SJB2-043, a USP1 Inhibitor, Suppresses A549 Cell Proliferation, Migration, and EMT via Modulation of PI3K/AKT/mTOR, MAPK, and Wnt Signaling Pathways

Current Issues in Molecular Biology, Journal Year: 2025, Volume and Issue: 47(3), P. 155 - 155

Published: Feb. 27, 2025

Objective: Non-small cell lung cancer (NSCLC) remains one of the most significant contributors to cancer-related mortality. This investigation explores influence and underlying mechanisms USP1 inhibitor SJB2-043 on A549 cells, with aim advancing development anti-NSCLC therapeutics. Methods: Publicly available databases were utilized assess expression its association progression NSCLC. Gene variations ascertained through RNA sequencing, followed by Kyoto Encyclopedia Genes Genomes Ontology pathway enrichment evaluations. Various doses administered cells evaluate impact multiplication, motility, apoptosis, cycle using CCK-8 assays, colony formation, wound healing, flow cytometry, Western blotting (WB). Results: was found be overexpressed in NSCLC specimens linked adverse prognosis. Treatment markedly inhibited proliferation migration, diminished clonogenic potential, triggered apoptosis a dose-dependent manner. Modifications observed, showing an elevated percentage G2 phase while exhibiting parallel decline G1 phase. WB examination demonstrated protein levels N-cadherin, CyclinB1, CDK1, C-myc, Bcl-2, p-ERK/ERK, p-p38/p38, p-JNK/JNK, p-AKT/AKT, p-mTOR/mTOR, alongside upregulation E-cadherin, ZO-1, occludin, p53, Bax, p-β-catenin/β-catenin, GSK3β. Conclusions: exerts suppressive effect proliferation, epithelial–mesenchymal transition enhancing apoptosis. These cellular effects appear mediated inhibition MAPK, Wnt/β-catenin, PI3K/AKT/mTOR signaling cascades, addition modulation cycle.

Language: Английский

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Calcium channels as pharmacological targets for cancer therapy

Clinical and Experimental Medicine, Journal Year: 2025, Volume and Issue: 25(1)

Published: March 25, 2025

Language: Английский

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Fexofenadine Overcomes Osimertinib Resistance by Inhibiting c‐Met in Non‐Small Cell Lung Cancer

MedComm – Oncology, Journal Year: 2025, Volume and Issue: 4(2)

Published: April 14, 2025

ABSTRACT Osimertinib is the only third‐generation EGFR tyrosine kinase inhibitor clinically approved for first‐line treatment of advanced NSCLC patients harboring mutations. However, drug resistance severely hinders its clinical efficacy. Acquired MET amplification an important mechanism causing osimertinib resistance. This study first to identify fexofenadine, originally indicated allergic rhinitis and chronic urticaria, as a putative Met‐inhibitor by in silico chemical‐protein interactome analysis known Met inhibitors. Fexofenadine was verified inhibit recombinant cell‐free assay phosphorylation other downstream signaling molecules osimertinib‐resistant cell lines. KINOME profiling revealed similar inhibition profile between fexofenadine Met‐inhibiting cabozantinib using Spearman rank‐order correlation analysis. Among tested lines, most efficacious potentiating NCI‐H820 (having EGFR‐T790M mutation). Transcriptome that differentially expressed genes following were enriched epithelial‐mesenchymal transition‐related biological pathways. Importantly, also shown significantly potentiate antitumor effect drug‐refractory patient‐derived tumor xenograft model NSG mice, without inducing notable adverse effects. These findings advocate evaluation repurposing overcome

Language: Английский

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HDAC8 Enhances the Function of HIF‐2α by Deacetylating ETS1 to Decrease the Sensitivity of TKIs in ccRCC

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: July 29, 2024

Drug resistance after long-term use of Tyrosine kinase inhibitors (TKIs) has become an obstacle for prolonging the survival time patients with clear cell renal carcinoma (ccRCC). Here, genome-wide CRISPR-based screening to reveal that HDAC8 is involved in decreasing sensitivity ccRCC cells sunitinib applied. Mechanically, deacetylated ETS1 at K245 site promote interaction between and HIF-2α enhance transcriptional activity ETS1/HIF-2α complex. However, antitumor effect inhibiting on sensitized TKI not very satisfactory. Subsequently, inhibition increased expression NEK1, up-regulated NEK1 phosphorylated T241 by impeded acetylation ETS1-K245 showed. Moreover, treatment STAT3 phosphorylation also found. These 2 findings highlight a potential mechanism acquired TKIs ccRCC. Finally, HDAC8-in-PROTACs optimize effects through degrading overcoming are synthesized. Collectively, results revealed as therapeutic candidate ccRCC-targeted therapies.

Language: Английский

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Phenotypic plasticity in a novel set of EGFR tyrosine kinase inhibitor-adapted non-small cell lung cancer cell lines

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 3, 2024

Abstract Here, we introduce sublines of the EGFR-mutant non-small cell lung cancer (NSCLC) lines HCC827 and HCC4006 adapted to EGFR kinase inhibitors gefitinib (HCC827 r GEFI 2µM , 1µM ), erlotinib ERLO afatinib AFA 50nM 100nM ). All displayed resistance gefitinib, erlotinib, afatinib, third-generation inhibitor osimertinib that overcomes T790M-mediated resistance. a spindle-like morphology in agreement with previous findings had detected epithelial-mesenchymal-transition (EMT) its precursor line 0.5µM . EMT also been reported for but morphologies or did not support this, suggesting plasticity regulation during drug adaptation process established resistant lines. Accordingly, MEK AKT contrast We metabolic plasticity, i.e., temporary Warburg metabolism, Response profiles cytotoxic anti-cancer drugs, inhibitors, HDAC resulted complex patterns were specific each individual subline without obvious overlaps, indicating phenotypes. remained sensitive collateral sensitivity at least one investigated drugs. In conclusion, comparison kinase-resistant NSCLC their previously characterised lower level investigations indicated phenotypic formation This may contribute well-known variability phenotypes observed between different laboratories intra-laboratory experiments.

Language: Английский

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Computational Insights in Repurposing Cardiovascular Drug for Alzheimer's Disease: The Role of Aromatic Amino Acids in Stabilizing the Drug through π-π Stacking Interaction

Physical Chemistry Chemical Physics, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 2, 2024

HDAC2 represents a promising and visually striking epigenetic target to address Alzheimer's disease calculation suggests that π–π stacking interactions play major role in helping the ligand bind zinc binding domain of protein.

Language: Английский

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