Search Results (5,061)

Background/Objectives: Ascorbic acid (AA)is a micronutrient with concentration-dependent anticancer properties, acting either as a reactive oxygen species (ROS) scavenger or inducer. Methods: Conventional redox-based assays such as MTS/MTT often overestimate cell proliferation due to AA’s interaction with tetrazolium salts, leading to increased formazan production. To overcome this limitation, we employed the Propidium Iodide Triton X-100 (PI/TX-100) assay to evaluate AA’s cytotoxic effects across a diverse panel of cancer and normal cell lines, including prostate (22Rv1, C4-2B, DU-145, LNCaP), breast (MCF-7, MDA-MB-231, MDA-MB-453), lung (A549), liver (HepG2, SK-HEP-1, Huh7), and kidney (Vero) cells. Results: AA significantly suppressed cancer cell viability compared to normal cells (RWPE1 and Vero), with the strongest effects observed in hormone receptor-positive lines. The relative sensitivity to AA followed distinct patterns within each cancer type. Mechanistically, AA-induced cell death involved ROS generation, lipid peroxidation, cell cycle arrest, ferroptosis, apoptosis, and downregulation of pyruvate dehydrogenase kinase 1 (PDHK1). Conclusions: These findings further support the potential of AA as a selective anticancer agent and highlight the importance of assay choice in evaluating its therapeutic efficacy. Full article

Breast cancer is a common and chronic condition, and despite improvements in diagnosis, treatment, and prevention, the number of cases of breast cancer is rising annually. New therapeutic drugs that target specific checkpoints should be created to fight breast cancer. Mandragora autumnalis possesses substantial cultural value as a herb and is regarded as one of the most significant medicinal plants; however, little is known about its anticancerous biological activity and chemopreventive molecular pathways against the triple-negative breast cancer (MDA-MB-231) cell line. In this study, the antioxidant, anticancer, and underlying molecular mechanisms of the Mandragora autumnalis ethanolic leaves extract (MAE) were evaluated, and its phytochemical composition was determined. Results indicated that MAE diminished the viability of MDA-MB-231 cells in a concentration- and time-dependent manner. Although MAE exhibited 55% radical scavenging activity at higher concentrations in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, the attenuation of its cytotoxic effects in MDA-MB-231 cells with N-acetylcysteine (NAC) co-treatment suggests a potential role of oxidative stress. Additionally, MAE caused an increase in the tumor suppressor p53. Moreover, this extract caused a significant decrease in the expression of Ki-67 (a cellular proliferation marker), MMP-9 (matrix metalloproteinase-9, an enzyme involved in extracellular matrix degradation and metastasis), and STAT-3 (a transcription factor regulating cell growth and survival). Also, MAE altered cell cycle, cell migration, angiogenesis, invasion, aggregation, and adhesion to suppress cellular processes linked to metastasis. All of our research points to MAE’s potential to function as an anticancer agent and opens up new possibilities for the development of innovative triple-negative breast cancer treatments. Full article

The plants from the Ocimum genus, belonging to the Labiatae family, serve as important bioresources of essential oils (EOs) rich in biologically active secondary metabolites, widely used in medicine, food, and cosmetics. This study explored the volatile composition, enantiomeric distribution, and in vitro biological activities of EOs from three Ocimum species native to Nepal: O. tenuiflorum L., O. basilicum L., and O. americanum L. EOs were extracted via hydro-distillation and analyzed using gas chromatography–mass spectrometry (GC-MS) for chemical profiling and chiral GC-MS for enantiomeric composition. Hierarchical cluster analysis was performed for major chemotypes. Antioxidant activity was assessed using DPPH and ABTS assays. Antimicrobial efficacy was evaluated using the microbroth dilution method, and cytotoxicity was tested on NIH-3T3 (normal) and MCF-7 (breast cancer) cell lines via the Cell Counting Kit-8 assay. EO yield was highest in O. tenuiflorum (1.67 ± 0.13%) during autumn and lowest in O. americanum (0.35 ± 0.02%) during winter among all Ocimum spp. The major compounds identified in O. tenuiflorum were eugenol (32.15–34.95%), trans-β-elemene (29.08–32.85%), and β–caryophyllene (19.85–21.64%). In O. americanum, the major constituents included camphor (51.33–65.88%), linalool (9.72–9.91%), germacrene D (7.75–1.83%), and β–caryophyllene (6.35–3.97%). For O. basicilum, EO was mainly composed of methyl chavicol (62.16–64.42%) and linalool (26.92–27.05%). The oxygenated monoterpenes were a dominant class of terpenes in the EOs except for O. tenuiflorum (sesquiterpene hydrocarbon). A hierarchical cluster analysis based on the compositions of EOs revealed at least three different chemotypes in Ocimum species. Chiral GC-MS analysis revealed β-caryophyllene and germacrene D as enantiomerically pure, with linalool consistently dominant in its levorotatory form. O. tenuiflorum exhibited the strongest antimicrobial activity, particularly against Candida albicans, and showed notable anticancer activity against MCF-7 cells (IC₅₀ = 23.43 µg/mL), with lower toxicity to normal cells. It also demonstrated the highest antioxidant activity (DPPH IC₅₀ = 69.23 ± 0.10 µg/mL; ABTS IC₅₀ = 9.05 ± 0.24 µg/mL). The EOs from Ocimum species possess significant antioxidant, antimicrobial, and cytotoxic properties, especially O. tenuiflorum. These findings support their potential application as natural agents in medicine, food, and cosmetics, warranting further validation. Full article

Neuroblastoma (NB) is an aggressive pediatric cancer, with high-risk patients facing a five-year survival rate of ~50%. Standard therapies, including surgery, chemotherapy, radiation, and immunotherapy, are associated with significant long-term toxicities and frequent relapse. Histone deacetylase (HDAC) inhibitors have emerged as promising agents for cancer therapy, given their role in modulating gene expression and tumor phenotypes. This study evaluated M344 [4-(dimethylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide], an HDAC inhibitor, for its efficacy and mechanisms of action against NB. Analysis of clinical NB Gene Expression Omnibus data revealed advanced-stage tumors exhibit higher HDAC expression relative to early-stage samples. M344 treatment effectively increased histone acetylation, induced G0/G1 cell cycle arrest, and activated caspase-mediated cell death. Relative to vorinostat, an HDAC inhibitor in clinical use for lymphoma and clinical trials for NB, M344 displayed superior cytostatic, cytotoxic, and migration-inhibitory effects. In vivo, metronomic M344 dosing suppressed tumor growth and extended survival. Combination therapy with M344 and topotecan improved topotecan tolerability, while M344 co-administration with cyclophosphamide reduced tumor rebound post-therapy. In total, M344 demonstrated strong therapeutic potential for NB, offering improved tumor suppression, reduced off-target toxicities, and enhanced control of tumor growth post-therapy. These findings support further investigation of HDAC inhibitors, such as M344, for clinical application in NB treatment. Full article

Esophageal squamous cell carcinoma (ESCC) accounts for the majority of esophageal cancers worldwide, with a poor prognosis and increasing resistance to conventional treatments. Faced with these limitations, nanoparticles (NPs) are attracting growing interest as innovative therapeutic agents capable of improving specificity and efficacy and reducing systemic toxicity. This study critically examines the pharmacological effects, mechanisms of action, and toxicity profiles of different metallic or organic nanoparticles tested on ESCC cell lines. Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines were followed by a meticulous literature search of Google Scholar, Web of Science, PubMed/Medline, and Scopus databases to achieve this goal. The results show that the anti-tumor properties vary according to the type of nanoparticle (copper(II) oxide (CuO), silver (Ag), gold (Au), nickel(II) oxide (NiO), nano-curcumin, etc.), the synthesis method (chemical vs. green), and the biological activity assessment method (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Bromodeoxyuridine (BrdU), Cell Counting Kit-8 (CCK8) assays, etc.). NPs derived from green synthesis, such as those based on Moringa oleifera, Photinia glabra, or pomegranate bark, exhibit moderate cytotoxic activity (50% inhibitory concentration (IC₅₀) between 92 and 500 µg/mL) but show good tolerance on normal cells. In contrast, chemically synthesized NPs, such as Cu(II) complexes with 1,3,5-benzenetricarboxylic acid (H₃btc) or 1,2,4-triazole (Htrz), show lower IC₅₀ (34–86 µM), indicating more marked cytotoxicity towards cancer cells, although data on their toxicity are sometimes lacking. In addition, multifunctional nanoparticles, such as gold-based nano-conjugates targeting Cluster of Differentiation 271 (CD271) or systems combined with doxorubicin, show remarkable activity with IC₅₀ below 3 µM and enhanced tumor selectivity, positioning them among the most promising candidates for future clinical application against ESCC. The most frequently observed mechanisms of action include induction of apoptosis (↑caspases, ↑p53, ↓Bcl-2), oxidative stress, and inhibition of proliferation. In conclusion, this work identifies several promising nanoparticles (silver nanoparticles derived from Photinia glabra (PG), gold-based nano-immunoconjugates targeting CD271, and silver–doxorubicin complexes) for future pharmaceutical exploitation against ESCC. However, major limitations remain, such as the lack of methodological standardization, insufficient in vivo and clinical studies, and poor industrial transposability. Future prospects include the development of multifunctional nanocomposites, the integration of biomarkers for personalized targeting, and long-term toxicological assessment. Full article

Background: Insulin-degrading enzyme (IDE) has become an essential target for the clinical treatment of various important diseases, including type 2 diabetes, Alzheimer’s disease, and breast cancer, owing to its diverse substrate specificity. Particularly in cancer therapy, IDE inhibitors have received significant attention. Methods: We evaluated the in vitro inhibitory activity (IC₅₀) of ethyl 2-(3,5-dioxo-2-p-tolyl-1,2,4-thiadiazolidin-4-yl) acetate (1) against wild-type IDE. The mechanism of action was investigated using Lineweaver–Burk double reciprocal plots and molecular docking analyses. Additionally, we examined the structure–activity relationship, cytotoxicity, selectivity, and effects on cell migration to assess its potential druggability. Based on molecular docking results, we prepared the mutant protein T142A and compared its inhibitory effects with those of the wild-type and mutant proteins. Results: Compound 1 exhibited an inhibitory effect on IDE (IC₅₀ = 3.60 μM). This compound exerts its inhibitory effect through competitive binding to the catalytic site of IDE. Compound 1 demonstrated selective cytotoxicity toward cancer cells compared to normal cells, effectively inhibiting IDE at concentrations ≤ 10 μM. At a concentration of 3.6 μM, the inhibitory effect of the compound on cancer cell migration was significantly stronger than that observed in normal cells. Although the T142A mutant retained catalytic hydrolysis activity with a similar K_m value, its reaction rate was markedly lower than that of the wild-type enzyme. Conclusions: Compound 1 exhibits a competitive inhibitory effect on IDE, selectively targeting IDE with greater toxicity toward cancer cells compared to normal cells. It also inhibits cancer cell migration. Notably, 1 demonstrates significantly stronger inhibitory activity against the T142A mutant than the wild-type IDE, indicating that the Thr142 residue plays a crucial role in the interaction between the IDE hydrophobic pocket and 1. These findings suggest that 1 holds potential as a chemotherapeutic agent for treating IDE-related cancers, including breast, prostate, and pancreatic cancers. Full article

Background: Breast cancer is a complex, multifactorial malignancy characterized by the uncontrolled proliferation of epithelial cells, with certain subtypes exhibiting resistance to conventional therapies. Plant-derived essential oils have been proposed as potential anticancer agents due to their bioactive compounds. Recent studies have demonstrated that Decatropis bicolor essential oil exhibits activity against breast cancer, attributed to diverse secondary metabolites such as δ-cadinene. Aberrant expression of adhesion and invasion proteins, including MMPs, CD44, N-cadherin, and ZEB-2, are key signs of breast cancer progression and metastasis; they represent relevant molecular targets. Objectives: To investigate the interaction of δ-cadinene with these proteins using in silico approaches and in vitro evaluations. Methods: In silico analyses were conducted to assess the interaction and stability of δ-cadinene with target proteins. In vitro assays, including cytotoxicity, morphological analysis, and cell invasion assays, were performed using MDA-MB-231 and MCF10-A cell lines. Results: Interaction analysis suggest that δ-cadinene interacts with key catalytic residues in MMP-2, sharing features with Quercetin. Blind docking revealed a second high-affinity site in the Fibronectin type II domain.Molecular dynamics simulations confirmed the stability of these complexes. In vitro studies showed that δ-cadinene significantly reduced MDA-MB-231 cell viability in a concentration-dependent manner, without affecting MCF10-A cells, and significantly inhibited invasion and MMP-2 activity after 24 h. Conclusions: δ-cadinene exhibits selective cytotoxic and anti-invasive activity in MDA-MB-231 cells, likely through dual inhibition of the catalytic and adhesion domains of MMP-2. These findings support δ-cadinene as a potential candidate for future therapeutic development in metastatic breast cancer. Full article

Cancer, a leading global cause of death responsible for nearly 10 million deaths annually, demands innovative therapeutic strategies. Intrinsic cytotoxicity and biocompatibility of zinc oxide nanoparticles (ZnO-NPs) have rendered them promising nanoplatforms in oncology. We herein systematically review their applications for targeted cancer chemotherapy, with a focus on physicochemical properties, drug delivery mechanisms, and interactions with the tumor microenvironment (TME). We searched PubMed, SCOPUS, and Web of Science from inception through December 2024 for peer-reviewed preclinical studies on cancer models. Results were qualitatively synthesized. Quality was assessed with the SYRCLE risk of bias tool. Among 20 eligible studies, ZnO-NPs were frequently functionalized with ligands to enhance tumor targeting and minimize systemic toxicity. Chemotherapeutic agents (doxorubicin, 5-fluorouracil, docetaxel, cisplatin, gemcitabine, and tirapazamine) were loaded into ZnO-based carriers, with improved anticancer efficacy compared to free drug formulations, particularly in multidrug-resistant cell lines and in vivo murine xenografts. The mildly acidic TME was exploited for pH-responsive drug release, premature leakage reduction, and improvement of intratumoral accumulation. Enhanced therapeutic outcomes were attributed to reactive oxygen species generation, zinc ion-mediated cytotoxicity, mitochondrial dysfunction, and efflux pump inhibition. Deep tumor penetration, apoptosis induction, and tumor growth suppression were also reported, with minimal toxicity to healthy tissues. ZnO-NPs might constitute a versatile and promising strategy for targeted cancer chemotherapy, offering synergistic anticancer effects and improved safety profiles. Future studies emphasizing long-term toxicity, immune responses, and scalable production could lead to clinical translation of ZnO-based nanomedicine in oncology. Full article

Iron(III) (Fe(III)) complexes have recently emerged as safer alternatives to magnetic resonance imaging (MRI) contrast agents (CAs), reigniting interest in biomedical research. Although gadolinium Gd(III)-based contrast agents (CAs) have been widely used in MRI over the past four decades, their use in the current clinical routine is severely constrained due to concerns about high toxicity and environmental impact. Research is now focusing on synthesizing safer contrast agents with alternative paramagnetic ions like Fe(III) or Mn(II). MRI CAs with integrated potent therapeutic moieties may offer synergistic advantages over traditional contrast agents in clinical use. The study explored the use of salinomycin-ferrihydrite composites as possible effective ensembles of imaging and therapeutic units in the same molecule, evaluating their anticancer activity and influence on the signal in MRI. The composites were characterized using Mössbauer spectroscopy and ICP-MS for iron content determination. The in vitro relaxivity measurements in a high-field MR scanner demonstrated the potency of the composites as T₂ enhancers. The antitumor activity of one selected Sal-ferrihydrite composite was tested in three human cancer cell lines: A549 (non-small cell lung cancer); SW480 (colon cancer); and CH1/PA1 (ovarian teratocarcinoma) by the MTT cell viability assay. The new Sal-ferrihydrite composite showed a pronounced cytotoxicity in all three human cancers in line with enhanced signal in MRI, which makes it a promising candidate for future biomedical applications. The superior cytotoxic effect, together with the strong signal enhancement, makes these compounds promising candidates for further detailed investigations as future theranostic agents. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, limiting the efficacy of conventional targeted therapies. As a result, novel therapeutic strategies are urgently needed. Photodynamic therapy (PDT), which relies on the activation of photosensitizers (PSs) by light to induce cytotoxic effects, has emerged as a promising alternative for TNBC treatment. Furthermore, the conjugation of PSs with targeting peptides has demonstrated enhanced selectivity and therapeutic efficacy, particularly for porphyrin-based photosensitizers. In this study, we report the synthesis of novel porphyrin–peptide conjugates designed to selectively target the epidermal growth factor receptor (EGFR), which is frequently overexpressed in TNBC. The conjugates were prepared via thiol displacement of the meso-nitro group in a 5,15-diarylporphyrin scaffold using EGFR-binding peptides. Photodynamic activity was evaluated in two EGFR-overexpressing TNBC cell lines. Cellular uptake of the conjugates correlated with EGFR expression levels, and PDT treatment resulted in differential induction of necrosis, apoptosis, and autophagy. Notably, the conjugates significantly inhibited EGFR-expressing cell line migration, a critical hallmark of metastatic progression. These findings underscore the potential of EGFR-targeted porphyrin–peptide conjugates as promising PDT agents for the treatment of TNBC. Full article

Metabolic anticancer therapy based on enzymatic arginine (Arg) deprivation (ADT) is currently being evaluated in clinical trials. The combination of ADT with low doses of the plant cytotoxic analogs of Arg, canavanine (Cav) or indospicine (Isp), have been proposed as being more efficient and selective against malignant cells. The leguminous plant Indigofera spicata contains one of the highest known amounts of Isp. Here we demonstrate for the first time that the Isp-containing ethanolic extract from I. spicata is growth-inhibiting and toxic for cultured human colorectal and ovarian carcinoma cells. The extract reduces the viability of colorectal carcinoma cells two-fold under Arg-deficient conditions and entirely abrogates their residual proliferative potential (growth recovery) after the treatment. Pre-exposure of the extract to recombinant human arginase I (rhARGI) as a therapeutic Arg-depleting agent did not impact the extract’s efficacy. Further development of Isp as a component of combinatorial anticancer metabolic targeting strategies is discussed. Full article

Three new series of indolizines (5a–f, 6a–f and 7a–g), functionalized with bromine or ethyl ester substituents on the pyridine ring, were designed and synthesized as promising anticancer agents. The synthesis of indolizine derivatives was carried out using the 1,3-dipolar cycloaddition of pyridinium N-ylides to ethyl propiolate as a key step. Spectral characterization (using NMR, FT-IR, HRMS and X-ray diffraction) showed that two types of cycloadducts 5a–f and 6a–f were obtained when the ylides generated by the 3-bromopyridinium salts were used as 1,3-dipoles in Huisgen cycloaddition reactions to ethyl propiolate. The anticancer effect of selected compounds was in vitro assessed against the National Cancer Institute (NCI) panel of 60 human tumor cells, at 10 μM concentration, with three compounds (5c, 6c and 7g) showing promising inhibitory activity on the growth of several cell lines including lung, brain, renal cancer and melanoma, as well as a cytotoxic effect against HOP-62 non-small cell lung cells (34% for compound 5c and 15% for compound 7g) and SNB-75 glioblastoma cells (15% for compound 5c and 14% for derivative 7c). Molecular docking revealed favorable binding affinities for 5c, 6c and 7g (–9.22 to –9.88 kcal/mol) at the colchicine-binding site of tubulin with key interactions involving βASN-258, βALA-317, and βLYS-352 residues for 5c, βASN-258 in case of 6c, and αVAL-181 and βLYS-254 for derivative 7g. According to the in silico ADMET analysis, the active compounds are predicted to exhibit good oral bioavailability, promising drug-like qualities and low toxicity risks. Full article

Background/Objectives: The use of food waste in nanomaterial development represents an efficient and sustainable strategy for producing value-added products. Methods: In this study, silver nanoparticles (AgNPs) were synthesized from the hydroethanolic and aqueous extracts of buckwheat (Fagopyrum esculentum Moench) hulls, under optimized conditions. The resulting AgNPs were characterized using spectroscopic and microscopic techniques. To evaluate their bioactivity, free radical scavenging assays, cytotoxicity assays against tumor and normal cells, and broth microdilution assays were conducted. Results: AgNPs, synthesized from the hydroethanolic and aqueous buckwheat hull extracts under optimized conditions, were small (mean diameters of 19.97 ± 7.86 and 5.55 ± 1.34 nm, respectively), well dispersed (polydispersity index values of 0.204 and 0.345, respectively), negatively charged, and stable (zeta potential values of −24.10 ± 6.73 and −23.5 ± 10.3 mV, respectively). The latter were more homogenous in shape, being predominantly spherical. Both samples of AgNPs demonstrated remarkable cytotoxic activity against A-375 human malignant melanoma cells (IC₅₀ values below 5 μg/mL). AgNPs derived from the hydroethanolic buckwheat hull extract suppressed the growth of methicillin-resistant Staphylococcus aureus ATCC 43300 and Staphylococcus epidermidis ATCC 12228, with minimum inhibitory concentration (MIC) values of 37.50 and 4.68 μg/mL, respectively. AgNPs derived from the aqueous buckwheat hull extract exhibited higher free radical scavenging activity (EC₅₀ values of 132.6 ± 0.3 and 77.40 ± 3.52 μg/mL in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays, respectively). Conclusions: AgNPs synthesized from the buckwheat hull extracts demonstrated notable potential as antimelanoma and antibacterial agents. Full article

The concept of hybrid drugs that integrate cytotoxic and anti-inflammatory activity, enabling the simultaneous delivery of a chemotherapeutic agent and a non-steroidal anti-inflammatory drug (NSAID) into the tumor microenvironment (TME), was created with the aim of blocking the mitogenic signals that lead to tumor renewal. Here, we provide for the first time a detailed insight into the mechanism of action of a platinum(IV) complex based on the cisplatin (CP) scaffold bearing two deprotonated NSAID ligands (naproxenate (Npx)) in axial position ([CP(Npx)₂]), free and immobilized in nanostructured silica SBA-15 (SBA-15|[CP(Npx)₂]), in a melanoma model. The conjugate in free or loaded form diminished the viability of cancer cells more potently than CP, with an exceptional preference for the malignant phenotype. Type I and II programed cell death, senescence, and terminal differentiation of the surviving cell fraction were the basic mechanisms of action by which the new hybrid molecule achieved its effect in vitro. In the mouse melanoma model, the application of the therapeutic agents led to a reduction in tumor volume, extinguishing of intratumoral inflammation, and an overall better toxicity profile compared to CP. Overall, this approach improved the efficacy of chemotherapy by removing obstacles that cause chronic inflammation in the TME. Full article

Background: The increasing prevalence of antibiotic-resistant bacterial strains highlights the urgent need for new membrane-targeting antimicrobial agents. Bisquaternary ammonium compounds (bisQACs) have attracted attention for their ability to disrupt bacterial membranes more effectively than monoquaternary analogs. Quinuclidine, known for its health-beneficial properties, has previously been explored for monoQAC derivatization, but studies using natural scaffolds to generate bisQACs remain limited. Methods: Here, we synthesized twelve novel quinuclidine-based bisQACs, systematically varying alkyl chain and linker lengths to investigate structure–activity relationships. Results: Several compounds, including 2(QC₁₆)₃, 2(QC₁₆)₄, 2(QC₁₄)₆, and 2(QC₁₆)₆, exhibited strong activity against Staphylococcus aureus (including MRSA), Listeria monocytogenes, and Escherichia coli, with 2(QC₁₆)₆ being the most potent (MICs 5–38 µM). While cytotoxicity was observed on human RPE1 and HEK293 cells, selectivity indices indicated a favorable therapeutic window relative to reference QACs. Conclusions: These compounds also inhibited biofilm formation and induced rapid bacterial killing through a membrane-disruptive mode of action. Molecular docking showed that alkyl chain and linker variations modulate binding to the QacR efflux regulator, revealing a lower potential for efflux-mediated resistance. Overall, quinuclidine-based bisQACs represent promising leads for potent, selectively active next-generation antimicrobials with a reduced likelihood of resistance development. Full article