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International Journal of Molecular... Aug 2023Pulmonary arterial hypertension (PAH) is a complex disorder characterized by vascular remodeling and a consequent increase in pulmonary vascular resistance. The... (Review)
Review
Pulmonary arterial hypertension (PAH) is a complex disorder characterized by vascular remodeling and a consequent increase in pulmonary vascular resistance. The histologic hallmarks of PAH include plexiform and neointimal lesions of the pulmonary arterioles, which are composed of dysregulated, apoptosis-resistant endothelial cells and myofibroblasts. Platelet-derived growth factor receptors (PDGFR) α and β, colony stimulating factor 1 receptor (CSF1R), and mast/stem cell growth factor receptor kit (c-KIT) are closely related kinases that have been implicated in PAH progression. In addition, emerging data indicate significant crosstalk between PDGF signaling and the bone morphogenetic protein receptor type 2 (BMPR2)/transforming growth factor β (TGFβ) receptor axis. This review will discuss the importance of the PDGFR-CSF1R-c-KIT signaling network in PAH pathogenesis, present evidence that the inhibition of all three nodes in this kinase network is a potential therapeutic approach for PAH, and highlight the therapeutic potential of seralutinib, currently in development for PAH, which targets these pathways.
Topics: Humans; Pulmonary Arterial Hypertension; Endothelial Cells; Familial Primary Pulmonary Hypertension; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-kit
PubMed: 37628831
DOI: 10.3390/ijms241612653 -
Leukemia Dec 2023Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel...
Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel dasatinib anhydrate containing formulation was to demonstrate improved absorption and lower pharmacokinetic variability compared to dasatinib monohydrate. In a bioavailability study comparing formulations containing 110.6 mg and 140 mg of dasatinib as anhydrate and monohydrate, respectively, both C and AUC of dasatinib were within standard 80.00-125.00% range, while the intra- and inter-subject variability for AUC after the test product was approximately 3-fold and 1.5-fold less than after the reference, respectively.In a drug-drug interaction study, omeprazole 40 mg reduced the mean AUC of dasatinib by 19%, when the test was ingested 2 h before the 5th omeprazole dose. This decrease of exposure is clinically irrelevant and substantially less than after the reference. Co-prescription analysis supports the importance of pH-dependent solubility of dasatinib, as >21% of patients were treated concomitantly with a PPI and dasatinib despite warnings against this co-medication in the SmPC.The novel dasatinib anhydrate containing formulation demonstrated improved absorption and less pharmacokinetic variability compared to dasatinib monohydrate product, which may translate into improved clinical outcomes, although this needs to be proven by an appropriate trial.
Topics: Humans; Dasatinib; Biological Availability; Omeprazole; Cross-Over Studies; Area Under Curve; Administration, Oral
PubMed: 37789147
DOI: 10.1038/s41375-023-02045-1 -
NPJ Precision Oncology Feb 2024Cancer cell growth, metastasis, and drug resistance pose significant challenges in the management of lung adenocarcinoma (LUAD). However, there is a deficiency in...
Cancer cell growth, metastasis, and drug resistance pose significant challenges in the management of lung adenocarcinoma (LUAD). However, there is a deficiency in optimal predictive models capable of accurately forecasting patient prognoses and guiding the selection of targeted treatments. Programmed cell death (PCD) pathways play a pivotal role in the development and progression of various cancers, offering potential as prognostic indicators and drug sensitivity markers for LUAD patients. The development and validation of predictive models were conducted by integrating 13 PCD patterns with comprehensive analysis of bulk RNA, single-cell RNA transcriptomics, and pertinent clinicopathological details derived from TCGA-LUAD and six GEO datasets. Utilizing the machine learning algorithms, we identified ten critical differentially expressed genes associated with PCD in LUAD, namely CHEK2, KRT18, RRM2, GAPDH, MMP1, CHRNA5, TMPRSS4, ITGB4, CD79A, and CTLA4. Subsequently, we conducted a programmed cell death index (PCDI) based on these genes across the aforementioned cohorts and integrated this index with relevant clinical features to develop several prognostic nomograms. Furthermore, we observed a significant correlation between the PCDI and immune features in LUAD, including immune cell infiltration and the expression of immune checkpoint molecules. Additionally, we found that patients with a high PCDI score may exhibit resistance to immunotherapy and standard adjuvant chemotherapy regimens; however, they may benefit from other FDA-supported drugs such as docetaxel and dasatinib. In conclusion, the PCDI holds potential as a prognostic signature and can facilitate personalized treatment for LUAD patients.
PubMed: 38409471
DOI: 10.1038/s41698-024-00538-5 -
Clinical Lymphoma, Myeloma & Leukemia Sep 2023Treatment outcomes for children with Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL) remained poor despite the use of intensive chemotherapy,... (Review)
Review
Treatment outcomes for children with Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL) remained poor despite the use of intensive chemotherapy, imatinib or dasatinib, and consolidative allogeneic hematopoietic cell transplantation. Oleverembatinib, a third-generation ABL inhibitor, was found to be highly effective and safe in adults with chronic myeloid leukemia and in some adults with relapsed or refractory Ph ALL. We reviewed the efficacy and safety profile of olverembatinib treatment in 6 children with relapsed Ph ALL and 1 with T-ALL and ABL class fusion, all of whom had previously received dasatinib or intolerance to dasatinib. The median duration of olverembatinib treatment was 70 days (range: 4-340) and the median cumulative dose was 600 mg (range: 80-3810). Complete remission with negative minimal residual level (<0.01%) was achieved in 4 of the 5 evaluable patients, 2 of whom were treated with olvermbatinib as a single agent. Safety profile in 6 evaluable patients was excellent with grade 2 extremity pain occurred in 2 patients and grade 2 myopathy of lower extremity and grade 3 fever in 1 patient each. Olverembatinib appeared to be safe and effective in children with relapsed Ph ALL.
Topics: Adult; Humans; Child; Dasatinib; Protein Kinase Inhibitors; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Fusion Proteins, bcr-abl
PubMed: 37301632
DOI: 10.1016/j.clml.2023.04.012 -
Cellular & Molecular Biology Letters Aug 2023Peripheral nerve damage causes neuroinflammation, which plays a critical role in establishing and maintaining neuropathic pain (NeP). The mechanisms contributing to...
BACKGROUND
Peripheral nerve damage causes neuroinflammation, which plays a critical role in establishing and maintaining neuropathic pain (NeP). The mechanisms contributing to neuroinflammation remain poorly elucidated, and pharmacological strategies for NeP are limited. Thus, in this study, we planned to explore the possible link between astrocyte senescence and NeP disorders following chronic sciatic nerve injury.
METHODS
An NeP animal model was established by inducing chronic constrictive injury (CCI) to the sciatic nerve in adult rats. A senolytic drug combination of dasatinib and quercetin was gavaged daily from the first postoperative day until the end of the study. Paw mechanical withdrawal threshold (PMWT) and paw thermal withdrawal latency (PTWL) were evaluated to assess behaviors in response to pain in the experimental rats. Senescence-associated β-galactosidase staining, western blot analysis, and immunofluorescence were applied to examine the levels of proinflammatory factors and severity of the senescence-like response in the spinal cord. Lipopolysaccharide (LPS) was administered to induce senescence of spinal astrocytes in primary cultures in vitro, to explore the potential impacts of senescence on the secretion of proinflammatory factors. Furthermore, single-cell RNA sequencing (scRNA-seq) was conducted to identify senescence-related molecular responses in spinal astrocytes under neuropathic pain.
RESULTS
Following sciatic nerve CCI, rats exhibited reduced PMWT and PTWL, increased levels of spinal proinflammatory factors, and an enhanced degree of senescence in spinal astrocytes. Treatment with dasatinib and quercetin effectively attenuated spinal neuroinflammation and mitigated the hypersensitivities of the rats subjected to sciatic nerve CCI. Mechanistically, the dasatinib-quercetin combination reversed senescence in LPS-stimulated primary cultured astrocytes and decreased the levels of proinflammatory factors. The scRNA-seq data revealed four potential senescence-related genes in the spinal astrocyte population, and the expression of clusterin (CLU) protein was validated via in vitro experiments.
CONCLUSION
The findings indicate the potential role of astrocyte senescence in neuroinflammation following peripheral nerve injury, and suggest that targeting CLU activation in astrocytes might provide a novel therapeutic strategy to treat NeP.
Topics: Rats; Animals; Astrocytes; Peripheral Nerve Injuries; Dasatinib; Neuroinflammatory Diseases; Lipopolysaccharides; Quercetin; Neuralgia
PubMed: 37582709
DOI: 10.1186/s11658-023-00474-5 -
Cardiovascular Diabetology Aug 2023Cardiac steatosis is an early yet overlooked feature of diabetic cardiomyopathy. There is no available therapy to treat this condition. Tyrosine kinase inhibitors (TKIs)...
BACKGROUND
Cardiac steatosis is an early yet overlooked feature of diabetic cardiomyopathy. There is no available therapy to treat this condition. Tyrosine kinase inhibitors (TKIs) are used as first or second-line therapy in different types of cancer. In cancer patients with diabetes mellitus, TKIs reportedly improved glycemic control, allowing insulin discontinuation. They also reduced liver steatosis in a murine model of non-alcoholic fatty liver disease. The present study aimed to determine the therapeutic effect of the second-generation TKI Dasatinib on lipid accumulation and cardiac function in obese, type 2 diabetic mice. We also assessed if the drug impacts extra-cardiac fat tissue depots.
METHODS
Two studies on 21-week-old male obese leptin receptor mutant BKS.Cg-+Leprdb/+Leprdb/OlaHsd (db/db) mice compared the effect of Dasatinib (5 mg/kg) and vehicle (10% DMSO + 90% PEG-300) given via gavage once every three days for a week or once every week for four weeks. Functional and volumetric indices were studied using echocardiography. Post-mortem analyses included the assessment of fat deposits and fibrosis using histology, and senescence using immunohistochemistry and flow cytometry. The anti-adipogenic action of Dasatinib was investigated on human bone marrow (BM)-derived mesenchymal stem cells (MSCs). Unpaired parametric or non-parametric tests were used to compare two and multiple groups as appropriate.
RESULTS
Dasatinib reduced steatosis and fibrosis in the heart of diabetic mice. The drug also reduced BM adiposity but did not affect other fat depots. These structural changes were associated with improved diastolic indexes, specifically the E/A ratio and non-flow time. Moreover, Dasatinib-treated mice had lower levels of p16 in the heart compared with vehicle-treated controls, suggesting an inhibitory impact of the drug on the senescence signalling pathway. In vitro, Dasatinib inhibited human BM-MSC viability and adipogenesis commitment.
CONCLUSIONS
Our findings suggest that Dasatinib opposes heart and BM adiposity and cardiac fibrosis. In the heart, this was associated with favourable functional consequences, namely improvement in an index of diastolic function. Repurposing TKI for cardiac benefit could address the unmet need of diabetic cardiac steatosis.
Topics: Humans; Male; Animals; Mice; Dasatinib; Tyrosine Kinase Inhibitors; Diabetes Mellitus, Experimental; Protein Kinase Inhibitors; Non-alcoholic Fatty Liver Disease; Fibrosis; Diabetes Mellitus, Type 2
PubMed: 37592236
DOI: 10.1186/s12933-023-01955-9 -
MedComm Oct 2023Cellular senescence plays a pivotal role in wound healing. At the initiation of liver fibrosis regression, accumulated senescent cells were detected and genes of...
Cellular senescence plays a pivotal role in wound healing. At the initiation of liver fibrosis regression, accumulated senescent cells were detected and genes of senescence were upregulated. Flow cytometry combined with single-cell RNA sequencing analyses revealed that most of senescent cells were liver nonparenchymal cells. Removing senescent cells by dasatinib and quercetin (DQ), alleviated hepatic cellular senescence, impeded fibrosis regression, and disrupted liver sinusoids. Clearance of senescent cells not only decreased senescent macrophages but also shrank the proportion of anti-inflammatory M2 macrophages through apoptotic pathway. Subsequently, macrophages were depleted by clodronate, which diminished hepatic senescent cells and impaired fibrosis regression. Mechanistically, the change of the epigenetic regulator enhancer of zeste homolog2 (EZH2) accompanied with the emergence of hepatic senescent cells while liver fibrosis regressed. Blocking EZH2 signaling by EPZ6438 reduced hepatic senescent cells and macrophages, decelerating liver fibrosis regression. Moreover, the promoter region of EZH2 was transcriptionally suppressed by Notch-Hes1 (hairy and enhancer of split 1) signaling. Disruption of Notch in macrophages using Lyz2 (lysozyme 2) -RBP-J (recombination signal binding protein Jκ) transgenic mice, enhanced hepatic cellular senescence, and facilitated fibrosis regression by upregulating EZH2 and blocking EZH2 abrogated the above effects caused by Notch deficiency. Ultimately, adopting Notch inhibitor Ly3039478 or exosome-mediated RBP-J decoy oligodeoxynucleotides accelerated liver fibrosis regression by augmenting hepatic cellular senescence.
PubMed: 37614965
DOI: 10.1002/mco2.346 -
Journal For Immunotherapy of Cancer Oct 2023Immunotherapy, in the form of hematopoietic stem cell transplantation (HSCT), has been part of the standard of care in the treatment of acute leukemia for over 40 years....
Immunotherapy, in the form of hematopoietic stem cell transplantation (HSCT), has been part of the standard of care in the treatment of acute leukemia for over 40 years. Trials evaluating novel immunotherapeutic approaches, such as targeting the programmed death-1 (PD-1) pathway, have unfortunately not yielded comparable results to those seen in solid tumors. Major histocompatibility complex (MHC) proteins are cell surface proteins essential for the adaptive immune system to recognize self versus non-self. MHC typing is used to determine donor compatibility when evaluating patients for HSCT. Recently, loss of MHC class II (MHC II) was shown to be a mechanism of immune escape in patients with acute myeloid leukemia after HSCT. Here we report that treatment with the tyrosine kinase inhibitor, dasatinib, and an anti-PD-1 antibody in preclinical models of Philadelphia chromosome positive B-cell acute lymphoblastic leukemia is highly active. The dasatinib and anti-PD-1 combination reduces tumor burden, is efficacious, and extends survival. Mechanistically, we found that treatment with dasatinib significantly increased MHC II expression on the surface of antigen-presenting cells (APC) in a tumor microenvironment-independent fashion and caused influx of APC cells into the leukemic bone marrow. Finally, the induction of MHC II may potentiate immune memory by impairing leukemic engraftment in mice previously cured with dasatinib, after re-inoculation of leukemia cells. In summary, our data suggests that anti-PD-1 therapy may enhance the killing ability of dasatinib via dasatinib driven APC growth and expansion and upregulation of MHC II expression, leading to antileukemic immune rewiring.
Topics: Animals; Humans; Mice; Dasatinib; Histocompatibility Antigens Class II; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Tumor Microenvironment
PubMed: 37793852
DOI: 10.1136/jitc-2022-006619 -
Nature Communications Jan 2024Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for...
Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings.
Topics: Carrier Proteins; Proteolysis; Ubiquitin; Ubiquitin-Protein Ligases; Proteolysis Targeting Chimera
PubMed: 38177131
DOI: 10.1038/s41467-023-44237-4 -
International Journal of Molecular... Dec 2023Uterine aging is the process of the senescence of uterine tissue, observed in all middle-aged mammals. Since the aging-related changes in the uterus are associated with... (Review)
Review
Uterine aging is the process of the senescence of uterine tissue, observed in all middle-aged mammals. Since the aging-related changes in the uterus are associated with infertility and poor pregnancy outcomes, with a lack of studies discussing uterine aging, authors reviewed uterine aging and its consequences on reproduction. MEDLINE, Scopus, and PubMed searches during the years 1990-2023 were performed using a combination of keywords and terms on such topics. According to the author's evaluation, articles were identified, selected, and included in this narrative review. The aging process has an unfavorable impact on the uterus of mammals. There are different and selected molecular pathways related to uterine aging in humans and animals. Uterine aging impairs the function of the uterine myometrium, neurofibers of the human uterus, and human endometrium. These biological pathways modulate oxidative stress, anti-inflammatory response, inflammation, mitochondrial function, DNA damage repair, etc. All these dysregulations have a role in poorer reproductive performance and pregnancy outcomes in older mammals. The most recent data suggest that uterine aging is accompanied by genetic, epigenetic, metabolic, and immunological changes. Uterine aging has a negative impact on the reproductive performance in mammalian species, but it could be potentially modulated by pharmacological agents, such as quercetin and dasatinib.
Topics: Animals; Female; Humans; Middle Aged; Pregnancy; Aged; Uterus; Aging; Endometrium; Mammals; Biological Products
PubMed: 38203493
DOI: 10.3390/ijms25010322