Search Results (1,649)

Background/Objectives: MicroRNAs (miRNAs) are key regulators of gene expression and have been implicated in multiple aspects of cancer progression. However, the role of miR-214-3p in breast cancer remains controversial. In this study, we investigated the functional role of miR-214-3p and explored its potential regulatory target in breast cancer, particularly in triple-negative breast cancer (TNBC). Methods: miR-214-3p expression was evaluated in breast cancer cell lines. Luciferase reporter assays were performed to assess functional targeting of the FRK 3′-UTR. Functional assays, including proliferation, migration, and invasion assays, were conducted following miR-214-3p overexpression or FRK silencing. Results: miR-214-3p was markedly upregulated in TNBC cells (MDA-MB-231), while Fyn-related kinase (FRK), a potential tumor suppressor, showed an inverse expression trend. Luciferase reporter assays demonstrated that miR-214-3p functionally targets the 3′-UTR of FRK. Functional analyses revealed that overexpression of miR-214-3p significantly increased cell proliferation, migration, and invasion. Notably, silencing of FRK recapitulated these effects, supporting its role as a functional mediator of miR-214-3p. Conclusions: This study identifies a miR-214–FRK regulatory axis in breast cancer and suggests its contribution to aggressive tumor behavior. Targeting miR-214-3p or modulating FRK activity may represent a potential therapeutic strategy. Full article

Background/Objectives: MYC-driven tumors exhibit significant glutamine addiction, but the metabolic adaptation mechanisms enabling their survival under glutamine deprivation remain incompletely understood. Malic enzymes catalyze the oxidative decarboxylation of malate to pyruvate while generating NADPH, linking central carbon metabolism to redox homeostasis. This study investigates whether and how ME1 and ME2 mediate cell adaptation to glutamine starvation and explores their functional division in relation to p53 status. Methods: Using MYC-amplified, p53-mutant (G266E) SF188 glioblastoma cells, we performed siRNA-mediated knockdown, overexpression, and rescue experiments. Cell survival was assessed by trypan blue exclusion and Annexin V/PI staining. ROS levels and NADP⁺/NADPH ratios were measured by DCFH-DA fluorescence and enzymatic assays. Metabolite tracing was conducted using [U-¹³C₅] glutamine followed by LC-MS. Key findings were validated in additional cell lines including HCT116, U2OS and MDA-MB-231. Results: ME1 and ME2 promote SF188 cell survival under glutamine deprivation, an effect that depends on their catalytic activity but is independent of TCA cycle anaplerosis. ME1 maintains redox balance by generating NADPH, and antioxidant treatment rescues the survival defect caused by ME1 knockdown. In contrast, ME2 does not contribute to redox regulation but stabilizes mutant p53 (G266E) via proteasome inhibition. Both of these pro-survival functions are attenuated upon MYC knockdown, suggesting a dependency on MYC expression. Across all cell lines tested, ME1 and ME2 also promote survival through redox maintenance, although the isoform responsible for antioxidant function differs. Conclusions: ME1 and ME2 support metabolic adaptation to glutamine starvation through distinct, isoform-specific mechanisms that depend on MYC expression and p53 mutation status. These findings suggest malic enzymes as potential therapeutic targets in MYC-driven, p53-mutant tumors. Full article

Background: Electrochemotherapy enhances the intracellular delivery of anticancer agents through electroporation but is traditionally limited to cytotoxic drugs associated with significant side effects. Vitamin C (ascorbic acid) exhibits selective anticancer activity when accumulated at high intracellular concentrations; however, its therapeutic application is restricted by poor membrane permeability and rapid systemic clearance. Methods: In this study, we investigated whether reversible electroporation, applied using a custom-designed variable plate electrode system designed to deliver a uniform electric field, could potentiate the antitumor efficacy of low-dose vitamin C. Numerical simulations were performed to optimize electrode spacing and stimulation voltage, suggesting homogeneous electric field coverage throughout the tumor volume. The proposed approach was evaluated in vitro using MDA-MB-231 and 4T1 breast cancer cell lines and in vivo in a 4T1 murine breast cancer model. Results: Low-dose vitamin C alone produced minimal cytotoxic effects, whereas its combination with electroporation significantly reduced cell viability and increased apoptotic and necrotic cell death in vitro. In vivo, vitamin C–assisted electrochemotherapy resulted in pronounced tumor growth suppression, with tumor volumes reduced to approximately 0.34-fold of baseline by day 15, accompanied by decreased proliferation and marked tissue disruption. Conclusions: These findings demonstrate that uniform-field reversible electroporation markedly enhances the intracellular delivery and antitumor activity of low-dose vitamin C, supporting this technology-driven strategy as a promising, low-toxicity alternative to conventional chemotherapeutic agents in electrochemotherapy for solid tumors. Full article

Background: Lavandula stoechas has attracted increasing attention for its potential anticancer properties; however, evidence regarding its effects on apoptotic signaling across different tumor types remains limited. Methods: In this study, the effects of dry and fresh ethanol extracts of Lavandula stoechas L. subsp. stoechas (LsDE and LsFE) were investigated in MDA-MB-231 triple-negative breast cancer, RT4 bladder carcinoma, and T98G glioblastoma cell lines, providing a comparative evaluation of their apoptotic effects. Long-term proliferative capacity was assessed using clonogenic survival assays, while apoptosis-related responses were evaluated by Annexin V–FITC/propidium iodide staining, quantitative RT-PCR of BAX and BCL2 and Western blot analysis of Bax, Bcl-2, and cleaved PARP1. Results: Both extracts significantly reduced clonogenic survival in all tested cancer cell lines, with LsDE showing stronger inhibitory effects in RT4 and T98G cells. Annexin V/PI analysis revealed cell type-dependent response patterns. In MDA-MB-231 cells, both extracts increased the proportion of PI-positive cells, suggesting a loss of membrane integrity, whereas RT4 cells exhibited increased early apoptotic and membrane-compromised populations. In contrast, T98G cells showed comparatively limited changes associated with apoptosis. Transcriptional analysis demonstrated extract- and cell line-specific modulation of the BAX/BCL2 ratio. Western blot analysis further demonstrated activation of mitochondrial apoptotic signaling through coordinated regulation of Bax and Bcl-2 and increased PARP1 cleavage. LsFE showed the strongest apoptosis-associated changes in MDA-MB-231 cells, whereas LsDE showed stronger effects in T98G cells, while both extracts were effective in modulating these proteins in RT4 cells. Conclusions: These findings indicate that ethanol extracts of L. stoechas impair long-term proliferative capacity and induce tumor type-dependent modulation of apoptosis-related markers. This study provides an integrated experimental framework that combines clonogenic survival assays, apoptosis analyses, gene expression, and protein-level measurements, supporting further investigation of L. stoechas extracts in cancer research. Full article

Breast cancer is classified into distinct molecular subtypes, including Luminal A, Luminal B, HER2-enriched, Basal-like, and Claudin-low. While traditional studies mostly use 2D cell cultures, 3D models better mimic in vivo tumor conditions. In this study, we generated and characterized 3D spheroids from breast cancer cell lines representing different molecular subtypes. Morphologically, spheroids were either compact (MCF-7/AZ, T47D, BT474, MDA-IBC-3, BT-20, SUM149PT) or loosely adhered (MDA-MB-468, SK-BR-3, MDA-MB-231), while retaining key parental subtype biomarkers. Cell viability decreased with increasing spheroid size, but apoptotic cCasp3 staining was restricted to Basal-like spheroids. Compact spheroids expressed E- and/or P-cadherin, indicating epithelial or epithelial–mesenchymal transition (EMT) hybrid traits, while loose spheroids showed vimentin expression linked to a mesenchymal phenotype. In conclusion, EMT-associated features, rather than intrinsic molecular subtype, may contribute to 3D spheroid architecture of breast cancer cell lines. Full article

The emergence of antimicrobial resistance and the increasing incidence of cancer have highlighted the urgent need to develop new drugs; therefore, the discovery of new bioactive molecules is an important goal for future research. In this study, freshwater fungi isolated from submerged Phragmites australis from Egypt were screened for antimicrobial and cytotoxic activities. Using ITS1 and ITS4 primers, eight frequently occurring Sordariomycetes taxa were identified and were then selected for further evaluation of bioactivity. Ethyl acetate crude extracts (A–H) were evaluated for antimicrobial activity using the agar disk-diffusion method. Extracts A and E, derived from Chaetomium globosum SCUF0000404 (PX596738) and Chaetomium madrasense SCUF0000401 (PX596735), respectively, showed broad-spectrum activity at 100 mg/mL against bacterial pathogens, including Staphylococcus aureus ATCC 29213 (15.33 and 18.00 mm), Streptococcus pyogenes ATCC 19615 (11.00 mm), Escherichia coli ATCC 35218 (10.33 and 10.67 mm), Klebsiella pneumoniae ATCC 700603 (14.00 and 16.67 mm), and Pseudomonas aeruginosa ATCC 27853 (13.33 and 16.33 mm), and show antifungal activity against Candida albicans ATCC 14053 (20.33 mm), Candida krusei ATCC 6258 (15.67 and 15.33 mm), Trichosporon asahii AMS 187 (17.00 and 17.67 mm), Exserohilum rostratum AMS 1077 (34.00 and 33.67 mm), and Trichophyton indotineae AMS 180 (38.33 and 34.00 mm). Selective cytotoxic effects on the breast cancer cell line MDA-MB-231 were observed by extracts A and E at IC₅₀ = 309 and 277 μg/mL, while non-selective cytotoxic effects on the normal HUVEC cell line were found with IC₅₀ = 919 and 796 μg/mL, respectively. Characterization of the most effective extracts A and E by high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) shows that they have a wide range of secondary metabolites, including cytochalasans, azaphilone alkaloids, steroids, terpenoids, flavonoids, and phenols. These findings underscore the chemical diversity and therapeutic potential of freshwater fungi from Egypt. Full article

Background and Objectives: While nisin exhibits promising antitumor properties, its clinical utility is hindered by pharmacokinetic instability and rapid enzymatic degradation. This systematic review evaluates the critical role of advanced pharmaceutical formulations and targeted nanosystems in overcoming these limitations to enhance nisin’s cytotoxic and pro-apoptotic efficacy in vitro. Methods: Following PRISMA guidelines, a comprehensive search was conducted across six electronic databases (PubMed, ScienceDirect, Scopus, Web of Science, SpringerLink, and DOAJ). In vitro studies comparing free nisin against polymeric, metallic, and cyclodextrin-based nanocarriers across diverse neoplastic lineages were included. Methodological quality was assessed using the SciRAP 2.1 tool, and a within-line comparative analysis was performed for MDA-MB-231 and HT-29 models. Results: Twelve studies met the inclusion criteria. A definitive technological inflection point was identified: nisin-loaded nanosystems reduced effective concentrations by up to 2706-fold relative to the free peptide in MDA-MB-231 cells, and 71-fold in A549 lung cancer cells. Mechanistically, nanosystems facilitated membrane pore formation, mitochondrial-mediated apoptosis via Bax/Bcl-2 modulation, caspase 3/7/9 activation, and p53 reactivation. Three previously underreported mechanistic dimensions were identified: TWIST1 downregulation and FZD7 binding in hepatocellular carcinoma, and downregulation of CEA, CEAM6, MMP2F, and MMP9F in colorectal cancer lines. Conclusions: The therapeutic viability of nisin in oncology is strictly dependent on pharmaceutical engineering. Future research must prioritize in vivo pharmacokinetic validation, experimental confirmation of novel mechanistic targets, and standardized nisin purity reporting to consolidate its clinical translation. Full article

Surface-enhanced Raman spectroscopy (SERS) amplifies Raman scattering by placing molecules in the near-field of plasmonic nanostructures, enabling label-free molecular fingerprinting. While attractive for living cell phenotyping, many cellular SERS works rely on internalized colloidal nanoparticles, leading to variable uptake/localization, aggregation-driven hotspot fluctuations, and potential cellular perturbation. Here, we report a chip-like Au/SiO₂ nanolaminate SERS substrate that supports direct culture and label-free measurements of living cells on spatially defined hotspots without nanoparticle uptake. The periodic nanolaminate forms dense nanogaps and is engineered for 785 nm excitation, providing uniform enhancement over a large, culture-compatible area with high hotspot uniformity. By engineering the cell–substrate nano–bio interface, the platform enables reproducible acquisition of intrinsic cellular vibrational fingerprints under physiological conditions without Raman tags. Using MCF-7 and MDA-MB-231 breast cancer cells, we collected hundreds of spectra per line, and MDA-MB-231 exhibited broader spectral variations, indicating greater heterogeneity. Principal component analysis and linear discriminant analysis achieved 99% classification accuracy for MCF-7 and MDA-MB-231, and bright-field imaging confirmed preserved adhesion and canonical morphologies. This chip-based, label-free living cell SERS platform enables scalable, nonperturbative phenotyping and may support rapid malignancy classification and treatment response screening across subtle cancer states. Full article

While artemisinin and its derivatives demonstrate broad antitumor potential, the stereochemical influence on the bioactivity of higher-order artemisinin assemblies remains inadequately characterized. Herein, we report the synthesis, chromatographic separation, and structural elucidation of four stereoisomeric artemisinin trimers, followed by systematic evaluation of their antitumor efficacy against MCF-7 and MDA-MB-231 breast cancer cell lines. All trimers exhibited potent cytotoxicity against MCF-7 cells (IC₅₀ < 0.09 μM), with trimer 6a (β, β, β) demonstrating robust antitumor activity in both in vitro and in vivo xenograft models. Remarkably, pronounced stereochemistry-dependent activity emerged against MDA-MB-231 cells: 6a displayed approximately 100-fold greater potency than 6b (β, β, α) and 6.6-fold superiority over gemcitabine. Mechanistic investigations revealed that 6a downregulates Cyclin D1, CDK4, and CDK6 expression, thereby inducing G0/G1 phase cell cycle arrest. These findings underscore the pivotal role of stereochemical configuration in modulating artemisinin trimer bioactivity and provide rational guidance for structure-based design of artemisinin-derived anticancer therapeutics. Full article

A series of 6-azaindole pyridinium derivatives were synthesized, structurally characterized, and evaluated for their antimicrobial (against Staphylococcus aureus, Escherichia coli, and Candida albicans) and anticancer properties (against NCI 60 panel). Hemocompatibility was evaluated using the hemolytic index, while ADME properties were estimated using in silico methods. Structure–activity relationship analysis indicated that para-substitution of the phenyl ring, particularly with halogen or methoxy groups, influences antimicrobial activity, selectivity toward Gram-positive bacteria, and hemocompatibility. Compounds 2b and 2c showed the most notable antimicrobial effects, including inhibition of microbial adhesion at hemocompatible concentrations. Compound 2b exhibited growth inhibition against cancer cells, showing 57% percent growth inhibition (PGI) against the MDA-MB-468 breast cancer cell line at 10 mM. Overall, these results highlight 6-azaindole pyridinium salts as a promising class of compounds for further investigation. Full article

Breast cancer remains a major global health challenge, requiring novel therapeutic strategies that can overcome drug resistance and improve treatment efficacy. This study investigates the synergistic antitumor effects of etoposide, a conventional chemotherapeutic agent, and resveratrol, a natural polyphenol with anticancer properties, in human breast cancer cell lines, with particular focus on their ability to activate the parthanatos cell death pathway. Using MCF-7 (estrogen receptor-positive) and MDA-MB-231 (triple-negative) breast cancer cells, we assessed cell viability via MTT assays and evaluated parthanatos activation through multiple complementary approaches including AIF translocation determined by subcellular fractionation, NAD+ depletion measurement, and gene expression analysis. Synergy was quantified using the Chou–Talalay method across multiple effect levels (ED50, ED75, ED90). To establish causality, Olaparib PARP inhibitor experiments were performed to confirm that PARP-1 hyperactivation is essential for the observed cytotoxic effects. The results demonstrated that the etoposide–resveratrol combination significantly enhanced cell death and inhibited proliferation compared to single-agent treatments, with combination index (CI) values indicating strong synergism (CI = 0.62–0.75 for MCF-7; CI = 0.58–0.71 for MDA-MB-231). This synergy was associated with robust parthanatos activation, evidenced by increased PARP-1 expression, AIF nuclear translocation confirmed by subcellular fractionation, and significant NAD+ depletion. Critically, Olaparib pre-treatment (3 µM) significantly rescued cells from combination-induced death, restored NAD+ levels to near-control values, and prevented AIF translocation, establishing a causal link between PARP-1 hyperactivation and parthanatos-mediated cytotoxicity. The combination also induced significant DNA fragmentation, elevated oxidative stress, and cell death with morphological features consistent with parthanatos, while caspase activity remained low, confirming caspase-independent cell death. These findings suggest that targeting parthanatos with etoposide and resveratrol could offer a promising therapeutic strategy for breast cancer, potentially overcoming resistance and improving efficacy. Further in vivo studies and clinical investigations are needed to validate these results and explore translational applications. Full article

The development of effective and trackable drug delivery systems remains a major challenge in anticancer therapy. In this study, we designed novel polysaccharide-based theranostic carriers using a yeast-shell (YC) framework, providing a biocompatible platform for intracellular drug delivery. For the first time, a chitosan–genipin bioconjugate was synthesized via a solvent-free, green mechanochemical method and applied as an outer coating to microcarriers encapsulating the anticancer drug 5-fluorouracil (5-FU) and the fluorescent dye phenosafranin. The resulting system enabled simultaneous fluorescence tracking and the controlled release of the chemotherapeutic agent. In vitro evaluation using the MDA-MB-231 triple-negative breast cancer cell line demonstrated that 5-FU retained its antiproliferative activity, while the carriers facilitate sustained intracellular delivery. These findings highlight the potential of YC-based polysaccharide carriers, surface- modified with chitosan–genipin to enhance hydrophilicity, as a versatile platform for anticancer therapy, combining biocompatibility, traceability, and controlled drug release. Full article

Background: Breast cancer (BC) remains the most prevalent malignancy among women worldwide, with one in eight at risk during their lifetime. Platinum-based chemotherapeutic drugs, despite of their binding to the DNA of cancer cells, are plagued by toxicity and resistance, necessitating the need for safer and more effective alternatives, such as organometallic complexes. Both synthetic organometallic complexes and natural compounds have attracted attention in this regard. Organotin(IV) complexes are promising chemotherapeutics due to their structural versatility and bioactivity, while vitamins such as Vitamin D (VD) and Vitamin E (VE) exhibit antiproliferative, anti-inflammatory, and antioxidant properties, making them valuable candidates for combination therapy. Methodology: In this study, six novel organotin(IV) dithiocarbamate complexes [LMe₃Sn (Complex 1), LBu₃Sn (Complex 2), LPh₃Sn (Complex 3), LMe₂SnCl (Complex 4), LBu₂SnCl (Complex 5), and L₂Me₂Sn (Complex 6), where L = (E)-4-styrylpiperazine-1-carbodithioate], were synthesized and characterized by FT-IR, ¹H-, ¹³C-NMR, and elemental analysis. Results: Structural studies confirmed penta- and hexacoordination geometries. In silico docking against six BC-related proteins identified Complexes 2 and 4 with both vitamins as promising candidates, exhibiting strong binding affinities, with stable interaction profiles. However, integration of pharmacokinetic, antioxidant, and anti-inflammatory analyses highlighted Complex 4 with both vitamins as the most potent candidate owing to its superior ADME characteristics and balanced biological properties. Subsequent in vitro assays confirmed these findings, as Complex 4 demonstrated strong cytotoxic activity against both MCF-7 (>1.16-fold) and MDA-MB-231 (>1.46-fold) cell lines, surpassing the efficacy of cisplatin. Remarkably, co-administration of VD or VE with Complex 4 further enhanced its anticancer potential, with Chou–Talalay combination index values < 1 (0.66–0.91) indicating a synergistic interaction. Conclusions: Collectively, these results identify Complex 4 as a promising lead compound, and its synergistic activity with natural vitamins may promote cell death, likely through apoptosis induction and modulation of oxidative stress, underscoring its potential as an effective and less toxic therapeutic strategy for breast cancer management. Full article

Background/Objectives: The F3 peptide, a tumor-homing peptide known to bind cell-surface nucleolin, is frequently employed as a targeting vector in cancer research. However, the impact of the modification site on its cellular binding properties has not been investigated yet. In this work, we aimed to design an improved F3-based radioconjugate by identifying the optimal conjugation site and establishing a protocol for its biological evaluation in vitro. To achieve this, we compared F3 peptide derivatives modified at their N- or C-termini with DOTA for complexation of indium-111 (¹¹¹In) for SPECT or Auger electron therapy or a fluorophore (FITC) for optical imaging. Methods: N-and C-terminal DOTA-modified F3 peptides were radiolabeled with indium-111 and compared for their in vitro stability in different physiologically relevant media. Suitable nucleolin-positive cell lines for further in vitro studies were identified by confocal microscopy of a FITC-labeled F3 peptide derivative. The radioconjugates were then investigated on MDA-MB-231 (breast cancer) and PC-3 (prostate cancer) cells for nucleolin-specific cell binding and uptake, and several parameters of the in vitro assays were varied to establish a suitable protocol. Results: In general, in vitro assays with F3 peptide conjugates are challenging, as the outcome depends on a number of experimental parameters, leading, in some cases, to varying results. In particular, the presence of Ca²⁺ and Mg²⁺ had a decisive impact on the results, likely because the metal ions compete with the binding of F3 conjugates to nucleolin. The C-terminal modified, ¹¹¹In-labeled F3 radioconjugate performed better than the N-terminal modified analog. While several parameters of the in vitro experiments were optimized, the overall cell uptake in vitro of radioactivity was still low (<2% of applied radioactivity). Conclusions: A standardized in vitro protocol for evaluating F3 peptide conjugates on cancer cells was established, revealing that the C-terminus is the preferred site for modification. Because the cellular uptake of the radiotracer was shown to likely not be sufficient for radiotracer development, further studies on the optimization of the F3 peptide conjugates, including structural modifications, are required. Full article

Oleocanthal (OC), an anti-inflammatory and antioxidant phenolic compound exclusively found in extra virgin olive oil (EVOO), has emerged as a potential anticancer agent through multiple mechanisms of action, yet its impact on key processes such as cellular metabolism remains insufficiently characterized. Here, we investigated the metabolic and mitochondrial responses to OC across different breast cancer molecular subtypes. Triple-negative (MDA-MB-231) and luminal (MCF7, T47D) breast cancer cell lines were treated with OC to evaluate cell viability, cell cycle progression, metabolic enzyme expression, mitochondrial respiration, and mitochondrial network organization. OC responsiveness differed, being highest in MDA-MB-231 and lowest in T47D cells. Lactate dehydrogenase levels decreased in all cell lines, while mitochondrial response varied. MDA-MB-231 mitochondrial function was fully impaired, while MCF7 cells showed increased respiratory activity, with marked mitochondrial fragmentation, and T47D cells largely preserved mitochondrial integrity and function. Notably, the magnitude of OC effects correlated with MET expression, an established target of OC and a prognostic factor associated with reduced relapse-free survival within the triple-negative subtype. Collectively, these findings identify OC as a modulator of cancer cell metabolism and mitochondrial dynamics, with particular relevance in MET-high triple-negative breast cancers. Full article