Search Results (9,457)

Silver nanoparticles synthesized using natural polysaccharides have received attention for their biocompatibility and potential selective anticancer activity. In this study, the physicochemical properties and biological activity of silver nanoparticles prepared using gums from Acacia senegal (ASS) and Acacia seyal (ASY) were compared. The gums were analyzed to determine their physicochemical characteristics and used as natural reducing and stabilizing agents in nanoparticle synthesis. The resulting nanoparticles were characterized using UV–visible spectroscopy, FTIR, dynamic light scattering, and zeta potential analysis. Their cytotoxicity was evaluated in MCF-7 breast cancer cells and HEK-293 normal cells using MTT assay, flow cytometry, and intracellular reactive oxygen species (ROS) measurement. Both gums showed properties consistent with Gum Arabic, with a higher protein content in ASS. ASS-derived nanoparticles were smaller and had greater colloidal stability. Both formulations reduced MCF-7 cell viability in a dose-dependent manner, with lower IC₅₀ values observed for the ASS-based nanoparticles. Apoptosis induction was associated with increased ROS generation. Limited cytotoxicity toward HEK-293 cells resulted in favorable selectivity indices. Acacia gum–mediated silver nanoparticles demonstrate selective anticancer activity, and gum composition significantly influences nanoparticle stability and bioactivity, supporting their potential application in breast cancer nanotherapy. Full article

Background: Cancer has emerged as the primary cause of death worldwide in recent years. Current cancer treatment strategies require improvement, creating a pressing need for the development of novel therapeutic agents. This study investigated the anticancer effects of a series of newly synthesized tri- and difluoromethylated spiro[5.5]trienone compounds and evaluated the antitumor efficacy of a lead compound, 3s. Methods: The methyl thiazolyl tetrazolium (MTT) assay was used to assess the effect of the trienone compounds on the growth of cancer cells. Cell cycle distribution and intracellular reactive oxygen species (ROS) levels were analyzed by flow cytometry. Protein expression was examined by Western blot. A mouse xenograft model was utilized to test the anticancer effects and toxicity of 3s in vivo. Results: All 21 tri- and difluoromethylated spiro[5.5]trienones exhibited inhibitory effects on the growth of cancer cells. Among them, compound 3s showed the strongest inhibitory effect. It induced cell cycle arrest at the G2/M phase and promoted apoptosis. Mechanistically, 3s activated JNK and ERK signaling and elevated intracellular ROS levels. Furthermore, in a mouse xenograft model, 3s significantly inhibited tumor growth with minimal toxicity. Conclusions: Compound 3s exhibits potent anticancer efficacy both in vitro and in vivo. The discovery of 3s offers new potential for cancer therapy. Full article

Melanoma remains a highly aggressive malignancy, particularly in advanced metastatic stages where therapeutic options are limited. Natural compounds provide a structural basis for discovering novel anticancer agents. In this study, we employed an integrated in silico approach to evaluate the pharmacokinetic properties, toxicity profiles, and molecular targets of key alkaloids from Chelidonium majus, including berberine, sanguinarine, chelerythrine, chelidonine, protopine, umbelliferone and coptisine. ADME/T predictions (SwissADME and DeepPK) revealed favorable drug-likeness and oral bioavailability for most compounds, with berberine exhibiting the most balanced safety and absorption profile. All compounds demonstrated high intestinal absorption (>99%) and implicated key melanoma targets, including APE1/Ref-1, CXCR4, CCR2, TLR8, galectin-3, and VEGFR2. These molecules represent valuable templates for the development of melanoma therapies. Among the tested compounds, chelidonine emerged as a potential APE1 inhibitor, exhibiting the highest binding affinity and forming specific interactions within the enzyme’s catalytic site, suggesting its potential as a DNA repair-targeted agent in melanoma. These findings support the further exploration of natural alkaloids, including structural optimization or advanced formulation strategies, to enhance safety, bioavailability, and therapeutic efficacy in melanoma. Full article

Anticancer peptides (ACPs) offer a promising alternative to conventional chemotherapy but face challenges, including poor selectivity, limited tumor penetration, low cellular uptake, and rapid degradation in serum. To address these barriers, we developed synthetic mRNAs encoding chimeric ACPs designed for enhanced intracellular delivery and activity. mRNAs for constructs SAK6L9AS(1X), SAK6L9AS(4X), and WTAS-K6L9(4X) were transcribed in vitro and tested against 4T1 breast cancer cells. Cytotoxicity was assessed by cell confluence and MTT assays, while apoptosis was evaluated using caspase 3/7 activation, PI staining, and Annexin V flow cytometry. Our results demonstrate that all SAK6L9AS variants induced robust apoptosis and cellular toxicity in 4T1 cells. Importantly, this work provides the first demonstration of intracellular expression of an mRNA-encoded ACP fused to a cell-penetrating peptide, thereby validating a modular platform for RNA-based delivery of anticancer agents. This study highlights the feasibility of mRNA-encoded peptide therapeutics as a scalable and customizable strategy for cancer treatment. By combining the advantages of mRNA delivery with rational peptide design, ACP chimeras can be expressed directly inside tumor cells, overcoming the limitations of exogenous peptide administration. Our findings support further development of synthetic mRNA therapeutics to generate potent, selective anticancer peptides with reduced systemic toxicity and improved translational potential. Full article

Hepatocellular carcinoma (HCC) poses a critical threat to global health because of the scarcity of effective therapeutic approaches. Sorafenib, a first-line treatment for advanced HCC, often faces efficacy limitations due to acquired resistance. Therefore, it is urgent to explore novel and effective anti-cancer drugs and combination therapies. This study explored the anti-HCC potential of Enocyanin (Eno), a natural anthocyanin-rich extract derived from grapes, either alone or combined with sorafenib. Our findings indicated that 100 μg/mL Eno remarkably suppressed the proliferation, invasion and migration of HepG2 cells, which was related to the induction of ferroptosis characterized by increased intracellular Fe²⁺, lipid peroxidation (LPO) and Acyl-CoA synthetase long chain family member 4 (ACSL4) levels, coupled with decreased glutathione (GSH) and glutathione peroxidase 4 (GPX4). Mechanistically, Eno promoted ferroptosis which was associated with inhibition of the p62/Keap1/Nrf2/HO-1 signaling pathway. Notably, Eno (100 μg/mL) combined with sorafenib (2 μM) had a synergistic anti-tumor effect (Q = 1.47), which further enhanced the inhibition of HepG2 cell growth and metastasis, aggravated ferroptosis, and more strongly suppressed the p62/Keap1/Nrf2/HO-1 axis. In the C57BL/6 mouse subcutaneous HCC transplantation model, the combination of Eno and sorafenib showed a stronger inhibitory effect on tumor growth, reaching a 70% inhibition rate, compared to 33% with Eno alone and 55% with sorafenib alone. In summary, this study demonstrates that Eno may be a novel inducer of ferroptosis, and it has the potential to be used in the treatment of hepatocellular carcinoma. It also provides a potential combined treatment strategy for enhancing the sensitivity of sorafenib. Full article

Background/Objectives: Drug repurposing offers a time- and cost-efficient strategy for accelerating the development of anticancer therapies by leveraging the established safety profiles of existing pharmaceuticals. This study aimed to investigate the anticancer potential of three tetracycline analogues chemically modified tetracycline-3 (COL-3), doxycycline (DOX), and minocycline (MIN) in leukemia models, with a particular focus on their cytotoxic effects and modulation of the JAK2/STAT3 signaling pathway. Methods: Cytotoxicity was evaluated in K562, KG-1a and Jurkat cell lines using luminescence-based viability assays, whereas the mechanisms of cell death were analyzed by Annexin-V/7-AAD staining and Western blotting. Results: COL-3 displayed the highest cytotoxic potency across all cell lines, with Jurkat cells showing the greatest overall sensitivity. Flow cytometry revealed that tetracycline analogues primarily induced apoptosis, although the molecular mechanisms differed between cell lines. In K562 and KG-1a cells, apoptosis occurred largely through JAK2/STAT3-independent mechanisms, involving differential regulation of BCL-2 family proteins: COL-3 reduced BCL-2 expression, whereas DOX and MIN increased BAX expression. In contrast, Jurkat cell apoptosis correlated with suppression of phosphorylated JAK2 and STAT3 and downregulation of BCL-2, implicating a JAK2/STAT3-dependent mechanism. Conclusions: Taken together, these findings demonstrate that tetracycline analogues exert cell line-specific anticancer activities through distinct molecular pathways. Among them, COL-3 emerges as the most potent analogue and acts through both JAK/STAT-dependent and -independent mechanisms. This work supports further investigation of COL-3 as a candidate for drug repurposing strategies in hematological malignancies. Full article

Background/Objectives: Retinoblastoma represents the most common intraocular malignancy in childhood; however, the clinical applicability of mitomycin C (MMC) is restricted by dose-dependent ocular toxicity. Consequently, the development of pharmacological strategies that sensitize tumor cells to MMC while allowing dose reduction remains an unmet therapeutic objective. In this context, quercetin, a bioactive flavonoid with pleiotropic anticancer properties, has emerged as a potential chemosensitizing agent. Methods: Human retinoblastoma cell lines Y79 and WERI-Rb1 were exposed to MMC and quercetin, administered either individually or in fixed-ratio combinations. Cytotoxic responses were quantified through dose–response modeling and IC₅₀ determination following 24 and 48 h of treatment. Drug–drug interactions were quantitatively characterized using the Chou–Talalay combination index (CI) approach and isobologram analysis. Cell cycle distribution was assessed by propidium iodide (PI)-based flow cytometric analysis to evaluate treatment-associated alterations in cell cycle progression. Apoptotic cell death was assessed by Annexin V-FITC/PI flow cytometry, while transcriptional modulation of genes associated with apoptosis, cell cycle regulation, and oxidative stress (BAX, BCL-2, TP53, CASP3, CDKN1A, and HMOX1) was evaluated by qRT-PCR. Modulation of tumor-supportive signaling was examined by measuring VEGF and IL-6 secretion. Translational relevance was further investigated using a three-dimensional (3D) tumor spheroid model, and the functional contribution of reactive oxygen species (ROS) was interrogated through N-acetyl-L-cysteine (NAC) rescue experiments. Results: Quercetin significantly enhanced the cytotoxic activity of MMC in both retinoblastoma cell lines, with CI values below 1 across IC₅₀–IC₉₀ effect levels, indicating a synergistic pharmacological interaction. PI–FACS analysis revealed that combined MMC and quercetin treatment induced a pronounced accumulation of cells in the G2/M phase, consistent with cell cycle arrest, with a more marked effect observed in Y79 cells compared with WERI-Rb1 cells. Combination treatment resulted in a pronounced increase in apoptotic cell populations compared with single-agent exposure and triggered a coordinated pro-apoptotic transcriptional response, characterized by increased expression of BAX, TP53, CASP3, CDKN1A, and HMOX1, alongside suppression of BCL-2 and a marked shift in the BAX/BCL-2 ratio. Concurrently, VEGF and IL-6 secretion were significantly reduced, reflecting attenuation of pro-angiogenic and pro-inflammatory signaling. Notably, synergistic cytotoxicity was maintained in 3D tumor spheroids, where combined treatment induced spheroid shrinkage, architectural disruption, and reduced viability. NAC pretreatment diminished ROS accumulation and partially restored cell viability, indicating that oxidative stress contributes to, but does not solely account for, the observed synergistic cytotoxic effect. Conclusions: Collectively, these findings indicate that quercetin appears to function as an effective chemosensitizing adjuvant to MMC in retinoblastoma models, through transcriptional changes consistent with p53-associated apoptotic signaling at the transcriptional level, G2/M cell cycle arrest, and partial involvement of ROS-related cellular stress responses, along with suppression of tumor-supportive signaling pathways. The preservation of synergistic activity in 3D tumor spheroids supports the potential preclinical relevance of this combination. However, these findings are based on transcriptional and phenotypic analyses and should be interpreted as hypothesis-generating, requiring further validation through protein-level and in vivo studies before translational application. Full article

Background: Squamous cell carcinoma of head and neck (SCCHN) is a devastating disease with high morbidity and mortality and the 6th most common cancer worldwide. The 5-year relative survival for advanced-stage disease is below 50%, stressing the need for chemoprevention. In the current study, we investigated the chemopreventive efficacy of the combination of resveratrol and epigallocatechin gallate (EGCG). Methods: We used the 4-Nitroquinoline 1-oxide (4-NQO)-induced oral carcinogenesis model. C57BL/6 mice were exposed to drinking water containing 4-NQO for 10 weeks. From week 11, mice were treated with vehicle, resveratrol, EGCG and their combination until week 22. RNASeq, qPCR and in silico analysis were performed identifying differentially expressed genes and enriched pathways. Results: Resveratrol alone and in combination with EGCG significantly inhibited the number of visible lesions, whereas the number of microscopic lesions and lesion areas were significantly inhibited only by the combination. The expression of Ki-67 was also significantly inhibited in resveratrol and combination groups. Growth differentiation factor 15 (GDF15), Activation transcription factor 3 (ATF3) and several other genes associated with xenobiotic metabolism as significantly upregulated genes, with GDF15 being the most upregulated one. Furthermore, hallmarks of xenobiotic metabolism and several other anticancer pathways were enriched after treatment with resveratrol and the combination. Conclusions: Our data strongly demonstrate the chemopreventive potential of the combination of resveratrol and EGCG and pave the way for further clinical developments. Full article

Cancer is an alarming health concern and economic burden in both developed and developing countries. Recently, there has been a growing demand for new alternative medications with more effectiveness and fewer harmful effects. During the past decades, a set of chemotherapeutic agents has been developed to fight against a large spectrum of cancer types. Unfortunately, their use is associated with a high level of toxicity; they are expensive, also, and their deployment is restricted by the emergence of cellular resistance. Plant-based components are garnering attention due to their low toxicity, selectivity, efficiency, and ease of accessibility. Alkaloids are one of these targeted compounds. Indeed, they are a highly diverse group with basic heterocyclic nitrogen-containing alkaloids that exhibit potent anticancer effects against a large panel of solid and liquid tumors, such as lung, breast, leukemia, liver, and colon cancer. The main molecular mechanisms involved in alkaloids’ anticancer effect are the induction of apoptosis via the extrinsic and intrinsic pathways, DNA damage, and the inhibition of cell cycle progression. Amazingly, these auspicious compounds exhibited strenuous inhibitory effects against a whole range of key enzymes involved in cancer progression and metastasis, such as Cytochrome P450 (CYP450), Cyclooxygenase-2 (Cox-2), Lysine-Specific Demethylase 1 (LSD1), Poly [ADP-ribose] polymerase (PARP), and topoisomerase, mainly through two action modes, namely irreversible and reversible inhibition. Furthermore, several conventional extraction methods have been developed to extract bioactive compounds from natural matrices, such as Soxhlet and hot water extraction. However, these techniques have many drawbacks, as they require a large amount of organic solvents, which not only affect human health but also generate severe environmental issues. To overcome these limitations, multiple eco-extraction techniques have emerged as potential alternatives to traditional extraction methods such as ultrasonic extraction, microwave-assisted extraction, and supercritical fluid extraction. In fact, they are considered eco-friendly and efficient technologies with less time and solvent consumption. Overall, this review aims to provide an updated overview of the most prominent anticancer alkaloids that have not been well reviewed already, as well as the main green extraction techniques relevant to the extraction of antineoplastic alkaloids. Full article

The mitochondrial anti-viral signaling protein, MAVS, is a central regulator of innate anti-viral immunity. Recently, we demonstrated that MAVS is overexpressed in cancer, where its downregulation resulted in reduced cell proliferation and the expression and nuclear translocation of proteins associated with transcriptional regulation and inflammation. In this study, we demonstrate that CRISPR/Cas9-mediated MAVS depletion in PC-3 prostate cancer cells suppresses proliferation, disrupts immune evasion, and alters the tumor microenvironment. Proteomic profiling of the MAVS-KO cells by LC-MS/MS revealed changes in the expression of proteins associated with immunity, cell signaling, mitochondrial function, metabolism, protein synthesis and degradation, and epigenetic regulation. In contrast to MAVS-expressing cells, MAVS-KO cells implanted subcutaneously in mice formed very small tumors. This inhibited tumor growth was linked to reduced proliferation, and enhanced apoptosis, as indicated by strong TUNEL staining and elevated activated caspase-3. Importantly, the small “tumors” derived from MAVS-KO cells displayed a distinct morphology: diminished cancer stem-cell populations, an altered tumor microenvironment and inflammatory response, increased immune cell infiltration, and reduced PD-L1 expression. Together, these findings establish MAVS as a key mediator of cancer-cell survival, inflammation, and immune regulation, and, thus, its upregulation in tumors makes it a potential anti-cancer target. Full article

Background: Oral squamous cell carcinoma (OSCC) is an aggressive cancer closely associated with smoking and alcohol consumption, with a higher incidence in men. Despite changes in treatment strategies, poor survival persists in most patients, highlighting the need for novel and improved therapeutic options. Naphthoquinone analogs are being investigated because of their active redox structure and broad pharmacological profile; they demonstrate cytotoxic antitumor activity, making them potential candidates for new drug agents. Objective: This study investigated new benzyl-naphthoquinone compounds as potential anticancer agents for various genotypes of oral squamous cell carcinoma (OSCC) and other cancer cells. Methods: This study reports the synthesis and evaluation of a series of eight benzyl-naphthoquinone compounds against oral squamous cell carcinoma. Results: Four compounds 1–4 showed the best cytotoxic profiles, with a selectivity index ≥ 3 for all OSCC cell lines tested. Compound 1 was the most selective compound in all OSCC models, showing a higher selectivity index than both carboplatin and shikonin. Furthermore, compound 1 induced DNA fragmentation, cell-cycle arrest, and caspase-3/7 activation, changes consistent with apoptosis, and time-lapse imaging corroborated the apoptotic phenotype. Hemolysis assays showed minimal toxicity in human erythrocytes, and acute in vivo evaluation in mice revealed no evident adverse effects under the conditions tested, indicating low acute toxicity, although more detailed histopathological and biochemical studies will be required to fully establish the safety profile. Molecular modeling suggested that compound 1 may interact with topoisomerase II, RSK2, and PKM2, which could contribute to the activation of apoptotic pathways, although these interactions remain predictive and require biochemical validation. Finally, in silico analysis of physicochemical and ADMET parameters indicated properties compatible with oral absorption and systemic exposure, together with predicted low toxicity; however, these results are model-based and should be confirmed experimentally. Conclusions: Based on these findings, compound 1 emerges as a promising lead candidate for the development of a novel chemotherapeutic agent against OSCC, with potential therapeutic efficacy against other cancer types. Full article

Introduction/Objective: Common hop (Humulus lupulus L.) is a multi-component plant material that has been extensively studied for its antioxidant, anti-inflammatory, cardioprotective, metabolic, neuroprotective, immunomodulatory and anti-cancer properties. This review summarises current data on the molecular mechanisms of action of hop compounds, their therapeutic potential, metabolic interactions and biological significance, with particular emphasis on bioavailability, signalling pathways and organ-specific effects. Methods: A comprehensive literature review was conducted, covering in vitro and in vivo studies and available clinical trials analysing the biochemical activity, molecular targets and physiological effects of bioactive compounds in hops. Particular attention was paid to the regulation of oxidative stress, inflammatory signalling, mitochondrial function, metabolic pathways, interactions with the gut microbiota and their impact on the development of chronic diseases. Results: Bioactive compounds in hops modulate numerous key signalling pathways, including NF-κB, Nrf2, AMPK, MAPK, PPAR and PI3K/AKT/mTOR. They have been shown to reduce oxidative stress, inhibit the production of pro-inflammatory cytokines, regulate apoptosis, improve mitochondrial function, and activate endogenous antioxidant systems. Hops have a protective effect in cardiovascular diseases, metabolic disorders, neurodegenerative diseases and selected cancers through anti-inflammatory, anti-proliferative and metabolic mechanisms. In addition, hop compounds modulate the composition and activity of the gut microbiota, which promotes improved metabolic homeostasis. Despite relatively good intestinal absorption, systemic bioavailability remains limited; however, modern delivery systems significantly increase the stability and plasma concentrations of these compounds. Conclusions: Common hops have broad therapeutic potential due to their ability to regulate oxidative, inflammatory, metabolic and apoptotic processes at multiple levels. Their pleiotropic activity makes them a promising candidate for the prevention and treatment of chronic diseases. The development of delivery systems and consideration of the role of the gut microbiota may further increase its clinical application. Full article

The apple (Malus domestica Borkh.) is one of the most widely consumed fruits worldwide due to its pleasant sensory properties and rich phytochemical composition. Therefore, the present study aimed to comprehensively investigate the chemical composition, antioxidant activity, anticancer effects, and molecular interactions of peel and pulp extracts of the Hünkar apple cultivar collected from different locations, using a combined experimental and computational strategy. These factors had a big effect on the extracts’ phenolic composition and biological activity. Moreover, the anticancer results were corroborated by molecular docking analyses, which offered further understanding of the interactions between bioactive compounds and cancer-associated target proteins. This integrative approach underscores the impact of both biological and methodological variables on the antioxidant and anticancer properties of apple-derived extracts, reinforcing their potential as natural sources of bioactive compounds. Cytotoxic activity against HT-22 and C6 cell lines was evaluated using the MTT assay, showing dose- and time-dependent antiproliferative effects. Apple extracts exhibited anticancer effects that were dependent on dosage and duration. The activities of chemicals found in extracts of Hünkar apple samples collected from four different locations against brain cancer proteins (PDB ID: 2DME, 6YPE, 1RV1) were examined. ADME/T analysis was then performed on the three molecules with the highest activity. The quantum chemical properties of these three molecules were also examined using the Gaussian package program with B3LYP, HF, M062X level in 6–31g, 6–31++g, and 6–31++g(d,p) basis sets. Full article

Background: Exercise modulates the immune system and may enhance anti-cancer activity, offering potential synergy with cancer immunotherapy. Tumours with low immune cell infiltration (“cold” tumours) often respond poorly to immunotherapy and are associated with poor prognosis. Here, we demonstrate that exercise can reshape the immune landscape of tumours across the cold spectrum. Methods: C57BL/6 mice underwent orthotopic implantation of PANC02 (murine pancreatic adenocarcinoma) cells and BALB/c mice underwent intraperitoneal injections of AB-1 (murine mesothelioma) cells. Mice were then divided into groups; exercise with anti-Programmed Cell Death Protein 1 (PD-1), exercise with isotype, no exercise with anti-PD-1 and no exercise with isotype. Treadmill-running was performed for 20 min/day, 4 days/week at a speed of 12 metres/minute. Resistance training consisted of hanging upside down on a wire-mesh screen for 1 min 2 days/week. Flow cytometry was used to measure TME immune populations. Tumour and liver samples were harvested, paraffin wax-embedded/sectioned and analysed using SlideViewer 2.9.0™. A total of 22 healthy volunteers underwent a single bout of high-intensity interval cycling. Blood was collected pre- and post-exercise. Flow cytometry was used to measure leucocyte subpopulations. MSTO-211H (mesothelioma) and PANC-1 (pancreatic cancer) cells were cultured with pre- and post-exercise serum, with/without HSV1716, and viability determined using alamarBlue^®. PANC-1 apoptosis and migration were assessed using caspase-3/7 and scratch assays, respectively. Results: In an orthotopic pancreatic cancer mouse model, combining exercise with immunotherapy significantly increased tumour necrosis and reduced metastatic potential. In both pancreatic cancer and mesothelioma models, this combination remodelled the tumour microenvironment, enhancing cytotoxic CD8⁺ T cell infiltration, upregulating Programmed Cell Death Protein 1 (PD-1), and reducing Myeloid-Derived Suppressor Cells and regulatory T cells (Tregs). Complementary human studies revealed an acute systemic release of Natural Killer cells and a reduction in Tregs following high-intensity interval exercise in healthy volunteers. Moreover, exercise-conditioned serum from these participants exerted anti-cancer effects on pancreatic cancer and mesothelioma cell lines. Conclusions: Altogether, these findings highlight exercise as a promising adjunct to immunotherapy for poorly immunogenic cancers such as pancreatic cancer and mesothelioma. Full article