INTRODUCTION:Glypican-1 (GPC1), a heparan sulfate proteoglycan found on the cell surface, has been associated with carcinogenesis and chemoresistance in several malignancies. However, its function in rhabdomyosarcoma remains poorly understood. METHODS:GPC1 protein expression was evaluated in rhabdomyosarcoma tissue microarrays using immunohistochemistry and quantified using the Allred scoring system. Transcriptomic analysis was performed using the GSE108022 dataset, and protein-protein interaction networks were analyzed using STRING. Structural features were assessed using AlphaFold, and drug sensitivity associations were explored using CTRP data. RESULTS:GPC1 protein expression was detected in 61.5% (64/104) of rhabdomyosarcoma cases, while 75% of normal skeletal muscle samples were negative. A significant association was observed between GPC1 expression and tumor subtype (p = 0.002, Cramér's V = 0.403), as well as sex (p = 0.025, Cra-mér's V = 0.219). Transcriptomic analysis showed significantly higher GPC1 expression in rhabdomyosarcoma compared to normal muscle (p < 0.001). Protein interaction analysis revealed enrichment in pathways related to cell adhesion, growth factor signaling, and extracellular matrix organization. Drug-sensitivity analysis indicated that higher GPC1 expression was associated with resistance to PI3K and HDAC inhibitors and increased sensitivity to vincristine, topotecan, and alisertib. DISCUSSION:GPC1 is aberrantly expressed in rhabdomyosarcoma, influencing neoplastic signaling and treatment responses, and new patents emphasize its potential for therapeutic targeting and diagnostic purposes Conclusion: GPC1 is aberrantly overexpressed, readily accessible to ligands or other molecules, and is a functionally significant biomarker in rhabdomyosarcoma, with emerging potential for diagnostic purposes and targeted therapy development.
Abstract: Immunotherapy using immune checkpoint inhibitors represents a breakthrough in cancer treatment. The overexpressed CD47 on tumor surfaces functions as a 'don’t eat me' signal by binding to signal regulatory protein alpha (SIRPα) on macrophages, facilitating immune escape. However, the advancement of targeted CD47 inhibitors is currently challenged by uncertainties in efficacy, hematological safety, and dosing optimization. This paper provides a comprehensive overview of the structural domains and physiological functions of CD47. We evaluate the current research status of various inhibition strategies, including monoclonal antibodies, fusion proteins, bispecific antibodies, and small-molecule inhibitors, alongside their clinical combinations. The review further addresses developmental hurdles and highlights future prospects in utilizing this target for precision oncotherapy.
Introduction: Osteosarcoma (OS) is a common bone malignancy in adolescents and older adults and typically develops in the long bones. Outcomes in advanced cases remain poor despite the use of chemotherapeutic drugs like doxorubicin, methotrexate, and cisplatin, underscoring the urgent need for safer, more focused treatments. Methods: A comprehensive review of clinical trials and literature identified emerging OS therapies targeting DNA repair, immune pathways, and tumor-specific markers. The EMA’s approval of Mepact for nonmetastatic OS underscores the shift toward precision treatments and the evolving landscape of OS management. Patent protection can influence the pricing and accessibility of innovative medicines for OS by affecting market exclusivity and competition. Results: According to recent research, bone morphogenetic protein (BMP), RB, and TP53 gene alterations both contribute to the development of OS. These results highlight the importance of conducting further proteomic and genomic research in order to develop focused and efficient treatment plans. Furthermore, patent protection stimulates innovative drug development by encouraging research investment and faster launches, but restricts affordability due to exclusivity, posing a policy dilemma. Discussion: Treatment for OS is still challenging, particularly in high-grade and metastatic cases when conventional chemotherapy is frequently harmful and unsuccessful. While new targeted medicines and advances in understanding bone cell dynamics and genetic abnormalities such as TP53, RB, and BMPs offer hope for more accurate, less invasive treatments, the approval of Mapact represents progress. Conclusion: The necessity for integrated therapies combining immunotherapy, targeted delivery, and molecular insights to enhance OS treatment results is highlighted by developments in genomics and bone remodeling.
Introduction: Cancer remains one of the leading causes of mortality worldwide, with conventional therapies often limited by systemic toxicity, therapeutic resistance, and tumor heterogeneity. Multi-target drug discovery has emerged as a contemporary strategy to overcome these challenges, particularly through multi-kinase inhibitors and bispecific antibodies that simultaneously modulate multiple oncogenic pathways. Methods: This review integrates evidence from preclinical investigations, pivotal clinical trials, regulatory approvals, and key patent literature underpinning the development of multi-target anticancer agents. Representative multi-kinase inhibitors-including sorafenib, sunitinib, lenvatinib, cabozantinib, and regorafenib-are critically analyzed with respect to their molecular targets, therapeutic advantages, clinical performance, and associated intellectual property. Patented innovations covering kinase inhibition platforms, antibody engineering, and biomarkerbased cancer detection are also discussed. Results: MKIs act by concurrently inhibiting multiple signaling kinases, such as vascular endothelial growth factor receptors, platelet-derived growth factor receptors, fibroblast growth factor receptors, mesenchymal-epithelial transition factor, rearranged during transfection, and rapidly accelerated fibrosarcoma, thereby suppressing angiogenesis, limiting compensatory signaling, and addressing tumor heterogeneity. Clinical trials demonstrate significant survival benefits in hepatocellular carcinoma, renal cell carcinoma, and thyroid cancer. Parallel advances in patented bispecific antibodies and epigenetic diagnostic technologies further expand the therapeutic and diagnostic landscape. Discussion: Multi-targeting strategies delay resistance, reshape the tumor microenvironment, and improve outcomes, particularly when combined with immunotherapies or chemotherapies. However, challenges persist, including off-target toxicity, pharmacokinetic variability, high development costs, and limited accessibility. Patent trends reveal a growing emphasis on biomarker-guided patient selection, novel antibody formats, and rational combination therapies. Conclusion: MKIs and bispecific antibodies represent transformative modalities in modern oncology, supported by robust clinical evidence and extensive patent activity.
Introduction: Cancer drug discovery remains challenged by tumour heterogeneity and limited experimental scalability. Recently, virtual drug screening integrating machine learning algorithms has yielded numerous research results, some of which have been successfully patented and are expected to be further translated and deployed in drug discovery pipelines. Most current models for virtual drug screening fail to effectively integrate multi-omics data or capture nonlinear cross-omics interactions, restricting predictive accuracy and biomarker discovery across diverse cancers with high heterogeneity. Methods: We developed a multi-omics fusion deep learning model integrating mutation, methylation, transcriptomic, and metabolomic profiles from over 900 pan-cancer cell lines derived from the DepMap database. Our framework synergizes random forest-based feature selection to prioritize biologically relevant omics features and multi-head attention mechanisms to model nonlinear interactions between cellular multi-omics landscapes. Further biological analysis of the selected features enabled the deciphering of potential biomarkers related to drug effects. Results: Our multi-omics fusion model attained high-performance drug response prediction across nearly 900 cancer cell lines (median Pearson r = 0.50 vs Pearson r = 0.22 for the former model for all included drugs). Validation demonstrated robust accuracy for the MEK inhibitor Trametinib (r = 0.78, MAE = 0.59) and the non-oncology agent BMOV (r = 0.73). The model identified BRAF-mutant melanoma sensitivity and PI3K/AKT bypass resistance, consistent with existing findings. Feature mining revealed TERT modulation and oxidative stress induction as BMOV's probable anticancer mechanisms, while Benzamide targeted metabolic vulnerabilities. Discussion: This study introduced a deep-learning-based multi-omics fusion model to predict pan-cancer drug response. The framework achieved the expansion of the anticancer spectrum of existing anticancer drugs and explored the potential anticancer effects of non-anticancer drugs. Moreover, the integration of SHAP/MDI feature interpretation algorithms enabled mechanistic biomarker discovery. However, the prediction results that were not reported in previous research are yet to require further experimental verification. Conclusion: In conclusion, this work established a robust DL-driven platform for virtual drug screening and biomarker discovery, providing a computational platform that could aid virtual drug screening and biomarker discovery and facilitate the development of precision oncology.
Introduction: Breast cancer treatment remains challenged by molecular heterogeneity and drug resistance, highlighting the need for new therapeutic strategies. This study aimed to discover potential anti-breast cancer agents using a drug repurposing strategy. Methods: We screened a library of 192 FDA-approved drugs and identified the lipid-lowering agent lomitapide as a candidate anti-breast cancer compound. Its biological effects were evaluated in MDA-MB-231 and MCF-7 cells, and potential molecular targets were investigated through virtual screening and experimental validation. Results: Lomitapide significantly inhibited cell proliferation, invasion, and migration. Mechanistically, lomitapide directly interacted with ER-α and PPARγ. Moreover, it enhanced the sensitivity of MCF-7 cells to tamoxifen. Discussion: Lomitapide suppresses breast cancer progression through multiple mechanisms and may improve endocrine sensitivity. Conclusion: Lomitapide is a novel repurposed agent for breast cancer treatment. ER-α and PPARγ are potential therapeutic targets.
Introduction: Prostate cancer (PC) is the second leading cause of mortality in men. It originates in the prostate glands and may be influenced by genetic factors, ethnicity, diet, age, and other factors. Methods: Consequently, the diagnosis of PC occurs at an advanced stage, which shows high mortality in men. The existing therapies, chemotherapy, surgery, and radiation therapy, have shown limited success. Comparatively, nanotechnology-based approaches are more effective and extend survival rates than conventional ones. Results: The state-of-the-art review explores the novel biomarkers that indicate the disease condition before its progression. The novel biomarkers are the Prostate Health Index (PHI), STHLM3, PCA3, TMPRSS2-ERG Fusion, Prostate-Specific Antigen (PSA), Prostate-Specific Membrane Antigen (PSMA), Tumor Mutational Burden (TMB), Microsatellite Instability (MSI), Androgen Receptor (AR) Mutations, etc. Immunotherapy and targeted therapy have gained tremendous significance in tumor therapy and markedly improved survival rates. The adverse effects observed in conventional therapy are circumvented using immunotherapy and targeted therapy. Recently, novel patent innovations were reported for PC (US 20240319192 A1, US 20240309090 A1, US 20250075278 A1, US 20240181092 A1). Discussion: The novel immunotherapy approaches utilized for PC comprised immune checkpoint inhibitors (PD-1/PD-L1, CTLA-4 inhibitors), Vaccines, and Adoptive Cell Therapy (CAR-T Cells). Similarly, targeted therapy includes Androgen Receptor Signaling Inhibitors, PARP Inhibitors, PI3K/AKT/mTOR Pathway Inhibitors, Tyrosine Kinase Inhibitors (TKIs), and DNA Repair Pathway Targeting Agents, etc. Conclusion: Recent innovations in biomarkers help in the early diagnosis of PC. The advanced stage of PC is well-treated with either single Immunotherapy, targeted therapy, or combinations of both for extending patient survival and hope.
Introduction: Paclitaxel (PTX) is a widely explored antimitotic drug for the treatment of various cancers; however, various issues like its hydrophilic nature, lack of targeting ability, and toxic side effects may cause a reduction in its therapeutic effectiveness. By enhancing solubility, extending circulation, allowing tumor-targeted distribution, and decreasing systemic side effects, protein-based nanocarriers have arisen as a potential substitute to traditional formulations. Methods: An extensive literature review was carried out in PubMed, ScienceDirect, and Google Scholar databases of articles published in 2015-2025 using search strings that were predefined and included the terms that were related to paclitaxel, protein nanoparticles, and cancer therapy. The studies were used according to pre-established inclusion criteria (original research, proteinbased nanocarriers to deliver PTX, etc.) and exclusion criteria (non-protein carriers, conference abstracts, non-English articles, etc.). Google Patents and Espacenet were used in carrying out patent searches. The most recent articles (n=158) and 11 patents were selected, and relevant data were obtained. Results: Various types of protein nanocarriers greatly increase PTX solubility, encapsulation efficiency, and tumor accumulation through both passive and active targeting mechanisms. Important examples include Abraxane®, pH/redox-responsive gelatin systems, folate-targeted zein nanoparticles demonstrating a more than seven-fold increase in oral bioavailability, and multifunctional ferritin structures including chemo-photodynamic therapy. Clinical and preclinical trials have shown consistently good antitumor activity and reduced toxicity as compared to free paclitaxel. Discussion: Protein nanocarriers provide a flexible way to change the surface and release drugs in response to stimuli. They also solve some of the problems with conventional PTX dosage forms. But there are still problems that need to be solved before we can get scale production, controlled release kinetics, long-term stability, and high drug loading. Conclusion: Next-generation protein-based nanocarriers are a unique way to deliver paclitaxel. They have a greater therapeutic index and lead to better patient outcomes. There is a lot of optimism for precision oncology as these biocompatible technologies continue to be improved and used in clinical settings.
Introduction/Objective: Hormone receptor-positive (HR+) breast cancer remains a major therapeutic challenge due to endocrine resistance and disease progression. This study investigates the patent landscape of innovative pharmacological strategies for HR+ breast cancer, highlighting emerging targets, technological trends, and their alignment with clinical development. Methods: Patent documents were identified through searches of the European Patent Office databases via the keywords “breast cancer and hormone therapy” in the title and/or abstract, along with the International Patent Classification code A61K. The review also examines clinical trials to evaluate the development and approval of new drugs for medical use. Results: A total of 25 patents were selected. Notably, CDK4/6 inhibitors have emerged as promising agents for controlling tumor progression and overcoming endocrine resistance. Another significant innovation involves the use of PIK3CA inhibitors, which are effective in patients with specific mutations in this gene, which are commonly found in HR+ breast cancers. Discussion: The findings indicate that recent technological developments emphasize targeted mechanisms of action, deeper integration of precision oncology, and a continued shift toward strategies to delay or overcome endocrine resistance. These trends reflect an innovative landscape driving increasingly specific and personalized systemic therapies. Conclusion: This review describes current patent-driven innovations in hormone-sensitive breast cancer, highlighting the focus on precision systemic therapies and combination strategies for advanced disease. However, limited attention to the management of endocrine-related adverse effects reveals a critical unmet need for future research and technological development.
INTRODUCTION:Ovarian cancer remains the most lethal gynecological malignancy globally. While Clotrimazole (CTZ) exhibits antitumor potential, its specific efficacy and mechanisms in ovarian cancer require elucidation. METHODS:Proliferation and apoptosis were assessed in A2780 and SKOV3 cells using CCK-8, colony formation, and Annexin-V/PI assays. Mechanisms were explored via RNA sequencing, molecular docking, qRT-PCR, Western blotting, and immunofluorescence. In vivo efficacy and safety were validated using SKOV3 xenograft models. RESULTS:CTZ inhibited cell viability with 48-h IC50 values of 19.36 µM (A2780) and 46.01 µM (SKOV3). Apoptotic rates increased significantly to 48.4% and 20.3%, respectively. RNA-seq analysis identified 4,066 differentially expressed genes primarily enriched in the HER2/PI3K/AKT pathway. Experimental validation confirmed that CTZ significantly downregulated this pathway in vitro and in vivo. In xenograft tumor models, intraperitoneal CTZ administration reduced tumor volume by 48.68% compared to the vehicle group, with slight systemic toxicity. However, oral administration showed limited efficacy. DISCUSSION:It was found that CTZ inhibits ovarian cancer cell proliferation and induces apoptosis via the HER-2/PI3K/AKT signaling pathway. CTZ may bind to HER-2 and accelerate HER2 protein degradation. The Intraperitoneal administration of CTZ exerts potent in vivo antitumor effects, suggesting that future research should utilize novel drug delivery systems to improve oral bioavailability. CONCLUSION:CTZ is a promising therapeutic agent and may serve as a novel potent agent for ovarian cancer treatment. Its antitumor effects are at least partially mediated via the inhibition of the HER-2/PI3K/AKT signaling pathway.
INTRODUCTION:Cervical squamous cell carcinoma remains a major medical challenge worldwide, particularly in low-developed regions. This study integrated bulk transcriptomic (GSE63514) and single-cell RNA sequencing data (GSE168652) to investigate how senescencerelated mechanisms contribute to CESC progression. By leveraging this multi-omics integration, the study provides unprecedented resolution into cell-type-specific senescence programmes and their associated intercellular communication networks that drive CESC pathogenesis. METHODS:Differential expression analysis was performed on bulk data, followed by functional enrichment analysis. Single-cell analysis characterised senescence signals across cell types and intercellular communications. Network pharmacology identified potential therapeutic agents targeting senescence pathways. RESULTS:We identified 1,319 upregulated and 913 downregulated genes in tumours compared to normal tissues. Functional enrichment analysis revealed pathways involved in cell cycle arrest (CDKN2A/p16INK4A), DNA repair (DNA2), and extracellular matrix remodelling (MMP12, CTHRC1). CDKN2A mediated growth suppression via p53/Rb signalling, while SASP components (AIM2, CXCL9) and APOC1-associated metabolic dysregulation shaped an immunosuppressive microenvironment. Single-cell analysis showed strong senescence signals in epithelial cells and macrophages, involving CDKN2A and APOC1. MIF and MDK signalling between these cells appeared to support immune evasion and angiogenesis. Network pharmacology indicated possible therapies, including CDK4/6 inhibitors, a strategy supported by findings in related HPV-associated malignancies, as well as MMP12 inhibitors and combinations of PARP inhibitors with immune checkpoint blockade. DISCUSSION:These findings provide a more detailed picture of senescence in CESC, with tumour-suppressive effects through CDKN2A and pro-tumorigenic effects via SASP components and APOC1. Cell-cell interactions involving MIF and MDK may drive immune evasion. CONCLUSION:This study demonstrated both the promoting and suppressive roles of senescence in CESC and identified potential therapeutic targets, offering hope for improved outcomes in high-risk patients from low-resource regions.
INTRODUCTION:Cuproptosis is a newly discovered form of programmed cell death that offers a new perspective on glioma treatment. However, the clinical impacts of CuproptosisRelated Genes (CRGs) in glioma remain largely unclear. This study aimed to investigate the role and biological significance of CRGs in glioma. METHODS:The current study included 1573 glioma patients (603 from TCGA and 970 from the CGGA database) with clinicopathological information and mRNA sequencing data. The most relevant gene, SLC31A1, was identified among 16 CRGs through a series of approaches. Functional gene annotation was performed using GO, KEGG, and GSVA. Furthermore, correlations between CRGs and immune cell infiltration were analyzed by ESTIMATE and CIBERSORT algorithms. Single-cell RNA sequencing databases were used to verify the infiltration of M2 macrophages. Lastly, in vitro functional experiments were performed to assess the knockdown effects of SLC31A1 expression on the proliferation and invasion of glioma cells. Transcriptome sequencing of SLC31A1 knockdown cell lines was used to validate the functional enrichment analysis results. Mass spectrometry analysis was used to validate the protein-protein interactions. Immunofluorescence staining was used to co-localize the target protein with PD-L1, and the gene expression level was verified by immunohistochemistry. RESULTS:Among the 16 CRGs, SLC31A1 was highly expressed and had the most important prognostic value. The expression of SLC31A1 increased with the degree of malignancy in glioma. SLC31A1 is an independent prognostic factor for gliomas, and an SLC31A1-based prognostic nomogram can reasonably predict the survival of patients. Functional enrichment analysis revealed that SLC31A1 co-expressed genes are mainly involved in immune and metabolismrelated signaling pathways. CIBERSORT analysis revealed that M2 macrophage cells increased with increasing SLC31A1 expression. SLC31A1 was closely associated with immune checkpoints PD-L1 and TIM3. Knockdown of SLC31A1 in glioma cells decreased cellular proliferation, migration, and invasion in vitro. DISCUSSION:The strong correlation between SLC31A1 and M2 macrophage infiltration, coupled with its interaction with immune checkpoints, suggests that SLC31A1 mediates tumor progression by modulating the immunosuppressive microenvironment. These findings indicate that SLC31A1 is not only a copper transporter but also a key regulator of immune evasion in glioma. CONCLUSION:This study provides basic evidence that regulating cellular copper levels by targeting SLC31A1 is a feasible and patented therapeutic strategy. The high expression of SLC31A1 could promote the infiltration of M2 macrophages in glioma.
Introduction: Children with tumors experience multiple metabolic alterations, including increased lipid oxidation of free fatty acids, inhibition of lipoprotein lipase, and elevated production of inflammatory cytokines (TNF-α and IL-6), which may contribute to cachexia. The micronutrient selenium, with its antioxidant action, seems to play an important role in controlling metabolic changes. Aims: Thus, we aimed to evaluate the impact of selenium supplementation in children with leukemia and solid tumors through the analysis of inflammatory markers and expression of antioxidant regulatory genes using real-time PCR. Methods: This work recruited patients supplemented with selenium aged 3 to 19 years with leukemias and lymphomas or solid tumors from the Pediatric Oncology Service at FMABC. The inflammatory markers IL-6, TNF-α, RBP4, and Tbars were detected through serum evaluations, and the antioxidant regulatory genes, including Thioredoxin, Glutathione Peroxidase, Nuclear transcription factor kappa β, and Selenoprotein P, were analyzed in whole blood samples by real-time PCR. Results: This study evaluated 26 pediatric oncology patients. No significant differences were observed in Tbars or IL6 concentrations between groups. However, selenium supplementation significantly reduced the expression of SEPP1 (p =0.030), NFKB (p =0.003), and TRX (p =0.007) genes compared to baseline, suggesting a potential modulatory effect of selenium on inflammatory gene expression. Conclusion: This study suggests that selenium supplementation may help modulate inflammatory responses in pediatric oncology patients. While no significant differences were found in Tbars or IL-6, selenium significantly reduced the expression of SEPP1, NFKB, and TRX genes. These results indicate a potential role of selenium in controlling inflammatory gene pathways.
INTRODUCTION:NHWD-870 HCl is a next-generation oral BET inhibitor (US Patent 10,428,071 B2). We conducted a Phase I dose‑escalation study. METHODS:This multicenter, open-label, phase I study used a Bayesian optimal interval (BOIN) dose-escalation design. NHWD-870 HCl was administered once daily on an intermittent schedule (5 days on/2 days off) at doses ranging from 0.5 to 3.5 mg. The primary endpoints were safety, cycle 1 Dose-Limiting Toxicities (DLTs), the maximum tolerated dose (MTD), and the recommended phase II dose (RP2D). Secondary endpoints included Objective Response Rate (ORR), Disease Control Rate (DCR), and pharmacokinetics (PK). RESULTS:Thirty-one patients received NHWD-870 HCl. Overall, 93.5% (29/31) experienced at least one adverse event (AE), and 83.9% (26/31) experienced at least one treatment-related AE (TRAE). The most common TRAEs were thrombocytopenia (45.2%; grade ≥3, 25.8%), anemia (41.9%; grade ≥3, 12.9%), and increased blood bilirubin (32.3%; grade ≥3, 3.2%). Treatment-related Serious Adverse Events (SAEs) occurred in 4 patients (12.9%; thrombocytopenia, n=3; wound bleeding, n=1), and no treatment-related deaths were reported. Twenty-four patients were evaluable for DLTs, and all 3 DLTs occurred at the 2.75 mg dose level, corresponding to a cycle 1 DLT rate of 30.0%, which was within the BOIN target interval (0.18- 0.42). However, considering the concentration-dependent thrombocytopenia, the occurrence of grade 4 thrombocytopenia at 2.75 mg (2 events), the higher discontinuation rate, and the lessthan-dose-proportional increase in exposure at 2.75 mg, the RP2D was determined to be 2.0 mg on a 5-days-on/2-days-off schedule. Among the 29 response-evaluable patients, the ORR was 3.45%, and the DCR was 69.0%. Durable stable disease was observed in selected patients, including approximately 21 months in melanoma and more than 26 months in NUT carcinoma. PK analyses showed rapid absorption (median Tmax, approximately 1-2 h) and less-than-doseproportional increases in Cmax and AUC over the 0.5-2.75 mg dose range; the mean terminal half-life was approximately 11-16 h, with mild accumulation. DISCUSSION:NHWD-870 HCl showed manageable, predominantly hematologic toxicity, with thrombocytopenia demonstrating clear dose- and exposure-related trends. Although the cycle 1 DLT rate at 2.75 mg was consistent with the BOIN target interval, the occurrence of grade 4 thrombocytopenia, the higher frequency of treatment interruptions and discontinuations, and the subproportional increase in exposure supported selection of 2.0 mg (5 days on/2 days off) as the RP2D. Although the ORR was low, the durable disease control observed in BET-dependent tumors, including NUT carcinoma and DLBCL, supports further biomarker-driven studies. CONCLUSION:NHWD-870 HCl demonstrated manageable, mainly hematologic toxicity and preliminary antitumor activity, supporting further clinical evaluation, particularly in NUT carcinoma and DLBCL.
INTRODUCTION:Esophageal Cancer (EC) is a prevalent gastrointestinal malignancy. Despite significant advances in diagnostic and therapeutic approaches, the prognosis of Esophageal Squamous Cell Carcinoma (ESCC) remains poor. The development of new therapeutic agents for ESCC would greatly benefit patients and their families. Metformin has been found to be useful in other tumours, but its role and mechanism in ESCC have not been investigated. METHODS:The effect of metformin on inhibiting invasive metastasis in ESCC cells was explored by in vitro cytology experiments. 4D-DIA proteomics and untargeted LC-MS metabolomics provided critical technical support for this study. The roles and mechanisms of differential proteins, metabolites, and key metabolic pathways in ESCC migration and invasion were further explored by identifying differentially expressed proteins and metabolites in metformin-treated ESCC cells using proteomics and metabolomics. RT-qPCR and Western blot were used to confirm metformin's inhibitory effects on key proteins in metabolic pathways associated with ESCC cell migration and invasion. Using the ESCC tissue microarray (TMA) to detect the expression levels of GLUL and SP1. RESULTS:This study demonstrated that metformin significantly reduced ESCC cells' viability, proliferation, migration, and invasion, while enhancing apoptosis. Integrated multi-omics pathway analysis revealed the activation of several metabolic pathways following metformin treatment in ESCC cells. In vitro experiments confirmed that metformin significantly downregulated the key proteins GLUL and SP1, as identified in the differential proteomics analysis. Immunohistochemistry (IHC) showed that GLUL and SP1 expression were significantly lower in ESCC tumor tissues from patients with a history of preoperative metformin administration than in those without. DISCUSSION:Enhanced glutamine metabolism in tumors promotes cancer progression. Downregulation of GLUL reduces glutamine production from the alanine, aspartate, and glutamate metabolic pathways, thereby inhibiting tumor progression. SP1 is an oncogenic factor in esophageal cancer and an unfavorable prognostic factor. Metformin downregulates both GLUL and SP1, affecting the alanine, aspartate, and glutamate metabolic pathways, as well as the choline metabolic pathway in cancer. CONCLUSION:In summary, metformin may inhibit the migration and invasion of ESCC cells through downregulation of GLUL and SP1, which play important roles in the mechanism of metformin's anti-tumor effects. These findings provide new insights into the therapeutic potential of metformin in the treatment of ESCC.
INTRODUCTION:This study aimed to investigate the biological function and molecular mechanisms of seizure-related 6 homolog-like 2 (SEZ6L2) in Cervical Cancer (CC) progression and evaluated its potential as a therapeutic target. METHODS:SEZ6L2 expression was analyzed in CC tissues and cells using online tools and experimental validation. Functional experiments, including cell-counting Kit-8, colony formation, wound-healing, transwell, and flow cytometry, together with in vivo models, were performed to assess the effects of SEZ6L2 on proliferation, migration, and metastasis. GSEA and Metascape enrichment were used to identify associated pathways. TargetScan was used to predict upstream miRNAs, followed by validation with dual-luciferase assays. RESULTS:SEZ6L2 was significantly overexpressed in CC and correlated with poor prognosis. Knockdown of SEZ6L2 inhibited CC proliferation, migration, and invasion while inducing cell cycle arrest. In vivo, SEZ6L2 silencing reduced tumor growth and metastasis. Mechanistically, SEZ6L2 was found to activate the Wnt/β-catenin pathway, leading to upregulating β-catenin and driving Epithelial-Mesenchymal Transition (EMT). GSEA confirmed the involvement of the Wnt pathway. Moreover, hsa-miR1271-5p was identified as a direct upstream regulator of SEZ6L2. DISCUSSION:Our findings identified SEZ6L2 as a novel oncoprotein in CC, contributing to tumor pathogenesis by activating the Wnt/β-catenin signaling and promoting EMT-driven metastasis. We further demonstrated that hsa-miR-1271-5p acts as a direct upstream repressor, providing mechanistic insight into the regulatory network governing SEZ6L2 expression. Collectively, these results position SEZ6L2 as a robust prognostic biomarker and illuminate its potential as a therapeutic target. CONCLUSION:SEZ6L2 promotes CC progression via Wnt/β-catenin signaling and EMT, serving as a prognostic biomarker and therapeutic target. Hsa-miR1271-5p may suppress SEZ6L2 expression, offering novel insights for CC treatment strategies.
INTRODUCTION:Schisandra chinensis has been reported to exhibit antitumor activity; however, its active components and molecular mechanisms in non-small cell lung cancer (NSCLC) remain unclear. METHODS:Network pharmacology was employed to identify active compounds and potential targets of Schisandra chinensis against NSCLC, followed by protein-protein interaction analysis, GO and KEGG enrichment analyses, and molecular docking. A549 cells were used for experimental validation. Cell viability was assessed by MTT assay, oxidative stress markers (GSH, SOD, MDA) were quantified, and the expression of PTGS2, inflammatory factors, and apoptosis-related genes was examined by qRT-PCR and Western blot. RESULTS:Eight active components of Schisandra chinensis were identified, with seven overlapping targets related to NSCLC. Molecular docking revealed that Gomisin R exhibited the strongest binding affinity to PTGS2, with a docking score of -7.3 kcal/mol. In vitro experiments demonstrated that Gomisin R significantly inhibited A549 cell proliferation in a dose- and time-dependent manner, with a pronounced effect observed at 25 µM (p < 0.01). Gomisin R markedly downregulated PTGS2 expression at both mRNA and protein levels (p < 0.001), accompanied by reduced expression of inflammatory cytokines IL-1β and IL-6, increased antioxidant capacity (elevated GSH and SOD levels and decreased MDA content), and modulation of apoptosis-related genes, characterized by decreased Bcl-2 and increased Caspase 9 expression (p < 0.05-0.001). These effects were partially reversed by the PTGS2 agonist rebamipide. DISCUSSION:These findings suggest that Gomisin R may modulate PTGS2-associated inflammatory and redox pathways in NSCLC cells. The integration of network pharmacology with experimental validation provides a mechanistic framework for understanding the potential role of Gomisin R in NSCLC-related research, although further in vivo studies are required to confirm its translational relevance. CONCLUSION:Gomisin R exerts anti-NSCLC effects, in part, by regulating PTGS2 expression, leading to suppression of cell proliferation, attenuation of oxidative stress and inflammatory responses, and induction of apoptosis in A549 cells. This study provides quantitative evidence supporting Gomisin R as a key active component of Schisandra chinensis for the treatment of NSCLC.
INTRODUCTION:Hypoxia is a hallmark of aggressive breast cancers, particularly Triple- Negative Breast Cancer (TNBC), where stabilization of Hypoxia-Inducible Factor-1α (HIF-1α) upregulates Carbonic Anhydrase IX (CAIX), thereby enabling tumor pH homeostasis, proliferation, and resistance to therapy. Selective CAIX inhibition, therefore, offers a promising therapeutic strategy. In this study, a thiazolidine derivative was identified as a selective inhibitor of CAIX with the use of integrated computational, in vitro, and in vivo studies to develop targeted therapy against TNBC. METHODS:A series of thiazolidinone derivatives was subjected to in silico molecular docking against human carbonic anhydrase isoforms. The most active compound, 2-(4-chlorophenyl)-3- (4-ethoxyphenyl)thiazolidin-4-one (BCS12), was tested and analyzed using 200 ns MD simulations to evaluate the stability of the complexes. Pharmacokinetic parameters were predicted using ADME profiling. Cytotoxicity was evaluated in MDA-MB-231 and MDA-MB-468 breast cancer cells, with IC50 values of 15.49 μM and 18.81 μM, compared to 121.6 μM in noncancerous MCF-10A cells (n = 3, p < 0.05). Free Radical generation, mitochondrial membrane depolarization, and expression of apoptosis markers (Bax, Bcl-2, caspase 9, caspase 7, and caspase 3, and PARP) were quantified using mechanistic studies in hypoxia-adapted MDA-MB- 231 cells by RT-qPCR, western blotting, and immunofluorescence. The number of apoptotic cells was also determined by flow cytometry. The in vivo activity was assessed against DMBAinduced breast tumor-bearing rats by histopathology and TUNEL staining. RESULTS:BCS12 showed strong docking affinity as well as stable binding with active-site residues of CAIX in simulations. It preferentially suppressed TNBC cell viability, promoted oxidative stress, impaired the integrity of mitochondria, and activated an intracellular apoptosis pathway. In vivo, BCS12 treatment induces an increase of TUNEL-positive nuclei in a dosedependent manner compared with the control, with significantly higher contrast index values at 20 mg/kg and 40 mg/kg (p < 0.0001). The apoptotic response was strongest in the 40 mg/kg group, and was associated with a marked decrease in tumor burden and restoration of tissue architecture. The lead compound reduced tumor mass, improved histological parameters, and increased TUNEL-positive apoptotic nuclei with an associated decrease in expression of CAIX and activation of pro-apoptotic proteins. DISCUSSION:Our findings suggest that BCS12 disrupts hypoxia-induced survival pathways through inhibition of CAIX to enhance TNBC cell sensitivity to apoptosis. These data reveal a therapeutic benefit of selective CAIX inhibition to counteract hypoxia-induced therapy resistance and further insights into the mechanism underlying hypoxia-targeted therapies for aggressive breast cancer. CONCLUSION:BCS12 selectively inhibits CAIX, leading to the effective impairment of hypoxic adaptation and apoptosis in TNBC. The in silico, in vitro, and pre-clinical model data together provide evidence for the candidacy of this compound as a lead candidate for hypoxia-targeted therapy of breast cancer. Due to its unique chemical structure and therapeutic characteristics, BCS12 may be a candidate for patent filing for future translational development.
Widespread drug resistance in the treatment of non-small cell lung cancer (NSCLC) seriously restricts clinical efficacy, so the development of new drug delivery systems to overcome drug resistance has become a key area of research. Currently, no systematic study has been conducted on anti-drug resistance drug delivery systems for NSCLC. This study systematically analyzed patent application trends and delivery system types for drug resistance in NSCLC over the past two decades using the WIPO, Espacenet, and Incopat global patent databases. The analysis focused on the evolution of delivery technology and the value and effectiveness of related technologies. The results showed that the number of patent applications has grown continuously, reflecting progressive innovation in this field of technology from basic research and development to breakthrough applications. The main technology types are nano delivery (56.6% of total patents) and coupled delivery (28.3%). Additionally, emerging technologies such as exosomes, vesicles, and siRNA have emerged. There has been a leap in technology evolution from single-carrier development to intelligent, responsive delivery. In recent years, research has focused on the synergistic application of stimuli-responsive nano systems and combination therapy. High-value patents typically offer the combined benefits of various technologies and mechanisms, particularly in terms of overcoming drug resistance, achieving precise delivery, and reducing toxic side effects. This study provides an important theoretical basis and practical guidance for optimizing the research and development (R&D) strategy and patent portfolio for anti-drug-resistance drug delivery technology in NSCLC.
INTRODUCTION:Genistein, a phytoestrogen with multi-target anticancer activity, and chitosan, a biocompatible polymer with versatile drug carrier properties, are increasingly investigated for use in advanced drug delivery systems. Cancer remains a leading cause of mortality globally, with current therapeutic approaches like systemic toxicity, non-specific drug delivery, multidrug resistance, and limited bioavailability of therapeutic compounds. METHODS:This review synthesized evidence from PubMed, Scopus, Web of Science, Science Direct, and Google Patents. Most of the studies involving genistein, chitosan, nano-formulations, pharmacokinetics, regulatory guidelines, and patents were screened. Some of the recent patents from 2020 to 2025 on drug delivery have been analyzed to map translation development. RESULTS:Moreover, the genistein chitosan systems are positioned as a synergistic co-therapy platform. Composite systems such as nanoparticles, liposomes, hydrogels, and micelles show significant improvements in bioavailability (5-10-fold), tumor retention, and reduced systemic toxicity in preclinical models. The clinical implications of this integrated system are profound. DISCUSSION:Despite strong preclinical data, regulatory challenges persist, including variability in the molecular weight of genistein and chitosan, limited nanotoxicology standards, and classification inconsistencies for natural products. The regulatory landscapes of the developing and non-developing countries, which evolved across key pharmaceutical jurisdictions including the FDA, EMA, CDSCO, PMDA, AND NMPA. CONCLUSION:Genistein and chitosan drug delivery systems represent a promising approach for precision oncology, offering improved pharmacokinetics, targeted delivery, and reduced toxicity. This review also critically addresses the regulatory gaps, biocompatibility, and modular delivery systems.
