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Human & Experimental Toxicology 2023Dasatinib is an effective treatment for chronic myeloid leukemia. However, cases of idiosyncratic hepatotoxicity were reported. This study was conducted to investigate...
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., = 6), dasatinib (50 mg/kg; i.p., = 6), hydroxychloroquine (10 mg/kg, i.p., = 6), and hydroxychloroquine + dasatinib (10 mg/kg + 50 mg/kg; i.p., = 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.
Topics: Animals; Mice; Dasatinib; Hydroxychloroquine; Antioxidants; Chemical and Drug Induced Liver Injury, Chronic; Superoxide Dismutase
PubMed: 37431997
DOI: 10.1177/09603271231188492 -
Journal of Pharmacological Sciences Jul 2022Although the use of BCR-ABL1 tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia is known to cause vascular adverse events (VAEs), the frequency of VAEs...
Although the use of BCR-ABL1 tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia is known to cause vascular adverse events (VAEs), the frequency of VAEs during dasatinib administration is not high, and the same holds for atherosclerosis-related VAEs. However, its effect on atherosclerosis remains controversial. In this study, our primary objective was to investigate how dasatinib affects atherosclerosis. Ldlr/Apobec1 mice, which are highly prone to develop atherosclerosis, were administered dasatinib. After 16 weeks, we evaluated their atherosclerotic lesions. We used bone-marrow-derived macrophages to investigate the uptake of oxidized low-density lipoprotein (LDL) complexed with DiI dye (DiI-oxLDL). RNA sequencing and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were performed to explore the potential effects of dasatinib on cholesterol metabolism. Dasatinib administration significantly reduced atherosclerotic lesions (P < 0.001 and P = 0.013) and DiI-oxLDL uptake (P < 0.001) unlike other TKIs. RNA sequencing and RT-qPCR suggested that Sort1, which encodes sortilin, a known regulator of LDL uptake, and Cd36 were potential targets of dasatinib. In conclusion, dasatinib induced elevated LDL-C levels, but oxLDL uptake in macrophages were suppressed, resulting in reducing atherosclerotic lesions. These results further our understanding of the differences in VAEs between dasatinib and other TKIs.
Topics: Animals; Atherosclerosis; CD36 Antigens; Cholesterol; Dasatinib; Disease Models, Animal; Hypercholesterolemia; Macrophages; Mice; Mice, Knockout
PubMed: 35641028
DOI: 10.1016/j.jphs.2022.04.009 -
PloS One 2022Senescent cells accumulate with aging and have been shown to contribute to age-associated diseases and organ dysfunction. Eliminating senescent cells with senolytic...
Senescent cells accumulate with aging and have been shown to contribute to age-associated diseases and organ dysfunction. Eliminating senescent cells with senolytic drugs has been shown to improve age phenotypes in mouse models and there is some initial evidence that it may improve the health of persons with chronic diseases. In this study, we employed WI-38 human fibroblasts rendered senescent by exposure to ionizing radiation (IR) to screen several plant extracts for their potential senolytic and/or senomorphic activity. Of these, ginger extract (Zingiber officinale Rosc.) selectively caused the death of senescent cells without affecting proliferating cells. Among the major individual components of ginger extract, gingerenone A and 6-shogaol showed promising senolytic properties, with gingerenone A selectively eliminating senescent cells. Similar to the senolytic cocktail dasatinib and quercetin (D+Q), gingerenone A and 6-shogaol elicited an apoptotic program. Additionally, both D+Q and gingerenone A had a pronounced effect on suppressing the senescence-associated secretory phenotype (SASP). Gingerenone A selectively promotes the death of senescent cells with no effect on non-senescent cells and these characteristics strongly support the idea that this natural compound may have therapeutic benefit in diseases characterized by senescent cell accumulation.
Topics: Aging; Animals; Cellular Senescence; Dasatinib; Diarylheptanoids; Fibroblasts; Mice; Quercetin
PubMed: 35349590
DOI: 10.1371/journal.pone.0266135 -
Journal of Cellular and Molecular... Sep 2021Dasatinib is an inhibitor of Src that has anti-tumour effects on many haematological and solid cancers. However, the anti-tumour effects of dasatinib on human oral...
Dasatinib is an inhibitor of Src that has anti-tumour effects on many haematological and solid cancers. However, the anti-tumour effects of dasatinib on human oral cancers remain unclear. In this study, we investigated the effects of dasatinib on different types of human oral cancer cells: the non-tumorigenic YD-8 and YD-38 and the tumorigenic YD-10B and HSC-3 cells. Strikingly, dasatinib at 10 µM strongly suppressed the growth and induced apoptosis of YD-38 cells and inhibited the phosphorylation of Src, EGFR, STAT-3, STAT-5, PKB and ERK-1/2. In contrast, knockdown of Src blocked the phosphorylation of EGFR, STAT-5, PKB and ERK-1/2, but not STAT-3, in YD-38 cells. Dasatinib induced activation of the intrinsic caspase pathway, which was inhibited by z-VAD-fmk, a pan-caspase inhibitor. Dasatinib also decreased Mcl-1 expression and S6 phosphorylation while increased GRP78 expression and eIF-2α phosphorylation in YD-38 cells. In addition, to its direct effects on YD-38 cells, dasatinib also exhibited anti-angiogenic properties. Dasatinib-treated YD-38 or HUVEC showed reduced HIF-1α expression and stability. Dasatinib alone or conditioned media from dasatinib-treated YD-38 cells inhibited HUVEC tube formation on Matrigel without affecting HUVEC viability. Importantly, dasatinib's anti-growth, anti-angiogenic and pro-apoptotic effects were additionally seen in tumorigenic HSC-3 cells. Together, these results demonstrate that dasatinib has strong anti-growth, anti-angiogenic and pro-apoptotic effects on human oral cancer cells, which are mediated through the regulation of multiple targets, including Src, EGFR, STAT-3, STAT-5, PKB, ERK-1/2, S6, eIF-2α, GRP78, caspase-9/3, Mcl-1 and HIF-1α.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Line, Tumor; Dasatinib; Humans; Mouth Neoplasms; Protein Kinase Inhibitors
PubMed: 34318593
DOI: 10.1111/jcmm.16782 -
Seminars in Oncology Dec 2015The landscape of chronic myeloid leukemia (CML) management has changed with the advent of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 oncoprotein. Imatinib... (Review)
Review
The landscape of chronic myeloid leukemia (CML) management has changed with the advent of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 oncoprotein. Imatinib mesylate, followed by nilotinib and dasatinib, has been approved for newly diagnosed patients. Since none of these TKIs show survival superiority, the drug choice is a challenge. Even so, the rate of deeper and earlier responses is higher with second-generation TKIs than it is with imatinib, and, in general, better response is associated with a survival advantage, regardless of TKI type being used. Patients should be monitored carefully for response, and treatment failure should prompt a timely switch to another TKI. Side effect profile and drug cost are other important considerations in therapy choice. In several clinical studies, achieving undetectable and durable disease status allowed some patients to discontinue the TKI and enjoy long-term treatment-free remission. Cure for CML may be possible with TKIs alone or TKIs in combination with other investigational therapies. However, due to lack of long-term outcome data and absence of consensus for the definition of optimal response and time to stop TKIs, discontinuation is discouraged outside of a clinical trial.
Topics: Aniline Compounds; Antineoplastic Agents; Dasatinib; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Imidazoles; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Molecular Targeted Therapy; Nitriles; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridazines; Pyrimidines; Quinolines; Treatment Outcome
PubMed: 26615132
DOI: 10.1053/j.seminoncol.2015.09.030 -
Medicina (Kaunas, Lithuania) Oct 2022: The aim of this study is to investigate the characteristics of gastrointestinal bleeding events associated with BCR-ABL tyrosine kinase inhibitor (TKI) treatment,...
: The aim of this study is to investigate the characteristics of gastrointestinal bleeding events associated with BCR-ABL tyrosine kinase inhibitor (TKI) treatment, using the reporting odds ratio (ROR) of the adverse event reports submitted to the Japanese Adverse Drug Event Report database between 2004 and 2020, and to examine the number of reported TKI-related gastrointestinal bleeding cases according to sex and age, as well as the actual number of TKI prescriptions issued in Japan. : The RORs and 95% confidence intervals (CIs) of gastrointestinal bleeding events related to TKIs were calculated using the data of the 595,121 included cases. : Significant gastrointestinal bleeding events were detected for dasatinib (crude ROR: 4.47, 95% CI: 3.77-5.28) and imatinib (crude ROR: 1.22, 95% CI: 1.01-1.46). In multiple logistic regression analyses, significant gastrointestinal bleeding events were detected for dasatinib (adjusted ROR: 8.02, 95% CI: 5.75-10.2), imatinib (adjusted ROR: 1.81, 95% CI: 1.2-2.72), age (≥60 years, adjusted ROR: 2.22, 95% CI: 2.1-2.36), reporting year (adjusted ROR: 1.04, 95% CI: 1.04-1.05), and male sex (adjusted ROR: 1.47, 95% CI: 1.37-1.57). Interaction analysis revealed that the association of gastrointestinal bleeding with dasatinib was affected by age (≥60 years) and sex (female), with the number and proportion of dasatinib-related gastrointestinal bleeding cases increasing among those aged ≥60 years. : Specific TKIs and patient characteristics were associated with gastrointestinal bleeding. Our results aid the prompt identification and treatment of TKI-related gastrointestinal bleeding.
Topics: Male; Female; Humans; Dasatinib; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Pyrimidines; Protein Kinase Inhibitors; Gastrointestinal Hemorrhage
PubMed: 36295654
DOI: 10.3390/medicina58101495 -
Current HIV/AIDS Reports Oct 2019HIV-1 infection is incurable due to the existence of latent reservoirs that persist in the face of cART. In this review, we describe the existence of multiple HIV-1... (Review)
Review
PURPOSE OF REVIEW
HIV-1 infection is incurable due to the existence of latent reservoirs that persist in the face of cART. In this review, we describe the existence of multiple HIV-1 reservoirs, the mechanisms that support their persistence, and the potential use of tyrosine kinase inhibitors (TKIs) to block several pathogenic processes secondary to HIV-1 infection.
RECENT FINDINGS
Dasatinib interferes in vitro with HIV-1 persistence by two independent mechanisms. First, dasatinib blocks infection and potential expansion of the latent reservoir by interfering with the inactivating phosphorylation of SAMHD1. Secondly, dasatinib inhibits the homeostatic proliferation induced by γc-cytokines. Since homeostatic proliferation is thought to be the main mechanism behind the maintenance of the latent reservoir, we propose that blocking this process will gradually reduce the size of the reservoir. TKIs together with cART will interfere with HIV-1 latent reservoir persistence, favoring the prospect for viral eradication.
Topics: CD4-Positive T-Lymphocytes; Cytokines; Dasatinib; HIV Infections; HIV-1; Humans; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; SAM Domain and HD Domain-Containing Protein 1; Virus Latency
PubMed: 31506864
DOI: 10.1007/s11904-019-00462-5 -
Acta Pharmaceutica (Zagreb, Croatia) Sep 2022The present study was carried out in human schwannoma cells (HEI-193) to determine the combined anti-cancer effect of curcumin and dasatinib. Cells were treated with...
The present study was carried out in human schwannoma cells (HEI-193) to determine the combined anti-cancer effect of curcumin and dasatinib. Cells were treated with curcumin only, dasatinib only, or the combination of curcumin and dasatinib for 24 hours. Cellular toxicity, cell proliferation, and cell death were determined by LDH, MTT, and trypan blue dye assays, respectively. ELISA based kit was used to determine apoptotic cell death. Western blotting was used to determine the expression of apoptotic and autophagy-associated protein markers. Similarly, expression levels of Akt/mTOR/p70S6K signalling pathway-related proteins were studied using Western blotting. Cell death and apoptosis were significantly higher in HEI-193 cells treated with curcumin and dasatinib combination compared to individual controls. The combination of curcumin and dasatinib significantly enhances autophagy markers compared to individual controls. Furthermore, the combination of curcumin and dasatinib significantly activates Akt/mTOR/p70S6K signalling pathway compared to individual controls. In conclusion, our results suggest that the combination of curcumin and dasatinib significantly enhances cytotoxicity, apoptosis, and protective autophagy in HEI-193 cells through Akt/mTOR/p70S6K signalling pathway.
Topics: Humans; Dasatinib; Curcumin; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Cell Line, Tumor; TOR Serine-Threonine Kinases; Apoptosis; Autophagy; Neurilemmoma
PubMed: 36651538
DOI: 10.2478/acph-2022-0025 -
Mayo Clinic Proceedings Dec 2021To evaluate the antidiabetic effects of the senolytic agent dasatinib in older patients with type 2 diabetes mellitus.
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 value, serum glucose concentration, and diabetic medications) after 1 year of a strongly senolytic tyrosine kinase inhibitor, dasatinib (n=16), was compared with a weakly senolytic tyrosine kinase inhibitor, imatinib (n=32).
RESULTS
Relative to imatinib, patients treated with dasatinib had a mean reduction of 43.7 mg/dL (P=.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 (P=.08) in the setting of a 4.8-kg relative weight loss (5.3% of total body weight; P=.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 (P=.05) reduction in hemoglobin A and required 18.2 fewer total daily insulin units (P=.16) in the setting of a 5.9-kg relative weight loss (6.3% of total body weight; P=.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.
Topics: Blood Glucose; Dasatinib; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemic Agents; Imatinib Mesylate; Linear Models; Male; Middle Aged; Retrospective Studies; Senotherapeutics
PubMed: 34772496
DOI: 10.1016/j.mayocp.2021.06.025 -
Cell Cycle (Georgetown, Tex.) 2018Aging is characterized by progressive decay of biological systems and although it is not considered a disease, it is one of the main risk factors for chronic diseases... (Review)
Review
Aging is characterized by progressive decay of biological systems and although it is not considered a disease, it is one of the main risk factors for chronic diseases and many types of cancers. The accumulation of senescent cells in various tissues is thought to be a major factor contributing to aging and age-related diseases. Removal of senescent cells during aging by either genetic or therapeutic methods have led to an improvement of several age related disease in mice. In this preview, we highlight the significance of developing senotherapeutic approaches to specifically kill senescent cells (senolytics) or suppress the senescence-associated secretory phenotype (SASP) that drives sterile inflammation (senomorphics) associated with aging to extend healthspan and potentially lifespan. Also, we provide an overview of the senotherapeutic drugs identified to date. In particular, we discuss and expand upon the recent identification of inhibitors of the HSP90 co-chaperone as a new class of senolytics.
Topics: Aging; Animals; Antioxidants; Apoptosis; Cellular Senescence; Dasatinib; Drug Discovery; Drug Therapy, Combination; HSP90 Heat-Shock Proteins; Healthy Aging; Humans; Idiopathic Pulmonary Fibrosis; Mice; Protein Kinase Inhibitors; Quercetin
PubMed: 29886783
DOI: 10.1080/15384101.2018.1475828