Imatinib Research Articles

Significance of monitoring imatinib plasma concentration in second-line treatment decisions for c-kit 11 gene-mutated gastrointestinal stromal tumors.

For patients with advanced gastrointestinal stromal tumors (GISTs) carrying the c-kit exon 11 mutation, imatinib (IM) at a standard dosage of 400 mg per day is the preferred first-line treatment. In cases where treatment with IM fails, there is an urgent need for a more precise assessment method to determine whether to switch therapies or escalate the IM dosage. This approach will enhance clinical decision-making and optimize patient outcomes. To investigate IM plasma concentration's role in second-line treatment decisions for c-kit 11-mutated advanced GISTs post-IM failure. Patients with advanced GIST harboring c-kit 11 mutation who experienced failure with IM 400 mg per day as first-line treatment at our hospital were retrospectively analyzed. Patients were categorized into a low plasma (LP) concentration group (LP group, < 1100 ng/mL) and high plasma (HP) concentration group (HP group, ≥ 1100 ng/mL). Each group was further subdivided into Group A (dose-escalation group) and Group B (drug-switch group). Baseline characteristics were compared and Kaplan-Meier curves were used to analyze the survival of patients. Seventy-five patients were included in the analysis. For the LP group (n = 28), Group A (n = 14) had longer overall survival (OS) than Group B (n = 14) (P = 0.02). No differences were observed between the two subgroups in disease control rate (DCR), objective response rate, and progression-free survival (PFS) (P > 0.05). For the HP group (n = 47), Group B (n = 18) had a higher DCR and longer PFS than Group A (n = 29) (P = 0.008 and P = 0.03, respectively). No difference in OS was observed between the two subgroups (P > 0.05). Increasing IM dosage for c-kit 11-mutated advanced GISTs post-IM failure may prolong OS if plasma concentration is < 1100 ng/mL. Switching tyrosine kinase inhibitors may improve DCR and PFS if ≥ 1100 ng/mL.

Rapidly Growing Gastrointestinal Stromal Tumor on the Esophagus

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms that mainly occur in the stomach and small intestine; those arising in the esophagus are rarer. A 54-year-old woman was referred to our hospital with a one-month history of dysphagia. Esophagogastroduodenoscopy (EGD), performed approximately five months earlier, had not revealed any specific findings. However, an EGD performed in our hospital showed the presence of a round, protruding lesion (approximately 40×30 mm in size), with a normal overlying mucosal surface, 35–39 cm from the upper incisor. Chest computed tomography (CT) revealed a large esophageal mass. Enucleation was performed on the esophageal mass, and a GIST was diagnosed using immunochemical staining. Imatinib mesylate administration was initiated two months postoperatively. The patient was stable, without any evident recurrence in the 8-month postoperative follow-up EGD and chest CT examinations. Therefore, physicians should consider that patients with worsening dysphagia may have an underlying organic condition, such as an acute increase in size of an esophageal GIST, even if recent examinations were unremarkable.

Synergistic Effects of Green Nanoparticles on Antitumor Drug Efficacy in Hepatocellular Cancer

Background/Objectives: Cancer remains one of the leading causes of mortality worldwide. Despite significant advancements in treatment strategies and drug development, survival rates remain low and the adverse effects of conventional therapies severely impact patients’ quality of life. This study evaluates the therapeutic potential of plant-derived extracts in hepatocellular carcinoma treatment, with a focus on minimizing side effects while enhancing efficacy. Methods: This research investigates the in vitro synergistic effect of silver bio-nanoparticles synthesized from Clematis vitalba, Melissa officinalis, and Taraxacum officinale extracts (Clematis vitalbae extractum—CVE, Melissae extractum—ME, Taraxaci extractum—TE) in combination with liver cancer drugs, sunitinib (SNTB) and imatinib (IMTB), on HepG2 (human hepatocellular carcinoma) and HUVEC (human umbilical vein endothelial) cell lines. The silver nanoparticles (AgNPs) were characterized using UV-Vis spectroscopy, dynamic light scattering (DLS), zeta potential analysis, and scanning electron microscopy (SEM). The antitumor effects were evaluated through cell viability assays after 24 and 48 h of exposure, with additional cytotoxicity tests on HUVEC cells. Results: Results indicated that Melissa officinalis-derived silver nanoparticles (ME AgNPs) and Clematis vitalba extract with silver nanoparticles (CVE AgNPs) significantly reduced HepG2 cell viability. Their efficacy improved when combined with conventional therapies (SNTB + ME AgNPs 1:1 vs. SNTB: 20.01% vs. 25.73%, p = 0.002; IMTB + ME AgNPs 1:1 vs. IMTB: 17.80% vs. 18.08%, p = 0.036; SNTB + CVE AgNPs 1:1 vs. SNTB: 18.73% vs. 25.73%, p = 0.000; SNTB + CVE AgNPs 1:2 vs. SNTB: 26.62% vs. 41.00%, p = 0.018; IMTB + CVE AgNPs 1:1 vs. IMTB: 12.99% vs. 18.08%, p = 0.001). Taraxacum extract exhibited similar cytotoxicity to its nanoparticle formulation but did not exceed the efficacy of the extract alone at 24 h. Selectivity index assessments confirmed that AgNPs-based formulations significantly improve cytotoxicity and selectivity to HepG2 cells. Among the tested extracts, CVE demonstrated the strongest antitumor effect, enhancing the efficacy of synthetic drugs (CI &lt; 1). SNTB + TE AgNPs (5% EtOH) also demonstrated consistent synergy at high doses, while SNTB + CVE AgNPs provided broad-range synergy, making it suitable for dose-escalation strategies. Conclusions: These findings underscore the potential of nanoparticle-based formulations in combination therapies with targeted kinase inhibitors such as sunitinib and imatinib. Future research should focus on in vivo validation and clinical trials to confirm these findings.

Tenascin-C Facilitates Microglial Polarization via TLR4/MyD88/NF-κB Pathway Following Subarachnoid Hemorrhage.

This study primarily aims to elucidate the underlying mechanism of Tenascin-C in neuroinflammation and microglia polarization in a mouse model of subarachnoid hemorrhage (SAH). The subarachnoid hemorrhage model was constructed by injecting blood into the anterior chiasmatic cistern and stimulating primary microglia with hemoglobin in vitro. Then, Imatinib mesylate was used to inhibit Tenascin-C. Through neurological function scoring, brain edema, primary cell extraction, immunofluorescence staining, CCK8, Tunel staining, Elisa, Western blot and other methods, the potential mechanism of Tenascin-C induced microglia cell polarization was explored. The results of this study observed that the expression of Tenascin-C was up-regulated after subarachnoid hemorrhage. Inhibiting the increase of Tenascin-C by imatinib could significantly ameliorate neuroinflammation, neuronal apoptosis, blood brain barrier disruption and brain edema. When the level of Tenascin-C decreased, the numbers of TLR4 positive, MyD88 positive and NF-κB positive microglial cells decreased accordingly. Moreover, after subarachnoid hemorrhage, the number of microglial cells positive for M1-type markers increased significantly. After imatinib inhibited Tenascin-C, the number of M1-type microglial cells decreased and the number of M2-type microglial cells increased significantly. In summary, the elevated level of Tenascin-C after subarachnoid hemorrhage induces the activation of microglia, releasing a large number of inflammatory factors and aggravating early brain injury.

Inflammatory biomarker correlations and prognosis in high-risk gastrointestinal stromal tumor patients: a multicenter retrospective analysis

BackgroundThe accurate prognosis of gastrointestinal stromal tumors (GISTs) has garnered substantial attention, yet a gap persists in understanding the influence of inflammatory markers on the prognosis of high-risk GIST patients. This study investigated the relationship between various factors and the prognosis of high-risk GIST patients, with a specific focus on first recurrence-free survival (RFS) and overall survival (OS) as crucial prognostic indicators.MethodsA comprehensive collection of clinical data was conducted on 145 high-risk GIST patients meeting specific inclusion and exclusion criteria at 17 medical centers in Ningxia Hui Autonomous Region, China, covering the period from January 2013 to December 2019. Single-factor analysis and survival curves were used to analyze the variables, while the Cox regression model evaluated independent prognostic factors.ResultsWithin the cohort, a balanced male-to-female ratio of 1:1.1 was observed. Univariate analysis revealed compelling associations between RFS and age, preoperative neutrophil-to-lymphocyte ratio (NLR), preoperative platelet-to-lymphocyte ratio (PLR), preoperative systemic immune-inflammatory index (SII), preoperative prognostic nutritional index (PNI), mitotic index, and whether or not imatinib (IM) was taken regularly in high-risk GIST patients (P < 0.05). Except age, these other variables were also significantly correlated with OS (P < 0.05). Cox regression analysis showed that age, preoperative PNI, mitotic index and postoperative IM adjuvant therapy independently affected RFS (P < 0.05). In addition, preoperative PNI and postoperative IM adjuvant therapy were also independent factors of OS, with statistical significance (P < 0.05). Age was negatively correlated with RFS, and early routine IM treatment after operation significantly reduced the risk of recurrence and death. Higher mitotic index is closely related to poor RFS, and higher preoperative PNI indicates a better prognosis.ConclusionA close correlation between young age, low preoperative PNI, high mitotic index, and lack of IM treatment had an unfavorable prognosis in high-risk GIST patients. Notably, the PNI was identified as a potential additional prognostic factor, enhancing the accuracy of predicting treatment efficacy and patient outcomes in high-risk patients with GISTs. Therefore, we advocate for the serious consideration of the PNI as a valuable addition to standard clinical practice for managing high-risk GIST patients.

Chitosan-Coated Silver Nanourchins for Imatinib Mesylate Delivery: Biophysical Characterization, In-Silico Profiling, and Anti-Colon Cancer Efficacy.

This study investigates the synthesis and characterization of silver nanourchins coated with chitosan (IMT-CS-AgNUs) as a novel platform for the delivery of imatinib mesylate (IMT) for the treatment of colon cancer. In-silico analysis discovered 10 key metabolites for IMT, which have associated respiratory and neurotoxic risks. Molecular docking studies showed the high affinity binding of IMT to critical proteins, including BCL2 (-6.637 kcal/mol), Caspase-6, and EGFR, which proved its potential therapeutic value. IMT-CS-AgNUs were prepared by ionic gelation, and the nanoparticles had a size of 192.98 nm, with an entrapment efficiency of 85.7%. The FTIR and XRD structural characterization confirmed that the nanocarriers were stable and amorphous in nature. In vitro studies of HCT116 cells showed significantly increased cytotoxicity with an IC50 of 0.4 μg/mL; apoptosis by 42.5% and ROS generation by 47.8% when compared to only IMT. The release of drugs from the nanoparticles was sustained over 85% over 60 h, selectively inhibited pathogenic bacteria without harming beneficial microbes, and showed antiangiogenic activity, which is validated through the HET-CAM assay. Gene expression analyses showed that there was marked downregulation of BCL2 and upregulation of apoptotic genes. Pharmacokinetic studies in Wistar rats showed improved bioavailability by 1.8, which allows targeted drug concentrations in the colon with lessened systemic toxicity. Thus, the development of IMT-CS-AgNUs represents a potent approach for targeted colon therapy against cancer, providing therapeutic efficacy, controlled drug release, and added safety.

CDK8/19 inhibition attenuates G1 arrest induced by BCR-ABL antagonists and accelerates death of chronic myelogenous leukemia cells

Imatinib mesylate (IM) and other BCR-ABL tyrosine kinase inhibitors (BCR-ABLi) are the mainstay of chronic myelogenous leukemia (CML) treatment. However, activation of circumventing signaling pathways and quiescence may limit BCR-ABLi efficacy. CDK8/19 Mediator kinases have been implicated in the emergence of non-genetic drug resistance. Dissecting the effects of pharmacological CDK8/19 inhibition on CML survival in response to BCR-ABLi, we found that a selective, non-toxic CDK8/19 inhibitor (CDK8/19i) Senexin B (SenB) and other CDK8/19i sensitized K562 cells to different BCR-ABLi via attenuation of cell cycle arrest. In particular, SenB prevented IM-induced upregulation of genes that negatively regulate cell cycle progression. SenB also antagonized IM-activated p27Kip1 elevation thereby diminishing the population of G1-arrested cells. After transient G1 arrest, cells treated with IM + SenB re-entered the S phase, where they were halted and underwent replicative stress. Consequently, the combination of IM and SenB intensified apoptotic cell death, measured by activation of caspase 9 and 3, subsequent cleavage of poly(ADPriboso)polymerase 1, positive Annexin V staining and increase of subG1 fraction. In contrast, IM-treated BCR-ABL-positive KU812 CML cells, which did not induce p27Kip1, readily died regardless of SenB treatment. Thus, CDK8/19i prevent the quiescence-mediated escape from BCR-ABLi-induced apoptosis, suggesting a strategy for avoiding the CML relapse.

Compatibility Studies of Different Crystal Forms of Imatinib Mesylate with Pharmaceutical Excipients.

Imatinib mesylate has been identified as a tyrosine kinase inhibitor that selectively inhibits Abl tyrosine kinases, including Bcr-Abl. It exhibits many polymorphic forms, with the most stable and commercialized polymorphs known as the α and β forms. In the present study, the compatibility between the polymorphs of Imatinib mesylate and selected excipients (MCC, HPMC, PVPP, SiO2, MS, and CaHPO4) was investigated by differential scanning calorimetry (DSC), Raman spectra, X-ray diffraction (XRD) technique, and isothermal stress testing (IST). The results revealed that polymorph α of Imatinib mesylate has poor compatibility with selected excipients at high temperatures. As a contrary, polymorph β of Imatinib mesylate shows high compatibility with the selected excipients except MS under high temperatures.

Final analysis of the GMALL-PH-01 trial: phase II study of standard chemotherapy in combination with dasatinib in first line treatment of Philadelphia chromosome positive acute lymphoblastic leukemia

Imatinib (IMA) plus chemotherapy followed by allogeneic hematopoietic cell transplantation (HCT) is established treatment for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). We investigated the use of dasatinib (DASA) combined with intensive chemotherapy in ALL (18–55 years) first-line in a prospective, multicenter phase II trial by the GMALL study group. 140 mg DASA QD was used with a pediatric-based induction and consolidation chemotherapy according to GMALL 07/2003 protocol with recommended consecutive HCT. Nineteen of 20 planned patients were enrolled in 12 centers. The hematologic CR rate after induction was 79% with an overall MRD negativity rate of 62.5%. Six patients died during induction and two discontinued therapy. This regimen achieved deep molecular responses but was associated with a higher than expected early mortality (21%) and was stopped prematurely due to toxicities. The GMALL therefore adopted a combination of low intensity chemotherapy plus IMA as its current induction regimen.

REPEATED THERAPEUTIC LEUKAPHERESIS - A SOLE TREATMENT DURING PREGNANCY AS A BRIDGE BEFORE TYROSINE KINASE INHIBITORS FOR A PREGNANT WOMAN WITH CHRONIC MYELOGENOUS LEUKEMIA – A CASE REPORT AND DISCUSSION

Objective: Chronic myelogenous leukemia (CML) is a disease, that in cases with high leukocyte numbers, is treated with hydration and cytoreductive therapy. Materials and Methods:A 20-year-old female patient, during a routine examination for pregnancy, presented with elevated white blood cells (WBC) count (over 275x109/L) and splenomegaly without any complaints. The diagnosis of Ph-positive CML was confirmed by cytology and PCR [presence of p210 type BCR::ABL1 [e13a2 (b2a2)] transcripts. Since she was in her 6th month of pregnancy, abortion or conventional treatment (tyrosine kinase inhibitors (TKI), chemotherapy and/or allogeneic haematopoietic stem cell transplant) were contraindicated due to the high risk for both the mother and the fetus. The patient was treated with two consecutive leukaphereses followed by weekly apheresis for about 3,5 months until the day of the delivery. Each procedure included the processing of 1000-1200 ml of whole blood with the separation of around 600 ml white blood cell concentrate and plasma. Results:The patient's WBC count was kept between 170 and 270 x 109/L until childbirth, and immediately after delivery, imatinib mesylate therapy was initiated.A healthy male child with a weight of 2250 kg and height of 46 сm was born. The mother achieved hematologic, cytogenetic and molecular remission within the next 6-9 months after initiation of tyrosine kinase inhibitor therapy. Discussion: The classical treatment for CML includes tyrosine kinase inhibitors, chemotherapy and/or allogeneic haematopoietic stem cell transplantation. All of these approaches have teratogenic potential, and therapeutic schemes should involve contraception. In cases with existing advanced pregnancy, therapeutic leukapheresis is a valid option for controlling WBC counts until the delivery date. Despite the later initiation of TKI therapy, the deep molecular response is still present thirteen years after the initiation of therapy.

Poly Lactic Co-glycolic Acid d-α-tocopheryl Polyethylene Glycol 1000 Succinate Fabricated Polyethylene Glycol Hybrid Nanoparticles of Imatinib Mesylate for the Treatment of Glioblastoma Multiforme.

This study aimed to develop Imatinib Mesylate (IMT)-loaded Poly Lactic-co-Glycolic Acid (PLGA)-D-α-tocopheryl polyethylene glycol succinate (TPGS)- Polyethylene glycol (PEG) hybrid nanoparticles (CSLHNPs) with optimized physicochemical properties for targeted delivery to glioblastoma multiforme. Glioblastoma multiforme (GBM) is the most destructive type of brain tumor with several complications. Currently, most treatments for drug delivery for this disease face challenges due to the poor blood-brain barrier (BBB) and lack of site-specific delivery. Imatinib Mesylate (IMT) is one of the most effective drugs for GBM, but its primary issue is low bioavailability. Therefore, nanotechnology presents a promising solution for targeted IMT delivery to GBM. This article primarily explores the fabrication of IMT-loaded core-shell lipid-polymer hybrid nanoparticles (CSLHNPs) to achieve enhanced brain delivery with therapeutic efficacy. The primary objective of this study is to develop optimized, stable IMT-loaded hybrid nanoparticles with an encapsulated polymer matrix and to evaluate these nanoparticles using sophisticated instruments such as SEM and TEM to achieve smooth, spherical nanoparticles in a monodispersed phase. The enhanced stable formulation yielded a notable increase in entrapment efficiency, reaching 58.89 ± 0.5%. The physical stability analysis of nanoparticles was assessed over 30 days under conditions of 25 ± 2°C and 60 ± 5% relative humidity. Hemolytic assays affirmed the biocompatibility and safety profile of the nanoparticles. in vitro drug release kinetics revealed a sustained IMT release over 48 hours. The formulated CSLHNPs achieved a narrow size distribution with a mean vesicle diameter of 155.03 ± 2.41 nm and a low polydispersity index (PDI) of 0.23 ± 0.4, indicating monodispersity. A high negative zeta potential of -23.89 ± 3.47 mV ensured excellent colloidal stability in physiological conditions. XRD analysis confirmed the successful encapsulation of IMT within the nanoparticle matrix, with the drug transitioning to an amorphous state for enhanced dissolution. During Cell-Cell viability assays on LN229, glioblastoma cells were treated with IMT-loaded nanoparticles and showed a significantly enhanced inhibitory effect compared to free IMT. These hybrid nanoparticles demonstrated potential in reducing oxidative stress-induced cellular damage by mitigating reactive oxygen species (ROS). Thus, the prepared IMT hybrid nanoparticles showed higher cellular uptake and superior cytotoxicity compared to the plain drug. This study posits the IMT-PLGA-TPGS-DSPE PEG 2000-CSPLHNPs as a formidable and innovative drug delivery system for Glioblastoma Multiforme (GBM) treatment, warranting further exploration into their clinical application potential. Future work could involve conducting in vivo studies to evaluate the pharmacokinetics, biodistribution, and therapeutic efficacy of the IMT-PLGA-TPGS-DSPE PEG 2000-CSPLHNPs in animal models of Glioblastoma Multiforme (GBM). Additionally, further research may focus on optimizing the nanoparticle formulation for enhanced targeting capabilities, investigating long-term stability under varied storage conditions, exploring potential combination therapies to synergize with the nanoparticles, and assessing the scalability and manufacturability of the developed drug delivery system for potential clinical translation. Integration of advanced imaging techniques for real- time tracking and visualization of nanoparticle distribution within tumours could also be a promising direction for future investigations.

Impact of First- and Second-Generation Tyrosine Kinase Inhibitors on the Development of Graft-Versus-Host Disease in Individuals with Chronic Myeloid Leukemia: A Retrospective Analysis on Behalf of the Polish Adult Leukemia Group.

Background: The implementation of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) has brought a significant improvement in the prognosis for CML patients and a decrease in the number of patients requiring allogeneic hematopoietic stem cell transplantation (allo-HCT). Nevertheless, the impact of TKIs on allo-HCT outcomes has not been thoroughly explored. Objectives: The main endpoint of our research was to assess the impact of prior TKI treatment on acute graft-versus-host disease (aGvHD) and chronic graft-versus-host disease (cGvHD). Methods: In our retrospective analysis, we included 240 patients treated between 1993 and 2013 and divided them into three groups according to the therapy administered prior to haploidentical, matched-related, or matched-unrelated donor allo-HCT (imatinib group n = 41, dasatinib/nilotinib group n = 28, TKI-naïve group n = 171). Results: Both the cumulative incidence of aGvHD (p = 0.044) and cGvHD (p < 0.001) in individuals receiving second-generation TKIs (2G-TKIs) prior to allo-HCT were decreased compared to patients receiving no TKIs or imatinib (IMA) (40.7% vs. 61.4% vs. 70.7%, p = 0.044; 25.0% vs. 76.4% vs. 51.2%, p < 0.001, respectively). In the case of the 2G-TKI cohort, the number of low-grade aGvHD and cGvHD was significantly lower compared to the IMA and TKI-naïve groups (p = 0.018, p = 0.004; p < 0.001 versus TKI-naïve, respectively). In terms of 3-year overall survival (OS), there were no important variations between TKI-naïve, IMA, and 2G-TKI (55% vs. 49.9% vs. 69.6%, p = 0.740). Conclusions: The results of our study suggest that TKI treatment prior to allo-HCT may have a protective impact on immune-mediated outcomes.

Tyrosine Kinase Inhibitor Therapy Enhances Stem Cells Profile and May Contribute to Survival of Chronic Myeloid Leukemiastem Cells.

Background/Objectives: Treatment with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) has revolutionized disease management and has transformed CML from a life-threatening disease to a chronic condition for many patients. However, overcoming resistance, particularly related to leukemic stem cells (LSC) that can persist even when the bulk of the leukemic cells are eliminated, remains a significant challenge. Methods: K562 and KU812 cell lines were treated in vitro with the TKI Imatinib (IM). Gene expression, protein analysis, and metabolomic screening were conducted to investigate the ability of the drug to enhance stem cell (SC) features. Moreover, a gene ontology analysis was performed on different available datasets, to further consolidate our data. Results: 48 h of IM treatment can significantly increase the expression of genes related to SC self-renewal, particularly SOX2 and OCT 3/4. Interestingly, these modulations occur in cells that remain alive after drug treatment and that displayed features consistent with leukemia stem-like CML cells, suggesting that SC genes levels are crucial even in cell population survived upon TKI treatment. Moreover, after in silico analysis of available data, we observed an enrichment of SOX2/NANOG and OCT 3/4 signatures after TKI treatment, thus strengthening our results. Conclusions: Our results confirmed the relevance of LSC features after TKI treatment, highlighting the need for more effective and potentially curative strategies targeting LSCs to overcome resistance in CML.

Multi-Omics Analysis for Identifying Cell-Type-Specific Druggable Targets in Alzheimer's Disease.

Analyzing disease-linked genetic variants via expression quantitative trait loci (eQTLs) is important for identifying potential disease-causing genes. Previous research prioritized genes by integrating Genome-Wide Association Study (GWAS) results with tissue-level eQTLs. Recent studies have explored brain cell type-specific eQTLs, but they lack a systematic analysis across various Alzheimer's disease (AD) GWAS datasets, nor did they compare effects between tissue and cell type levels or across different cell type-specific eQTL datasets. In this study, we integrated brain cell type-specific eQTL datasets with AD GWAS datasets to identify potential causal genes at the cell type level. To prioritize disease-causing genes, we used Summary Data-Based Mendelian Randomization (SMR) and Bayesian Colocalization (COLOC) to integrate AD GWAS summary statistics with cell-type-specific eQTLs. Combining data from five AD GWAS, three single-cell eQTL datasets, and one bulk tissue eQTL meta-analysis, we identified and confirmed both novel and known candidate causal genes. We investigated gene regulation through enhancer activity using H3K27ac and ATAC-seq data, performed protein-protein interaction and pathway enrichment analyses, and conducted a drug/compound enrichment analysis with the Drug Signatures Database (DSigDB) to support drug repurposing for AD. We identified 27 candidate causal genes for AD using cell type-specific eQTL datasets, with the highest numbers in microglia, followed by excitatory neurons, astrocytes, inhibitory neurons, oligodendrocytes, and oligodendrocyte precursor cells (OPCs). PABPC1 emerged as a novel astrocyte-specific gene. Our analysis revealed protein-protein interaction (PPI) networks for these causal genes in microglia and astrocytes. We found the "regulation of aspartic-type peptidase activity" pathway being the most enriched among all the causal genes. AD-risk variants associated with candidate causal gene PABPC1 is located near or within enhancers only active in astrocytes. We classified the genes into three drug tiers and identified druggable interactions, with imatinib mesylate emerging as a key candidate. A drug-target gene network was created to explore potential drug targets for AD. We systematically prioritized AD candidate causal genes based on cell type-specific molecular evidence. The integrative approach enhances our understanding of molecular mechanisms of AD-related genetic variants and facilitates the interpretation of AD GWAS results.

Paeoniflorin sensitizes imatinib mesylate-resistant chronic myeloid leukemia cells via the inhibition of Cyr61 production.

Imatinib mesylate (IM) is a first-line therapy for chronic myeloid leukemia (CML) and exhibits good therapeutic effects, but not in all patients with CML owing to drug resistance. Our previous study showed that Cyr61 plays a key role in IM resistance in CML cells. Paeoniflorin (PF) is a bioactive compound isolated from the traditional Chinese medicine Paeonia lactiflora Pall that displays anticancer activity. Little is, however, known regarding the role of PF in IM-resistant CML cells. This study aimed to evaluate whether PF could decrease Cyr61 production and improve IM-resistant CML cell sensitivity to IM and to investigate the underlying mechanisms. CML cell lines (K562 and KCL22) and IM-resistant cell lines (K562G and KCL22R) were used as CML study models. Cyr61 expression was assessed in both parental and IM-resistant CML cells by western blotting, real-time quantitative PCR , and ELISA. Lentiviral vectors were used to induce the knockdown of Cyr61 expression, followed by a comprehensive evaluation of cell proliferation and apoptosis. The results showed that PF decreased the production of Cyr61 in the presence of IM by inhibiting extracellular regulated protein kinases 1/2 activation. PF significantly decreased the IC50 value of IM and increased IM-induced apoptosis of IM-resistant CML cells. Importantly, PF also improved the sensitivity of CML cells to bosutinib and dasatinib via inhibition of Cyr61 production. In conclusion, we report for the first time that PF may effectively improve the sensitivity of IM-resistant CML cells to IM, bosutinib, and dasatinib, at least in part, by subsequently downregulating Cyr61.

Bola-Amphiphilic Dendrimer Enhances Imatinib to Target Metastatic Ovarian Cancer via β-Catenin-HRP2 Signaling Axis.

Ovarian cancer is the leading cause of death among all gynecological malignancies, and drug resistance renders the current chemotherapy agents ineffective for patients with advanced metastatic tumors. We report an effective treatment strategy for targeting metastatic ovarian cancer involving a nanoformulation (Bola/IM)─bola-amphiphilic dendrimer (Bola)-encapsulated imatinib (IM)─to target the critical mediator of ovarian cancer stem cells (CSCs) CD117 (c-Kit). Bola/IM offered significantly more effective targeting of CSCs compared to IM alone, through a novel and tumor-specific β-catenin/HRP2 axis, allowing potent inhibition of cancer cell survival, stemness, and metastasis in metastatic and drug-resistant ovarian cancer cells. Promising results were also obtained in clinically relevant patient-derived ascites and organoids alongside high tumor-oriented accumulation and favorable pharmacokinetic properties in mouse models. Furthermore, Bola/IM displayed synergistic anticancer activity when combined with the first-line chemotherapeutic drug cisplatin in patient-derived xenograft mouse models without any adverse effects. Our findings support the use of Bola/IM as a nanoformulation to empower IM, providing targeted and potent treatment of metastatic ovarian cancer. Our study thus represents a significant advancement toward addressing the unmet medical need for improved therapies targeting this challenging disease.

A novel imatinib analogue inhibitor of chronic myeloid leukaemia: design, synthesis and characterization-explanation of its folded conformation.

Chronic myeloid leukaemia (CML) is primarily treated using imatinib mesylate, a tyrosine kinase inhibitor (TKI) targeting the BCR::ABL1 oncoprotein. However, the development of drug resistance and adverse side effects necessitate the exploration of alternative therapeutic agents. This study presents the synthesis and characterization of a novel imatinib analogue, 3-chloro-N-(2-methyl-5-((4-(pyridin-2-yl)pyrimidin-2-yl)amino)phenyl)benzamide (PAPP1). The compound's structure was elucidated using X-ray crystallography and spectroscopic techniques, including NMR, infrared and UV-visible. Crystallographic analysis reveals that PAPP1 consists of a phenyl-amino-pyridine-pyrimidine (PAPP) scaffold with substituted aromatic rings forming a nearly coplanar geometry. Additionally, supramolecular interactions in the crystal are mediated by hydrogen bonds and dispersion forces, forming dimers and layered structures. Molecular docking studies demonstrate strong binding affinity to the ABL1 enzyme, with PAPP1 showing comparable binding energy to imatinib, indicating its potential as a lead compound for further development. Computational studies, including molecular electrostatic potential and vibrational analysis, provide further support for the structural stability and bioactivity of PAPP1. These findings suggest that PAPP could be a promising scaffold for future CML drug design, offering a potential alternative to existing TKIs, and PAPP1 is a promising lead susceptible to optimization.

Toxicity assessment of imatinib mesylate and a related impurity: in vitro and in vivo approaches.

Imatinib mesylate (IM) is a widely used anticancer drug, mainly for treating chronic myeloid leukemia. However, pharmaceutical formulations may contain impurities, which in some cases can be more toxic than the parent compounds. This study aimed to compare the toxicity of IM and one of its impurities (IMP), N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidine amine, using progressively complex models. Cytotoxicity was evaluated using 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium, neutral red uptake and sulforhodamine B colorimetric assays. Mutagenic activity was assessed using the Ames test. In vivo assays were performed using both the invertebrate C. elegans and vertebrate zebrafish embryo models. In Vero cell cultures, the cytotoxicity of IM and IMP was found to be similar across the colorimetric assays tested. Neither IM nor IMP showed mutagenic effects in the Ames test. In the C. elegans lethality and development assay the toxicity profiles of the compounds were similar. However, in the Fish Embryo Acute Toxicity assay, the LC50 value for IMP (0.735μg/mL) was significantly lower than that for IM (60.86μg/mL), indicating greater toxicity for IMP. Furthermore, sublethal effects such as yolk-sac edema, pericardial edema, and tail deformities, were observed in embryos treated with IMP, even at low concentrations, indicating potential hazards associated with IMP. This study is the first to evaluate the toxicity of an IM subproduct, previously reported in pharmaceutical formulations, using different models. The Zebrafish model demonstrated higher sensitivity in predicting the toxic response of the TKI subproduct.

Extracellular vesicle-mediated regulation of imatinib resistance in chronic myeloid leukemia via the miR-629-5p/SENP2/PI3K/AKT/mTOR axis

ABSTRACT Background Imatinib (IM) is the primary treatment for patients with chronic-phase CML (CML-CP). However, an increasing number of CML-CP patients have developed resistance to IM. Our study aims to explore the expression of miR-629-5p in extracellular vesicles (EVs) from both IM-sensitive (K562) and resistant (K562-Re) CML cell lines and to investigate the impact of regulating miR-629-5p expression on the biological characteristics of K562 and K562-Re cells. Methods Assess miR-629-5p expression levels in IM-sensitive and resistant CML cell lines. Separate EVs and verify it. EVs from K562-Re cells were co-cultured with K562 cells to detect the expression level of miR-629-5p. Target genes of miR-629-5p were determined and validated through luciferase experiments. Examined by manipulating miR-629-5p expression in cells using transfection techniques. The expression level of phosphorylated proteins in the PI3K/AKT/mTOR signaling pathway after IM was detected in CML cell lines. In K562-Re cells, the expression level of phosphorylated protein in the PI3K/AKT/mTOR signaling pathway was detected after single transfection of miR-629-5p inhibitor and cotransfection of miR-629-5p inhibitor and siSENP2. Results Increasing concentrations of EVs from K562-Re cells elevated miR-629-5p expression levels. The expression levels of miR-629-5p in CML cells varied with IM concentration and influenced the biological characteristics of cells. SENP2 was identified as a target gene of miR-629-5p. Furthermore, miR-629-5p was found to modulate the SENP2/PI3K/AKT/mTOR pathway, impacting IM resistance in CML cells. Conclusion EVs from IM-resistant CML cells alter the expression of miR-629-5p in sensitive cells, activating the SENP2/PI3K/AKT/mTOR pathway and leading to IM resistance.

Immune-related genes for the prediction of response to imatinib therapy in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a malignant hyperplastic tumor that originates from pluripotent hematopoietic stem cells in the bone marrow. The introduction of tyrosine kinase inhibitors has significantly improved the survival rates of CML patients. This study aimed to identify immune-related genes associated with the response to imatinib (IM) therapy in CML. Gene expression profiles from IM-treated CML patients were obtained from the Gene Expression Omnibus database and categorized into high- and low-score groups based on immune scores calculated using the ESTIMATE algorithm. Subsequent bioinformatics analysis identified 428 differentially expressed immune-related genes in the CML context. Functional enrichment analysis revealed that these genes were involved in immune-related pathways, including T-cell receptor signaling and cytokine-cytokine receptor interaction. Finally, based on five modules in weighted gene co-expression network analysis and the top-ranked degree, 10 hub genes were identified. Receiver operating characteristic analysis in two Gene Expression Omnibus datasets identified IL10RA, SCN9A, and SLC26A11 as potential biomarkers for predicting IM response. We further validated these biomarkers in an independent clinical cohort of 60 CML patients treated with IM. Results from quantitative real-time polymerase chain reaction (qRT-PCR) revealed high expression of IL10RA and SLC26A11 in responders, while SCN9A showed low expression. All three genes had an area under the curve greater than 0.75, confirming their potential as predictive biomarkers. These findings deepen our understanding of functional characteristics and immune-related molecular mechanisms underlying IM response and offer promising predictive biomarkers.