. Dasatinib showed a significant increase in liver injury biomarkers (AST and ALT) with higher lymphocytes infiltration (as indicated by CD3+, CD4+, CD8+, and CD20+ immunohistochemistry). Hepatic tissue of Dasatinib group exhibited significant downregulation in the gene expression of antioxidant enzymes (CAT, SOD-2, and GPX-1) compared to the control group. However, the combination of hydroxychloroquine with dasatinib showed a slight increase in AST and ALT. Also, hydroxychloroquine + dasatinib treated mice showed a significant reduction in lymphocytes infiltration as compared to dasatinib. The results showed that dasatinib induces an immune response leading to an increase in lymphocytes infiltration which promotes hepatocyte destruction and persistent liver injury. The results also suggest that hydroxychloroquine ameliorates dasatinib-induced hepatotoxicity via reduction in hepatic infiltration of T and B immune cells.

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Section: Introductionmentioning

confidence: 99%

Hydroxychloroquine ameliorates dasatinib-induced liver injury via decrease in hepatic lymphocytes infiltration

Alhazzani,

Alrewily,

Aljerian

et al. 2023

Hum Exp Toxicol

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Mitochondrial Dysfunction in Cardiotoxicity Induced by BCR-ABL1 Tyrosine Kinase Inhibitors -Underlying Mechanisms, Detection, Potential Therapies

et al. 2023

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High-mobility group box 1 protein-mediated necroptosis contributes to dasatinib-induced cardiotoxicity

Jin

Hao

et al. 2018

Toxicology Letters

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Dasatinib shows remarkable activity against imatinib-refractory chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (PhALL). However, severe cardiovascular toxicity limits the clinical applications of dasatinib. Since the underlying mechanism of dasatinib-induced cardiotoxicity is still elusive, we aim to clarify this. Recent studies have shown that necroptosis and apoptosis participate in multiple toxicity development. Here, we first report that dasatinib could directly induce cardiomyocytes death, as analyzed by the Sulforhodamine B (SRB) assay. This type of cardiomyocytes death was mediated by the necrosis pathway rather than apoptosis, as determined by using flow cytometry to characterize the mode of dasatinib-induced cell death. Inhibition of receptor-interacting protein kinase 1 (RIP1)activity and knockdown of receptor-interacting protein kinase 3 (RIP3)expression can block dasatinib-evoked cardiotoxicity, which further confirmed the involvement of necroptosis. We next found that the classic substrates of RIP3, mixed lineage kinase domain-like protein (MLKL) and Ca-calmodulin-dependent protein kinase II (CaMKII) were not involved in dasatinib-induced cardiomyocytes necroptosis. What's more, unlike the inflammation-associated necroptosis, dasatinib-triggered necroptosis was dependent on intracellular instead of secreted High-mobility group box 1 (HMGB1) protein. Collectively, our study revealed that dasatinib-induced cardiotoxicity acted via leading cardiomyocytes to HMGB1-mediated necroptosis, indicating a viable strategy for prevention of dasatinib-induced cardiotoxicity.

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Pulmonary arterial hypertension and chronic heart failure as dasatinib cardiotoxicity. A case report

Cited by 3 publications

References 13 publications

Hydroxychloroquine ameliorates dasatinib-induced liver injury via decrease in hepatic lymphocytes infiltration

Hydroxychloroquine ameliorates dasatinib-induced liver injury via decrease in hepatic lymphocytes infiltration

Mitochondrial Dysfunction in Cardiotoxicity Induced by BCR-ABL1 Tyrosine Kinase Inhibitors -Underlying Mechanisms, Detection, Potential Therapies

High-mobility group box 1 protein-mediated necroptosis contributes to dasatinib-induced cardiotoxicity

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