Search Results (17,057)

Background/Objectives: Since redox balance is critical to colorectal cancer cell survival, and estradiol, a potent antioxidant, correlates with reduced disease incidence, understanding the redox basis of cellular responsiveness to estradiol is essential for advancing therapeutic insight. This study evaluates the adaptive and maladaptive redox responses of colorectal carcinoma cells to estradiol treatment by defining the basal redox set-point as the intracellular balance between pro-oxidants and antioxidants. Methods: Human colorectal cancer cell lines HCT-116 and SW-480 were treated for 24 h with pregnancy-range and pharmacological-range concentrations of estradiol. Redox biomarkers (superoxide anion/O₂^.−, hydrogen peroxide/H₂O₂, nitric oxide/NO, reduced glutathione/GSH and oxidized glutathione/GSSG), cell viability, and basal migration were analyzed. Correlation, network topology, PCA, and Jaccard similarity analyses were applied to characterize basal redox set-points and quantify estradiol-induced changes in redox profiles in the two cell lines. Results: HCT-116 cells exhibited an O₂^.−-centered redox set-point associated with NO and GSH. SW-480 cells displayed a H₂O₂-centered redox set-point associated with NO and GSH. In HCT-116 cells, estradiol triggered a maladaptive response associated with antioxidant activation and reduced proliferation. Conversely, SW-480 cells exhibited an adaptive response characterized by modulation of NO levels and the GSH pool and associated with increased proliferation. Conclusions: These findings identify redox set-point organization as a potential determinant of estradiol responsiveness in colorectal cancer cells. From a clinical perspective, characterizing basal redox set-points in patient-derived tumor cells may enable stratification of colorectal cancer patients by predicted responsiveness to redox-modulating therapies, informing personalized treatment. Full article

Persistent infection with high-risk human papillomavirus (HPV), particularly HPV16, is a major driver of HPV-associated cancers; however, strategies for treating established HPV-induced tumors remain scarce. Here, we developed a DNA-based vaccine linking the SARS-CoV-2 spike (S) protein with an HPV16 E7 epitope (aa 49-57) to simultaneously induce antiviral humoral immunity and antitumor cellular responses. We generated 2 constructs, S-E7 and S-RE7, with the latter incorporating a furin cleavage site (R) to enhance antigen processing. In vitro, S-RE7 significantly enhanced E7-specific CD8⁺ T cell activation compared to S-E7, highlighting the importance of the furin sequence. In vivo, both S-linked vaccines elicited robust E7-specific CD8⁺ T cell responses and provided complete protection against TC-1 tumor challenge in a prophylactic murine model, with long-lasting immunity upon tumor rechallenge. In therapeutic settings, vaccination with S-E7 or S-RE7 significantly suppressed tumor growth, extended survival, and reduced circulating myeloid-derived suppressor cells (MDSCs), indicating alleviation of systemic immunosuppression. Notably, S-RE7 demonstrated faster antitumor effects overall in early tumor progression. In addition to cellular immunity, both constructs induced high levels of anti-spike antibodies, with S-RE7 eliciting approximately fourfold higher responses than S-E7. Furthermore, S-RE7 effectively boosted pre-existing anti-spike immunity in mice that were previously vaccinated. This “two-in-one” strategy represents a promising and versatile platform for the prevention and treatment of HPV-associated cancers while maintaining preparedness against potential SARS-CoV-2. Full article

Nimotuzumab is a humanized anti-EGFR monoclonal antibody with a unique pharmacodynamic profile characterized by intermediate affinity and bivalent binding dependence, enabling density-selective tumor targeting while sparing normal tissues from the severe skin rash and other toxicities common to EGFR inhibitors. Since its first approval in 2002, nimotuzumab has been registered for eight cancer indications. Unlike conventional fixed-dose schedules, emerging evidence supports prolonged administration beyond initial combination therapy. This review summarizes clinical data from pancreatic cancer, esophageal cancer, high-grade glioma, pediatric diffuse intrinsic pontine glioma, head and neck squamous cell carcinoma, nasopharyngeal cancer and other solid tumors, showing that extended nimotuzumab exposure, often as maintenance monotherapy, may prolong overall survival, progression-free survival, and disease control compared to limited cycles. Despite heterogeneity in tumor types and treatment regimens, maintenance nimotuzumab was consistently associated with better results, particularly in terms of overall survival. Notably, significant survival benefits were observed in locally advanced SCCHN (24.9 vs. 12.5 months) and esophageal cancer (15.9 vs. 8.1 months) across independent clinical trials. Mechanistically, nimotuzumab exerts direct cytostatic effects via G1 arrest, potent anti-angiogenic activity through VEGF downregulation, indirect pro-apoptotic effects, and broad immunomodulation including ADCC, NK-DC cross-talk, EGFR-specific CD8+ T cell priming, upregulation of HLA class I, and favorable regulation of regulatory T cells. Its density-selective binding reduces selective pressure for acquired resistance. Future research priorities should include prospective randomized trials specifically evaluating maintenance strategies, biomarker-driven patient selection, the molecular characterization of resistance mechanisms, integration with immunotherapy and modern combination regimens, and the development of next-generation platforms, including antibody–drug conjugates and multi-specific constructs. Full article

Volatile organic compounds (VOCs) reflect cellular metabolic activities and may serve as non-invasive biomarkers in oncology. This study investigated whether acquired oxaliplatin resistance in colorectal cancer is associated with distinct volatilomic alterations. The human colorectal cancer cell line HCT116 and its oxaliplatin-resistant derivative (OXrHCT116) were analyzed under basal conditions and following oxaliplatin exposure. Chemoresistance was confirmed using dose–response, cell viability, and colony formation assays. VOCs were analyzed by headspace needle trap extraction coupled with gas chromatography–mass spectrometry (HS-NTE-GC-MS). OXrHCT116 cells exhibited markedly reduced oxaliplatin sensitivity, increased IC₅₀ values, and reduced proliferative and clonogenic capacity. Volatilomic profiling identified 55 significantly altered VOCs. Parental HCT116 cells displayed broader VOC diversity and higher turnover than OXrHCT116 cells. Hydrocarbons associated with lipid peroxidation and oxidative stress were more abundant in HCT116 cells, whereas resistant cells showed markedly reduced emission of these compounds. Additional alterations in aldehydes, alcohols, and aromatic compounds suggested reduced metabolic flux in resistant cells. Oxaliplatin exposure induced pronounced volatilomic changes in HCT116 cells but only minimal modulation in OXrHCT116 cells. These findings suggest that oxaliplatin resistance may be associated with distinct metabolic reprogramming and support VOC profiling as a promising approach for monitoring chemoresistance. Full article

Objectives: Transient Receptor Potential Ankyrin 1 (TRPA1) has emerged as a stress-responsive ion channel involved in calcium homeostasis, redox signaling, migration, and cancer cell survival; however, the therapeutic relevance of TRPA1 activation versus inhibition remains poorly understood. In this study, we comparatively investigated the anticancer potential of the TRPA1 agonist ASP7663 and the TRPA1 antagonist HC030031 across a broad panel of human cancer cell lines. Methods: Antiproliferative and cytotoxic effects were evaluated using MTT and LDH assays, while apoptotic signaling, DNA fragmentation, mitochondrial membrane potential, migration inhibition, DNA/BSA interactions, topoisomerase I inhibition, and molecular docking analyses were comprehensively assessed. Results: ASP7663 exhibited markedly lower GI₅₀ values than HC030031 in most cancer models and demonstrated favorable tumor selectivity relative to normal cells. Mechanistically, ASP7663 induced robust apoptotic activation characterized by significant upregulation of Caspase-3, Caspase-8, and Caspase-9, together with enhanced DNA fragmentation and pronounced nuclear condensation. Rhodamine-123 staining further revealed substantial mitochondrial membrane depolarization, indicating activation of intrinsic apoptotic pathways. In addition, ASP7663 produced selective membrane damage in malignant cells, stronger inhibition of migration in osteosarcoma and chondrosarcoma models, enhanced CT-DNA/BSA binding affinity, partial topoisomerase I inhibition, and superior docking interactions with apoptosis-related targets, including Caspase-3, Caspase-8, Caspase-9, Bax, and Bcl-2. Conclusions: Collectively, these findings suggest that ASP7663 is a promising multi-target candidate for anticancer therapy and support further investigation of TRPA1-associated pathways as potential therapeutic targets in cancer. Full article

Nanoemulsions are promising nanotechnology-based delivery systems that may improve the stability, bioavailability, and cellular uptake of therapeutic agents. Silver nanoparticles (AgNPs) have been reported to exhibit high antibacterial and anticancer activities via several mechanisms, such as the generation of oxidative stress and disruption of cellular membrane integrity. Breast cancer (MCF−7) and ovarian cancer (SK-OV−3) represent two highly aggressive malignancies that pose major global health challenges. Brown algae oil is a natural marine-derived product with a number of bioactive compounds, including fatty acids, sterols, and antioxidants, responsible for its numerous biological activities. Oil extracted from the brown alga Turbinaria turbinata, using hexane as an organic solvent, was formulated with silver nitrate (AgNO₃) using a surfactant-stabilized spontaneous emulsification method to prepare a silver-loaded T. turbinata oil nanoemulsion (Ag-TTO-NE). The biological performance of the system was evaluated against human cancer cell lines, including MCF−7 (breast cancer) and SK-OV−3 (ovarian cancer), in addition to pathogenic bacterial strains, and for antioxidant activity. The results demonstrated that the silver-loaded oil nanoemulsion (Ag-TTO-NE) exhibited anticancer activities against MCF−7 (breast cancer) and SK-OV−3, with IC50 values of 105.86 and 72.45 µg/mL and a Selectivity Index of 2.34 and 3.41, respectively. The silver-loaded oil nanoemulsion (Ag-TTO-NE) possessed antioxidant and antimicrobial activities against Bacillus subtilis (ATCC 6633), Staphylococcus aureus (ATCC 6538), Pseudomonas aeruginosa (ATCC90274) and Salmonella typhi (ATCC 6539). These results indicate that T. turbinata-based silver nanoemulsions deserve further exploration as multifunctional marine-derived nanoformulations. In silico ADMET analysis projected moderate to high oral absorption for most of the discovered compounds and suggested favorable pharmacokinetic properties of the individual ingredients. ADMET analysis suggested that the major compounds discovered by GC–MS have good medication-like characteristics. These computational predictions are supplemental information and are not to be taken as the pharmacokinetic behavior of the nanoemulsion itself. Overall, the present results are based on in vitro biological assays together with exploratory computational studies and constitute preliminary evidence for the subsequent exploration of this marine-derived nanoformulation. Full article

Antiproliferative activity of pyrrolo[3,4-d]isoxazolines and pyrrolo[2,1-a]isoquinolines derived from them was studied against human erythroleukemia (K562), cervical carcinoma (HeLa), and melanoma (Sk-mel-2) cell lines in vitro by MTS assays followed by study of their effect on actin cytoskeleton and cell motility by confocal microscopy, and apoptotic activity by flow cytometry. Most effective among the screened compounds were bicyclic hydroxylactams 6–9 with a pyrrolo[3,4-d]isoxazoline structure; they showed IC₅₀ values ranging from 12 to 36 μg/mL for all tested cancer cell lines with selectivity indexes up to 12 (as compared to the embryonic kidney HEK293T cell line). Loss of stress fibers with diffuse redistribution of granular actin throughout the cytoplasm in up to 25% of treated cells and a decrease in filopodia-like protrusions up to 69% were observed by confocal microscopy during an actin cytoskeleton study. Such cytoskeletal changes and the proposed altered cell motility were confirmed by scratch-test (revealed a three-fold decrease in cell motility). Full article

Antimicrobial resistance in various microorganisms and opportunistic pathogens associated with HIV/AIDS poses a serious threat to human life and healthcare systems worldwide. Different forms of cancer are likely to arise in immunocompromised patients. The antimicrobial and anticancer effects of methanol extract and fractions from Raphionacme hirsuta have been investigated. The carbon tetrachloride fraction showed a remarkably low minimum inhibitory concentration (MIC) of 0.02 mg/mL against Escherichia coli, Mycoplasma hominis, and Cryptococcus neoformans, while the n-hexane fraction showed a similar MIC against C. neoformans. Furthermore, the carbon tetrachloride fraction exhibited promising IC₅₀ values of 18.21 and 25.22 µg/mL against HeLa and MCF-7 cancerous cell lines, respectively. The fraction was subjected to GC-TOF-MS and yielded four major compounds, including 7,9-Di-tert-butyl-1-oxaspiro (4,5) deca-6,9-diene-2,8-dione (5.322%), Hexanedial (3.691%), 4-(4-tert-Butylphenyl)-1,3-thiazol-2-ylamine (3.329%), and Di-n-decylsulfone (3.201%). These substances could potentially account for the plant species’ initial biological activity, which is why it is necessary to investigate their in vivo actions. The gummy extract had less biological activity than the fractions. To the best of our knowledge, this is the first study to report the antimicrobial and anticancer activities, as well as the phytochemistry, of the plant species. Full article

Canine mammary tumors have been investigated to determine the causes of malignancy and to promote the development of more effective therapies. The current standard of care, surgical resection where possible, often still results in recurrence of disease. Thus, there is an unmet need for better, more effective therapies that can suppress recurrence in canine patients. Because canine and human mammary cancers, particularly carcinomas and adenocarcinomas, share many similarities in genetic defects, etiology, natural history, and environment, canine mammary cancer cell lines have also been used as effective models of human disease. The genetics and immune response to canine mammary/breast cancers have been investigated to better understand this disease complex and to promote the development of more effective therapies designed to treat individual canine patients. As cancer is a heterogeneous disease, the potential to determine and possibly predict the mechanisms promoting neoplasia would allow the advancement of targeted therapeutic targets/strategies to combat cancer directly. These investigations have led to the development and evaluation of immunotherapies designed to elicit immune recognition of cancer and its suppression, thus improving survival. Hybrid dendritic-cell fusion vaccines and other autologous cancer vaccine formulations have proven effective in suppressing recurrence and extending survival in canine mammary cancer patients following surgical resection. Although current vaccines are somewhat impractical for direct application in veterinary clinics, reported success points the way toward the development of more practical vaccines designed to promote the treatment of canine mammary cancer. They also suggest a possible mechanism whereby removing a tumor from its microenvironment can promote antigenicity by removing local extracellular vesicle-mediated immunosuppression. This review provides a novel perspective on the potential of canine genetics to inform and promote more successful immunotherapies and their value as models of human disease. Full article

Background: The diversity of RNA isoforms plays a critical role in regulating the development and progression of human cancers. Our previous work has demonstrated that piR-2158 exerts antitumor activity in breast cancer by repressing IL11-STAT3 signaling. Methods: The isoforms of piR-2158 were analyzed using Sanger sequencing, quantitative real-time PCR (qRT-PCR), and Gene Expression Omnibus (GEO) dataset. Cell proliferation capacity was assessed using Cell Counting Kit-8 (CCK-8) assays and Ki67 immunofluorescence staining. Cell migration was evaluated using wound healing assays. Cancer cell stemness was analyzed using mammosphere formation assay, stemness marker detection, and ALDH activity assay. Results: We identified two types of piR-2158 isoforms in mammary tissues: a 31 nt long isopiR (designated as iso-piR-2158-L) and a 28 nt short isopiR (designated as iso-piR-2158-S). Predominant expression of iso-piR-2158-L was observed in normal mammary epithelial cells and adjacent non-tumor breast tissues, whereas it was significantly downregulated in TNBC cell lines and primary tumor tissues. We experimentally demonstrated that iso-piR-2158-L and iso-piR-2158-S exert distinct effects on TNBC cell proliferation, migration, and stemness, with iso-piR-2158-L showing significantly stronger antitumor effects than iso-piR-2158-S. Subsequent mechanistic studies revealed that iso-piR-2158-L suppresses IL11 expression more effectively, compared to iso-piR-2158-S. Conclusions: Our findings reveal a piRNA isoform-based regulatory pathway that may be involved in regulating pathological transformation, tumor initiation, and progression in TNBC. Full article

This study aimed to develop a low-cost, computer-controlled, extremely low-frequency 50 Hz electromagnetic field (ELF-EMF) generator and to investigate the effects of EMF exposure at intensities of 0.1, 1, 5, and 10 mT (millitesla) on human osteosarcoma (U2OS) and healthy bronchial epithelial (BEAS-2B) cell lines. First, a computer-controlled ELF-EMF generator was successfully designed and developed for in vitro exposure studies. Subsequently, the cells were exposed to 50 Hz EMFs at flux densities ranging from 0.1 to 10 mT, and cell viability was assessed using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay 24 h after exposure. A significant decrease in cell viability was observed in U2OS cells exposed to 5 and 10 mT EMFs (p < 0.05), whereas no significant difference was detected at 0.1 and 1 mT exposures (p > 0.05). In BEAS-2B cells, a significant decrease in cell viability was observed only following exposure to 10 mT EMFs (p < 0.05), with no significant differences at 0.1, 1, or 5 mT exposures. These findings suggest that 50 Hz EMFs may affect cellular processes and inhibit the proliferation of U2OS cancer cells more than that of BEAS-2B cells. EMFs with specific frequencies and intensities may represent a novel approach for controlling the growth of U2OS cancer cells. Full article

Experimental evidence has shown that gallic acid (GA), a naturally occurring polyphenolic compound, and docetaxel (DTX), a taxane chemotherapeutic agent, each possess antitumor activity against multiple cancer types. Although both compounds have been investigated individually, their combined effects in triple-negative breast cancer (TNBC) have received limited attention, and the molecular basis of their interaction remains unclear. The present study examined the in vitro effects of GA and DTX in MDA-MB-231 TNBC cells while simultaneously assessing their comparative cytotoxicity in HaCaT human keratinocytes. Evaluation of treatment efficacy included measurement of cell viability by the MTT assay and assessment of drug interactions using the Chou–Talalay combination index (CI) method. Apoptosis together with cell-cycle distribution was subsequently examined using both Annexin V/PI flow cytometry and TALI^® image-based cytometry. Additional analyses included β-tubulin immunofluorescence (IF), caspase-9 immunocytochemistry, ELISA, wound-healing assays, quantitative real-time PCR, and bioinformatic analyses to investigate treatment-associated biological alterations. Combined exposure to GA and DTX produced a significant reduction in cell viability and exhibited synergistic activity in MDA-MB-231 cells. The coordinated biological response to the combined treatment was characterized by increased apoptotic cell death, arrest of the cell cycle at the G2/M phase, extensive disorganization of the β-tubulin network, and enhanced caspase-9 immunoreactivity. Beyond its effects on cell survival, the combined regimen substantially decreased the release of IL-6, IL-8, and TNF-α, limited wound-healing capacity, and reshaped the expression profile of the apoptosis- and cell cycle-related genes BCL2, BAX, CASP9, and CDKN1A. Bioinformatic analyses further revealed enrichment of apoptosis- and cell-cycle-associated pathways that were generally consistent with the experimental observations. The overall pattern of experimental responses indicates that combining GA with DTX enhances the in vitro antitumor efficacy of DTX in TNBC cells by simultaneously influencing apoptotic pathways, cell-cycle regulation, inflammatory cytokine secretion, and cellular migratory capacity. Although the bioinformatic findings provide supportive hypothesis-generating evidence, additional studies using three-dimensional models, in vivo experiments, and functional validation approaches are necessary to confirm the underlying molecular mechanisms and to further define the translational potential of this therapeutic combination. Full article

Cancer therapy remains limited by drug resistance and poor selectivity, while inflammation-driven tumor progression further complicates treatment outcomes. Antimicrobial peptides (AMPs) have emerged as promising therapeutic alternatives due to their multifunctional properties. In this study, we investigated the anticancer and immunomodulatory activities of KI17, a rationally designed peptide derived from GL18, a peptide fragment identified from the talisin protein of Talisia esculenta. KI17 exhibited dose-dependent antiproliferative effects against murine and human melanoma (B16F10-Nex2, SK-MEL-2, A375) and cervical cancer (HeLa) cell lines, while displaying reduced cytotoxicity toward non-tumoral BV-2 microglial cells, resulting in a favorable selectivity index. Mechanistic analyses revealed that KI17 induces morphological alterations, mitochondrial dysfunction, caspase activation, and late-stage apoptosis, together with G0/G1 cell cycle arrest accompanied by accumulation of the Sub-G0 population, indicating coordinated regulation of cell death and cell cycle progression. KI17 effectively suppressed lipopolysaccharide (LPS)-induced microglial activation, markedly reducing pro-inflammatory cytokine and nitric oxide production without compromising cell viability. These biological activities are consistent with the peptide’s optimized physicochemical features, including increased cationicity, amphipathicity, and α-helical folding. Overall, our findings demonstrate that KI17 combines selective anticancer activity with potent immunomodulatory effects, highlighting its potential as a bioinspired peptide for further preclinical development in cancer therapy. Full article

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas that arise from Schwann cells and lack effective therapies. RABL6A is an oncogenic Rab-like GTPase whose expression is associated with worse survival in many human cancers. It is required for human MPNST cell survival, and its expression is dramatically increased in patient MPNSTs compared to benign precursor lesions. Methods: To model elevated expression of RABL6A in vivo, we developed transgenic mice expressing Cre-inducible Rabl6a. These Rabl6a-tg mice express the murine Rabl6a cDNA with a 5′ hemagglutinin [HA] epitope sequence downstream of a CMV enhancer and separated by a lox–stop–lox cassette. Double transgenic DhhCre–Rabl6a-tg mice were generated to achieve Schwann-cell specific Cre expression from the Desert hedgehog (Dhh) promoter. De novo MPNSTs were induced by CRISPR editing of Nf1, Ink4a, and Arf genes in the mouse sciatic nerve. Results: Cre-dependent expression of transgenic Rabl6a was verified at the mRNA and protein levels in Cre-positive mouse embryo fibroblasts and tissues. Increased Rabl6a expression in DhhCre–Rabl6a-tg mice had no effect on de novo MPNST initiation but significantly accelerated tumor progression relative to DhhCre control mice. The Rabl6a phenotype was associated with increased tumor angiogenesis but not proliferation. Interestingly, many MPNSTs in the DhhCre background exhibited varying levels of rhabdomyoblastic (RMB) features. That immature muscle cell phenotype is a hallmark of malignant Triton tumors, a rare histological variant of human MPNSTs associated with worse outcomes. Conclusions: These data provide direct evidence that Rabl6a is a functional driver of MPNSTs while establishing Rabl6a-tg mice as a suitable model for investigating Rabl6a’s role in other lethal RABL6A-high tumors. Full article

Accurate assessment of early indicators of breast cancer (BC) is critical to improve detection strategies and patient prognosis. Our research group takes a comparative species approach to study early BC detection by capitalizing on data from species with inherently low or high incidence of mammary cancer to supplement rare human samples. Circulating microRNAs (c-miRNAs) are a promising class of molecules that have the potential to serve as biomarkers for BC risk and disease detection. The expression of these non-coding RNAs controls numerous cellular processes and their dysregulation is associated with various pathological conditions, including cancer. To explore whether c-miRNA expression profiles can identify individuals with early-stage BC, we conducted a multi-species pilot study. We analyzed biofluid samples (i.e., saliva, serum, and plasma) from patients with early-stage BC and patients with no prior history of cancer and mammosphere-derived epithelial cells (MDECs) from dogs (canines) and horses (equines), species with a relatively high and low incidence of mammary cancer, respectively. We identified 16 candidate c-miRNAs that were upregulated in saliva from patients in the early-stage BC group when compared to the control patient group. Notably, 6 of these c-miRNAs (i.e., miR-361, miR-148b, miR-205, miR-186, miR-223, and miR-197) were also found to be secreted at higher levels by canine MDECs when compared to equine MDECs. Although individual and combinatorial assessment of these six c-miRNAs in a larger human cohort did not confirm their potential association with early breast cancer detection, the data in this study do introduce a novel comparative framework in which species-to-species variation in cancer susceptibility may inform the identification of candidate biomarkers for human disease. Full article