Search Results (17,976)

Background: Ovarian cancer is frequently diagnosed at an advanced stage and remains one of the most lethal gynecologic malignancies. The development of multidrug resistance (MDR) during repeated chemotherapy is a major cause of treatment failure and is often associated with increased drug efflux mediated by transporters such as P-glycoprotein (P-gp). In this study, D-α-tocopheryl polyethylene glycol succinate (TPGS) and Soluplus^® (SOL) mixed micelles, abbreviated as TS, were developed to co-deliver apatinib (APA), a VEGFR-2 inhibitor, and etoposide (ETP), a topoisomerase II inhibitor, for MDR ovarian cancer models. The formulation was designed to improve the aqueous dispersion, cellular accumulation, and antitumor activity of APA and ETP. Methods: APA/ETP-loaded TS micelles (APA/ETP-mTS) were prepared and characterized in terms of particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency (EE), storage stability, and in vitro drug release. Anticancer efficacy was assessed using MTT assays, cellular uptake assays, and 3D tumor spheroid studies employing HeyA8-MDR cells, followed by in vivo toxicity and antitumor efficacy studies. Micellar formulations were denoted using the cargo–carrier format, where APA/ETP indicates co-loaded APA and ETP, C6 indicates coumarin-6 (C6) used as a fluorescent probe, mTS indicates TPGS/SOL mixed micelles, and mSOL indicates SOL-only micelles. Results: The selected APA/ETP-mTS formulation showed a particle size of 20.0 ± 5.1 nm, a PDI of 0.16 ± 0.05, near-neutral zeta potential, and encapsulation efficiencies exceeding 60% for both drugs. The micelles maintained colloidal stability at 4 °C for 4 weeks, although partial decreases in encapsulation efficiency were observed. Compared with APA/ETP solution, APA/ETP-mTS delayed the release of both drugs. C6-mTS showed higher intracellular fluorescence intensity than C6-mSOL, suggesting enhanced cellular accumulation associated with TPGS incorporation. APA/ETP-mTS showed greater cytotoxicity than free drugs in HeyA8-MDR monolayer cells and produced the strongest spheroid growth inhibition among the tested micellar formulations. In the HeyA8-MDR xenograft model, APA/ETP-mTS suppressed tumor growth and resulted in the lowest final tumor weight without apparent overt toxicity based on body weight and survival observations. Conclusions: These results suggest that APA/ETP-mTS is a promising micellar co-delivery platform for hydrophobic anticancer drugs in MDR ovarian cancer. Full article

Ferroptosis is a regulated form of cell death caused by iron-dependent membrane lipid peroxidation. Iron metabolism, membrane lipid composition, cellular metabolic pathways, and antioxidant defense systems regulate ferroptosis. Recently, ferroptosis has attracted interest as a target in cancer therapy, in particular cancer cells have developed several biological adaptative mechanisms to evade ferroptosis, thus enhancing tumor progression, metastatic dissemination, stemness, and resistance to conventional therapies. Interestingly, ferroptosis is regulated by the tumor microenvironment, where hypoxia, immune cells, and stromal components can either stimulate or inhibit ferroptotic cell death. It has been demonstrated that targeting ferroptosis, alone or in combination with chemotherapy, radiotherapy and immunotherapy, has anticancer effects in preclinical models and may contribute to avoid treatment resistance. However, the role of ferroptosis in pediatric cancer remains incompletely understood since these kinds of tumors show different developmental, genomic, and metabolic features that may contribute to create different ferroptosis vulnerabilities. Emerging evidence in neuroblastoma, B-cell acute lymphoblastic leukemia, osteosarcoma, and medulloblastoma supports the involvement of ferroptosis-related pathways in tumor biology and treatment response. Preclinical studies also indicate that ferroptosis induction may represent a therapeutic strategy in selected pediatric cancer models, although tumor heterogeneity, drug delivery, and potential toxicity to developing tissues remain important translational challenges. This review summarizes the molecular mechanisms underlining the relationship between ferroptosis and cancer biology, tumor progression, tumor microenvironment, and therapy resistance, with particular interest in its emerging relevance and therapeutic potential in pediatric oncology, while critically considering the current evidence and major challenges for clinical translation. Full article

Although advances in pediatric oncology have resulted in cure rates exceeding 80% among children with cancer, progress in survival outcomes has begun to plateau in recent years. Mortality in this population remains largely associated with aggressive disease features, particularly tumor resistance to chemotherapy and metastatic spread. At the same time, the growing population of childhood cancer survivors has drawn increasing attention to the persistent and potentially serious late effects associated with conventional chemotherapy. Thus, it is crucial to discover drugs with specific antitumor action, effective and safe drugs that, combined with chemotherapy or radiotherapy, could chemosensitize or radiosensitize the tumor and reduce the severe side effects of both. Substance P (SP) peptide and its Neurokinin-1 receptor (NK-1R) are known to be involved in pediatric cancer, promotion and progression. Pediatric cancer overexpresses SP/NK-1R and NK-1R is essential for viability of cancer cells and is not essential for normal non-tumor cells. SP induces mitogenesis, exerts anti-apoptotic effects, and promotes angiogenesis, invasion and migration for metastasis in cancer cells and produces inflammation. Conversely, NK-1R antagonists, such as aprepitant and similar drugs, inhibit mitogenesis and induce apoptosis in pediatric cancer cells in a concentration-dependent manner. They also inhibit angiogenesis, invasion, and migration in pediatric cancer cells and have an anti-inflammatory effect. Moreover, aprepitant in combination with chemotherapy or radiotherapy can produce chemosensitization or radiosensitisation and decreases the severe side effects of both. This review updates the role of the SP/NK-1R axis in pediatric cancers and analyzes its potential as a therapeutic target. It highlights NK-1R antagonists, particularly aprepitant, and their potential as drugs for the treatment of pediatric cancer. Full article

Inocutis levis (I. levis) is a rare edible and medicinal macrofungus with a traditional history of consumption as a dietary supplement and functional food raw material. However, the material basis and molecular mechanisms underlying its anti-breast cancer activity remain unclear. The present work aimed to systematically investigate the anti-proliferative activity of WYS, an active mycelial fraction isolated from I. levis, against MCF-7 breast cancer cells and to explore its underlying mechanisms. Firstly, 152 metabolites were putatively annotated in the WYS fraction via ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) combined with database matching. Through an integrated strategy combining network pharmacology and multi-algorithm machine learning screening, four core metabolites (dihydroartemisinin, cortisol, cinnamic acid, and guanosine) and five hub targets (CDK1, EGFR, TOP2A, FGF2, and KIT) were prioritized. Furthermore, 100 ns molecular dynamics simulations and molecular docking predicted favorable binding affinities between the core metabolites and their cognate target proteins and predicted that the anti-breast cancer effect of WYS may be associated with the regulation of cell cycle progression, mitochondrial apoptosis, and the MAPK signaling pathway. Subsequent in vitro functional assays validated that WYS inhibited the proliferation of MCF-7 cells in both dose- and time-dependent fashions, triggered G2/M phase arrest and intrinsic mitochondrial apoptosis, and inhibited the EGFR/MEK/ERK signaling axis, exhibiting limited cytotoxicity toward normal HUVEC cells. In vivo, WYS dose-dependently attenuated xenograft tumor growth, and its modulatory effects on cell cycle, apoptosis, and related signaling pathways were consistent with the in vitro observations. This study provides the first evidence that I. levis mycelial fraction WYS modulates EGFR/MEK/ERK-related signaling and induces G2/M cell cycle arrest, thereby exerting anti-proliferative and pro-apoptotic effects on MCF-7 breast cancer cells, providing a scientific basis for further investigation of I. levis as a functional food. Full article

Triple-negative breast cancer (TNBC) is a subtype associated with poor prognosis and low survival rates, largely due to limited treatment options. In recent years, histone deacetylase (HDAC) inhibitors have emerged as promising anti-cancer candidates due to their attractive epigenetic properties and distinct mechanisms of action but have shown limited success in solid tumors. Here, we explore ribitoborate along with HDAC inhibitors for potential use as a treatment for TNBC. Experiments were performed on the TNBC cell line MDA-MB-231. The results of the study revealed that ribitoborate and romidepsin showed synergistic responses leading to significant arrest of cell proliferation (80%) (p < 0.01) as well as migration inhibition. These effects were associated with downregulation of c-Myc, survivin, Bcl-2, and cyclin D1, as well as upregulation of p53 and p21 proteins; notably the changes were significantly greater with the combined treatment than with either ribitoborate or romidepsin alone. Romidepsin and ribitoborate combined treatment time-dependently increased cell death of MDA-MB-231 cells with greater efficiency than romidepsin alone. Cell death by apoptosis was supported by the upregulation of H3k9 and H3k27 acetylation with decreasing proliferation. These results suggest the great potential of the drug combination for treatment of TNBC. The underlying molecular mechanisms for synergy could be further explored for potential development of new combined therapy for breast cancer. Full article

Vascular endothelial growth factor (VEGF)-targeted therapies have been associated with thromboembolic events, although the magnitude and nature of this risk vary substantially according to the specific agent, mechanism of VEGF-pathway inhibition, malignancy, concomitant therapy, and patient-related factors. This comprehensive narrative review examines the epidemiology, mechanisms, clinical characteristics, and management of VTE in cancer patients receiving VEGF inhibitors. Evidence from clinical trials, observational studies, pharmacovigilance analyses, and preclinical investigations is synthesized to provide a clinically oriented overview of VEGF-targeted therapy-associated thrombosis. Reported VTE incidence ranges from 2.5% to 15.7% across studies, with substantial heterogeneity according to the VEGF-targeted agent, cancer type, treatment setting, and study design. Bevacizumab-treated patients receiving chemotherapy demonstrated increased arterial and venous thromboembolism risk (relative risk 1.32–2.45). Plasminogen activator inhibitor-1 (PAI-1) upregulation, endothelial dysfunction, and tissue factor activation represent key pathogenic mechanisms. Careful patient selection, risk stratification using validated scoring systems, thromboprophylaxis strategies, and individualized anticoagulation approaches are essential for managing this complication. Direct oral anticoagulants, particularly apixaban, demonstrate favorable efficacy and safety profiles compared to traditional anticoagulants in cancer-associated VTE. This review provides clinicians with comprehensive, evidence-based guidance for preventing and managing VTE in the growing population of cancer patients receiving VEGF-directed therapies. Full article

Folate-mediated one-carbon metabolism supports nucleotide biosynthesis, methylation reactions, and redox homeostasis, and the mitochondrial enzyme MTHFD2 has emerged as a cancer-associated metabolic target. However, the development of MTHFD2-preferential inhibitors remains challenging because MTHFD2 is structurally and functionally related to other folate-metabolism enzymes, including the cytosolic enzyme MTHFD1 and the mitochondrial isoenzyme MTHFD2L. In this study, a curated library of 115 phytochemicals was screened against the folate/substrate-binding pockets of MTHFD2 and MTHFD1 using a redocking-controlled molecular-docking protocol. Three compounds, dehydrotrametenolic acid, eburicoic acid, and rutaecarpine, met the docking-based prioritization criteria for predicted MTHFD2-preferential binding. Subsequent ADME, drug-likeness, and toxicity profiling indicated that the two triterpenoids had unfavorable physicochemical and pharmacokinetic properties and were therefore not advanced to biochemical testing, whereas rutaecarpine showed the most balanced predicted profile. In vitro enzyme-inhibition assays showed that rutaecarpine inhibited both MTHFD2 and MTHFD1 in a concentration-dependent manner. Rutaecarpine inhibited MTHFD2 with an apparent IC₅₀ of 31.35 μM and MTHFD1 with an apparent IC₅₀ of 54.20 μM, corresponding to a modest 1.73-fold preference for MTHFD2. In contrast, the reference antifolate LY345899 preferentially inhibited MTHFD1. These findings identify rutaecarpine as a natural-product scaffold with statistically supported but modest MTHFD2-preferential activity and support its further structure-guided optimization, including future profiling against MTHFD2L. These results should be interpreted as evidence of exploratory scaffold-level activity rather than identification of a potent, optimized, or broadly validated MTHFD2 inhibitor. Full article

Background: Triple-negative breast cancer (TNBC) exhibits aggressive biology and heterogeneous immune infiltration. Lysine-specific demethylase 1 (LSD1/KDM1A) is an epigenetic regulator implicated in oncogenic transcriptional programs, but its role in immune exclusion remains incompletely defined. Methods: LSD1 expression was evaluated by immunohistochemistry in TNBC specimens and correlated with survival. Functional effects of LSD1 depletion or pharmacological inhibition were assessed in TNBC cell lines and patient-derived xenograft organoids (PDXOs). Transcriptomic, ChIP-seq, multiplex immunofluorescence, and GeoMX digital spatial profiling analyses were integrated to characterize LSD1-associated transcriptional, chromatin, and immune programs. PBMC-PDXO co-cultures evaluated the effects of LSD1 inhibition on tumor growth and immune cell infiltration. Results: High LSD1 expression was associated with inferior overall survival, hypoxia-associated programs and suppressed immune pathways. LSD1-high tumors exhibited reduced infiltration of T cells, B cells, NKT-like cells, and macrophages. Spatial profiling revealed suppressed innate immune responses and type I interferon signaling within B-cell and T-cell compartments, respectively. ChIP-seq demonstrated preferential LSD1 occupancy at AP-1 motif-enriched regions, while co-immunoprecipitation supported association with AP-1 complexes. Integration of LSD1 chromatin occupancy sites with transcriptomics data identified SPPL2A and NCOA3 as candidate LSD1-regulated genes associated with interferon-γ response pathways. LSD1 depletion increased SPPL2A, NCOA3, MHC-I and PD-L1 expression. LSD1 inhibition reduced PDXO growth and increased immune cell infiltration. Conclusions: LSD1 is associated with a poor clinical outcome and immune exclusion in TNBC. These findings support a role for LSD1 in AP-1-associated chromatin regulation and interferon-γ-related transcriptional response; they warrant further investigation into LSD1 inhibition as a therapeutic strategy for immune-cold TNBCs. Full article

Background: Histone deacetylase inhibitors (HDACis) have been suggested as novel pharmacological agents for various clinical conditions, including cancer and neurodegenerative, inflammatory, autoimmune, and metabolic diseases. Periodontitis is a complex, multifactorial disease characterised by chronic inflammation, a dysbiotic microbiota, and the degradation of tooth-supporting tissues. It is influenced by factors such as immune capacity, genetic and epigenetic changes, lifestyle, and comorbidities. Objective: This systematic review with narrative synthesis examines the therapeutic potential of HDACis in the management of periodontitis. Method: The PubMed, ScienceDirect, and Web of Science databases were comprehensively searched to identify relevant articles published between 2000 and 2026. The systematic review is reported according to the 2020 PRISMA guidelines. Results: HDACis consistently attenuated periodontal inflammation, reduced alveolar bone loss, and inhibited osteoclast differentiation and activity by downregulating proinflammatory cytokines and osteoclastogenic markers. Trichostatin A, MS-275, and valproic acid were the most extensively investigated compounds. Conclusion: Overall, the findings indicate that HDAC inhibition may have therapeutic potential, although substantial methodological heterogeneity and limited translational evidence precluded conclusions regarding clinical efficacy. Full article

The immune response of our body, whether it is directed to infective agents, allergens, or tumors, should support our recovery but can also be dangerous if dysregulated. There are molecular systems that have the role of tuning the immune response, such as activating and inhibitory receptors and co-stimulatory molecules. Among this plethora of receptors, immune-checkpoint receptors (ICRs), as well as natural killer receptors (NKRs), expressed on NK and/or T cells can up- or downregulate the function of activating and inhibitory receptors during immune cell crosstalk. Among NKRs, NKRP1A/CD161 has shown to be a promising target molecule for immunotherapy. This receptor showed inhibiting or co-stimulatory effects depending on the cell type analyzed as well as the analytical procedures, reagents used, and the experimental context. The aim of the following review will be to explore the structural and functional features of this receptor on immune cells, its relevance in the tumor microenvironment and its targeting as an immunotherapeutic tool in cancers. Full article

Background: Papillary thyroid carcinoma (PTC) is the most common malignant tumor of the thyroid gland. Although most patients have favorable outcomes, a subset of patients develop aggressive disease characterized by lymph node metastasis and recurrence. Increasing evidence indicates that inflammatory factors participate in tumor progression. However, the expression pattern and functional role of interleukin-1 beta (IL1β) in PTC remain unclear. This study aimed to investigate the expression, biological function, and underlying molecular mechanisms of IL1β in PTC progression. Methods: IL1β expression and its clinical relevance were evaluated using public databases, 152 paired PTC and adjacent non-cancerous tissue samples, and PTC cell lines. Functional assays, including cell proliferation, colony formation, wound-healing, transwell invasion, and flow cytometry assays, were performed to investigate the effects of IL1β on malignant phenotypes. RNA sequencing, proteomic analysis, co-immunoprecipitation assays, rescue experiments, and a xenograft mouse model were conducted to identify and validate the downstream molecular mechanisms of IL1β. Results: IL1β expression was significantly reduced in PTC tissues and cell lines and was negatively associated with lymph node metastasis. Overexpression or recombinant protein treatment of IL1β inhibited PTC cell proliferation, migration, invasion, epithelial–mesenchymal transition, and tumor growth, while promoting apoptosis. Mechanistically, IL1β increased the expression of SMDT1 gene and suppressed MAPK signaling activity by reducing MEK/ERK phosphorylation. Knockdown of SMDT1 gene partially reversed the inhibitory effects of IL1β on PTC cell progression and MAPK pathway activation. Conclusions: This study demonstrates that IL1β functions as a tumor suppressor in PTC through regulation of the SMDT1-MAPK signaling axis. These findings provide new insights into the role of inflammatory regulation in thyroid cancer (THCA) progression and suggest that IL1β-related molecular pathways may represent potential biomarkers or therapeutic targets for aggressive PTC. Full article

Persistent infection with high-risk human papillomavirus (hrHPV) is the principal cause of cervical cancer and initiates a complex process of immune evasion that enables malignant progression despite continuous expression of the viral oncoproteins E6 and E7. Effective antitumor immunity depends on coordinated antigen presentation through human leukocyte antigen class I (HLA-I) molecules, activation of CD8⁺ cytotoxic T lymphocytes, and balanced regulation of immune responses. During cervical carcinogenesis, these mechanisms are progressively disrupted through HLA-I downregulation, CD8⁺ T-cell exhaustion, expansion of FOXP3⁺ regulatory T cells, and activation of the PD-1/PD-L1 and CTLA-4 immune checkpoint pathways, ultimately establishing an immunosuppressive tumor microenvironment that promotes immune escape. This narrative review integrates current evidence on HLA-I-mediated antigen presentation, CD8⁺ cytotoxic T-cell function, FOXP3⁺ regulatory T cells, and immune checkpoint signaling into a unified model of immune escape during cervical carcinogenesis. In addition, it discusses the clinical implications of these interconnected mechanisms, including immune checkpoint inhibition, emerging therapeutic strategies, integrated immune profiling, and future directions in personalized immunotherapy. A comprehensive understanding of the interactions between antigen presentation, immune-cell function, and immune checkpoint regulation provides the biological foundation for current and future immunotherapeutic approaches. Integrating molecular, cellular, and spatial immune characteristics may improve patient stratification, optimize treatment selection, and facilitate the implementation of precision immuno-oncology in cervical cancer. Full article

Background: Metabolic adaptability plays a critical role in supporting the growth and survival of metastatic breast cancer cells, and potentially supports site-specific metastasis. This study investigates the differential metabolism of glutamine and adaptability to varying glutamine levels of triple-negative breast cancer (TNBC) cells that metastasize to the lungs (metM-Wnt^Lung) or liver (metM-Wnt^Liver). Methods: The metastatic cell lines were exposed to varying in vitro glutamine concentrations (0.5, 2, and 4 mM). Cell viability, migration, ¹⁴C-glutamine uptake, mRNA abundance of metabolic enzymes, and ¹³C₅-glutamine cellular flux, were measured. Results: At an intermediate level of in vitro glutamine supplementation (2 mM), metM-Wnt^Lung cells exhibited greater glutamine uptake, catabolic enzyme expression, and flux of glutamine-derived carbon into the TCA cycle compared with metM-Wnt^Liver cells. Despite this, metM-Wnt^Liver cells were more viable and migratory than metM-Wnt^Lung cells under both higher (4 mM) and lower (0.5 mM) glutamine levels, suggesting metabolic adaptability. Exposure to ammonia upregulated ammonia-assimilating enzymes in metM-Wnt^Liver, but not metM-Wnt^Lung cells, plausibly mitigating ammonia toxicity in higher glutamine conditions. In glutamine-deprived conditions, the metM-Wnt^Lung cells maintained higher glutamine oxidation, but the metM-Wnt^Liver cells had higher total glutathione and GSH/GSSG ratios and enhanced resistance to oxidative stress, suggesting glutamate utilization toward glutathione synthesis. Additionally, metM-Wnt^Liver cells utilized glucose-derived carbons through pyruvate carboxylase (PC) to maintain TCA cycle activity, with elevated PC expression and M+3-labeled oxaloacetate enrichment to a greater extent than metM-Wnt^Lung cells. PC silencing in metM-Wnt^Liver cells enhanced cell viability under glutamine deprivation, which was reversed by inhibiting phosphoglycerate dehydrogenase (PHGDH, a key enzyme in de novo serine synthesis). We propose that PC activity compensates for low glutamine levels, including diverting glucose to adaptive pathways such as de novo serine synthesis. Conclusions: Overall, our findings demonstrate that metM-Wnt^Liver cells, but not metM-Wnt^Lung cells, exhibit glutamine-specific metabolic plasticity, characterized by the modulation of glutamine catabolism, enhanced ammonia metabolism and antioxidant defense, and support of glucose metabolism, which are associated with better cell survival and migration under glutamine excess and deprivation. Full article

The quinazoline/quinazolinone ring is known as a unique scaffold, and its derivatives possess a broad biological activity profile, including antibacterial, antifungal, anticonvulsant, anti-inflammatory, anti-HIV, and analgesic activity, primarily focusing on anticancer activity. In this study, the synthesis of 2-[[4-oxo-3-(substituted phenyl)-3,4-dihydro-(substituted quinazolin-2-yl)]thio]-N′-(aryl/heteroaryl methylene)acetohydrazide (4a–4x) derivatives and their potential anticancer activities were investigated on the lung cancer A549 cell line, the breast cancer MCF-7 cell line, and healthy fibroblast L929 cell line. Compounds 4c, 4i, 4m, and 4u were identified as the most cytotoxic and selective molecules on the A549 cell line (IC₅₀: 44.75–78.13 µM), while 4i, 4l, 4m, and 4u were identified as the most cytotoxic and selective molecules on the MCF-7 cell line (IC₅₀: 14.43–29.39 µM). The mechanisms of action of their anticancer activities were examined and studied. It was determined that these compounds induced strong apoptosis and significantly activated caspase-3 activation in both cell types and that they interrupted the cell cycle in the pre-G (sub G0) phase. Compounds 4m and 4u exhibited EGFR inhibition (IC₅₀: 4.80 µM, IC₅₀: 5.40 µM, respectively) at a level similar to the standard drug gefitinib (IC₅₀: 1.86 ± 0.43 µM). Based on the results of the biological activity assays, molecular docking, and molecular dynamics simulation studies, the 4-quinazolinone–acetyl hydrazone scaffold can be considered a promising structural framework with potential anticancer activity. More specifically, the findings of this study indicate that the acetyl moiety may function as an important pharmacophoric group, while the trisubstituted quinazolinone core may represent a favorable structural feature for caspase-3 activation. However, the same structural framework appears to be less favorable for EGFR inhibition, possibly due to steric constraints within the EGFR binding pockets. Full article

Breast cancer remains one of the leading causes of global mortality, which has growing driving interest in dietary natural products for potential chemopreventive and complementary approaches. Cherries (Prunus species) are rich in bioactive phytochemicals, notably anthocyanins, hydroxycinnamic acids, and the flavonols quercetin and kaempferol. This review aims to examine and discuss current research on the molecular targets and mechanisms of action of whole cherry extracts and their primary flavonols quercetin and kaempferol across various breast cancer subtypes. Preclinical studies indicate that these compounds exert multi-targeted effects by inducing apoptosis, inhibiting cell proliferation, and suppressing metastatic pathways. Additionally, these flavonols show potential in reversing multidrug resistance. A whole-food approach highlights the candidate synergistic properties of these phytochemical complexes, but low oral bioavailability and rapid metabolism severely limit their clinical translation. Therefore, utilizing innovative drug delivery systems remains crucial to improving their stability, absorption, and overall therapeutic efficacy. Full article