Search Results (275)

Phosphatidylinositol 5-phosphate 4-kinase type 2 alpha (PIP4K2A) is a key oncogenic driver that regulates the PI5P/PIP2 axis to promote metastatic migration in breast cancer. This study aimed to investigate the therapeutic potential of a crude extract from Tamarix aphylla against breast cancer progression and identify its primary active constituents. The crude extract was initially evaluated against MDA-MB-231 and MCF7 breast cancer cell lines using wound healing assays. Bioassay-guided isolation and screening were deployed to isolate individual components, and the most potent lead compound was structurally characterized using preparative HPLC and FTIR. To analyze its interaction with PIP4K2A, in silico molecular docking, MM/GBSA calculations, and 200 ns molecular dynamics simulations were conducted. In vitro validation was subsequently performed via dose-dependent cytotoxicity assays, scratch assays, single-cell tracking, and RT-qPCR expression analysis. Quercetin was identified as the most potent lead inhibitor against PIP4K2A. Computational modeling revealed that quercetin binds tightly within the PIP4K2A ATP-binding pocket, yielding a superior binding affinity of −10.77 kcal/mol and enhanced thermodynamic stability (ΔGMM/GBSA = −42.6 ± 2.1 kcal/mol) compared to the native ligand (ΔG MM/GBSA = −23.3 ± 1.8 kcal/mol). Molecular dynamics simulations confirmed an induced-fit structural transition that locked the complex into an ultra-stable conformation within a deep global energy minimum basin (−10.8 kcal/mol). In vitro assays demonstrated dose-dependent cytotoxicity, with aggressive triple-negative MDA-MB-231 cells exhibiting higher sensitivity (IC₅₀ = 82.23 µg/mL) than luminal MCF7 cells (IC₅₀ = 97.14 µg/mL). Furthermore, scratch and single-cell tracking assays showed a profound suppression of migration speed and wound closure (reduced to ~40%), while RT-qPCR revealed a near-complete transcriptional knockdown of PIP4K2A mRNA expression (down to 0.025-fold). Collectively, these findings elucidate a unique dual-action mechanism for Tamarix aphylla-derived quercetin—characterized by both direct competitive enzymatic inhibition and downstream transcriptional silencing—positioning it as a promising therapeutic scaffold for targeted anti-metastatic breast cancer interventions. Full article

Osteosarcoma remains the most common primary malignant bone tumor in adolescents and is characterized by aggressive metastasis, resistance to therapy, and extensive bone microenvironment remodeling. Therefore, the identification of novel multi-target therapeutic agents capable of simultaneously inducing ferroptosis and disrupting tumor-supportive signaling is urgently needed. This study employed a multi-omics-guided approach to investigate the anti-osteosarcoma potential of metabolites derived from the sea cucumber Holothuria scabra. LC–MS/MS profiling identified major bioactive constituents, including holothurins, scabrasides, fucosterol, desmosterol, and 24-methylenecholesterol. Integrated transcriptomic analysis of the GSE42352 dataset revealed key ferroptosis- and bone microenvironment-associated targets, including CXCR4, CTSK, RUNX2, VEGFA, and TFRC. In silico pharmacological prediction and molecular docking demonstrated favorable anticancer properties and strong binding affinities of several metabolites toward these targets, with fucosterol and holothurin A exhibiting the most promising interactions. Functional validation in MG-63 osteosarcoma cells showed concentration-dependent reductions in cell viability and migration following H. scabra treatment. Furthermore, treatment decreased GPX4, NRF2, and GSH levels while increasing TFRC and MDA, indicating activation of ferroptotic cell death. In a MG-63/RAW264.7 co-culture model, H. scabra suppressed RANKL, VEGFA, MMP9, and TRAP-positive osteoclast formation, suggesting inhibition of osteoclastogenesis, angiogenesis, and metastatic potential. Collectively, these findings identify H. scabra as a promising marine source of multi-target compounds for osteosarcoma management through coordinated induction of ferroptosis and remodeling of the bone tumor microenvironment. Full article

Background: Colorectal cancer (CRC) remains a leading cause of mortality worldwide, with a significant proportion of patients presenting with metastatic disease (mCRC). While molecularly targeted therapies, including anti-EGFR and anti-VEGF agents, have improved survival outcomes, their efficacy is often limited by drug resistance, toxicity, and high costs. There is a growing need for sustainable strategies to enhance therapeutic efficacy. Methods: This review explores the emerging role of plant-derived compounds as synergistic adjuvants. Specifically, PubMed, Scopus, and Web of Science were searched for English-language articles published between January 2004 and June 2026, using combination of terms related to colorectal cancer, metastatic disease, anti-EGFR/anti-VEGF targeted therapy, phytochemicals/natural products, and gut microbiota; both primary studies and reviews were eligible. Results: Targeted therapies such as cetuximab and bevacizumab are the standard of care but face challenges related to RAS/BRAF mutations and primary tumour location. Clinical data demonstrate that while cetuximab improves overall survival in patients with RAS wild-type, left-sided tumours (median OS 31 vs. 26 months; HR 0.76, p = 0.012), progression-free survival remains comparable to that of bevacizumab. Concurrently, natural products like Vitis vinifera, Dendrobium candidum, and quercetin demonstrate significant preclinical potential in inhibiting angiogenesis, inducing apoptosis, and modulating the tumour microenvironment. The gut microbiome, particularly Fusobacterium nucleatum (whose reported prevalence varies widely across cohorts and reaches up to ~98% of CRC tissues only in selected series), has emerged as a key factor in chemoresistance. It should be emphasised that the great majority of the phytochemical-targeted therapy combinations discussed here are currently supported primarily by preclinical (in vitro and animal) studies rather than by clinical trials. Conclusions: Integrating evidence-based phytochemicals with conventional targeted therapies is a mechanistically compelling and potentially sustainable strategy that may enhance therapeutic efficacy, help overcome resistance, and mitigate adverse effects in mCRC management. However, because current support is largely preclinical, these combinations should be regarded as hypothesis-generating and require validation in prospective, biomarker-stratified clinical trials before clinical adoption. Full article

Melanoma is a highly aggressive and metabolically adaptable cancer that often resists conventional therapies. Targeting core bioenergetic pathways may, therefore, represent an effective strategy to improve therapeutic responses, particularly in tumors dependent on mitochondrial function. SC18 is an imidazolidine-2,4-dione compound that binds the NADH-binding pocket of voltage-dependent anion channels (VDACs), inducing mitochondrial dysfunction. VDAC expression is increased in melanoma and strongly associated with advanced disease stage and poor prognosis. In this study, we evaluated the effects of SC18 in melanoma cell lines with distinct pigmentation states, including melanin-rich melanotic human MNT-1 and mouse B16-F1, as well as low/amelanotic human SKMel28 and mouse YUMM cells. VDAC1, VDAC2 and VDAC3 were highly expressed across these melanoma lines, all of which relied on both glycolysis and mitochondrial oxidative phosphorylation for ATP production. SC18 reduced mitochondrial membrane potential and oxygen consumption rates, accompanied by declines in intracellular ATP levels and TCA cycle substrate utilization. SC18 also increased reactive oxygen species, mitochondrial superoxide, and lipid peroxidation, indicating enhanced oxidative stress. These metabolic and redox disturbances were associated with reduced cell viability and significantly impaired migration in multiple melanoma cell lines, supporting a potential anti-metastatic effect. In addition, SC18 showed synergistic cytotoxicity when combined with other chemotherapeutic agents. Overall, SC18 disrupted mitochondrial metabolism, induced oxidative stress, and impaired survival and motility pathways, with more pronounced effects in low/amelanotic than in melanotic melanoma cells. Together, these findings support the further development of SC18 as a mitochondrial metabolic disruptor that targets redox vulnerabilities in melanoma. Full article

Background/Objectives: Uveal melanoma is the most common primary ocular cancer in adults. Patients with metastatic uveal melanoma (mUM) have limited treatment options and poor prognosis. mUM is characterized by high oxidative phosphorylation (OXPHOS), which may be a therapeutic vulnerability for this disease. ONC206 is an imipridone compound that can inhibit OXPHOS indirectly and is currently being evaluated in clinical trials. Thus, we tested the effects of ONC206 on human uveal melanoma cell lines and patient-derived xenografts (PDXs) in vitro and in vivo. Methods: The effects of ONC206 on cell survival, apoptosis, autophagy, oncogenic signaling pathways, and metabolic networks were assessed in vitro using human melanoma cell lines. ONC206 was then tested for safety and anti-tumor activity in vivo using two mUM PDX models. Results: ONC206 treatment produced dose-dependent inhibition of mUM cell growth in vitro, with induction of varying levels of apoptosis and autophagy. ONC206 treatment also downregulated OXPHOS effector proteins and metabolites, thereby impairing mitochondrial OXPHOS. Treatment with ONC206 significantly reduced tumor burden and improved survival in two UM PDX mouse models in vivo. Conclusions: Our findings position ONC206 as a mechanistically distinct agent to target mitochondrial metabolism and to inhibit mUM. As ONC206 is currently being evaluated in multiple clinical studies, our data support further evaluation as a potential new therapeutic strategy for mUM. Full article

Background/Objectives: Melanoma is a highly aggressive cancer with a strong metastatic potential, and therapeutic resistance remains a major clinical challenge despite advances in targeted therapies and immunotherapies. Secreted frizzled-related protein 1 (sFRP1) exhibits context-dependent roles in cancer; however, its function in metastatic melanoma remains poorly defined. This study investigated the role of sFRP1 in melanoma progression and evaluated the anti-tumor effects of the pharmacological compound WAY-316606. Methods: sFRP1 expression was quantified in metastatic melanoma cell lines, xenograft models, and TCGA datasets. The anti-tumor effects of WAY-316606 on cell viability, cell cycle progression, cell migration and invasion, and expression of extracellular matrix (ECM)-related genes were assessed using WST assays, flow cytometry, wound healing and transwell invasion assays, and quantitative real-time PCR, respectively. Results: sFRP1 expression was consistently elevated in metastatic melanoma cell lines, xenograft models, and TCGA datasets, and high sFRP1 expression was associated with poor overall survival. WAY-316606 selectively suppressed melanoma cell viability with minimal cytotoxic effects on non-tumorigenic cells, and induced G1 phase cell cycle arrest. Furthermore, WAY-316606 markedly impaired the migratory and invasive capacities of metastatic melanoma cells, accompanied by downregulation of key ECM remodeling and fibrosis-related genes, including VIM, CCN2, FN1, and TGFBI. sFRP1 knockdown partially phenocopied the anti-migratory and gene expression effects of WAY-316606. Conclusions: Collectively, our findings identify sFRP1-asscoaited signaling contribute to aggressive melanoma phenotypes and highlight the therapeutic potential of its pharmacological inhibition using WAY-316606. Full article

Natural bioactive compounds present promising avenues for the prevention and therapeutic intervention of cancer. Octacosanol has garnered significant attention for its distinctive biological properties, yet its specific antitumor effects and underlying mechanisms remain unclear. This study systematically evaluated its antitumor effects and elucidated the associated molecular mechanisms. We confirmed that it dose-dependently inhibited A549 cell proliferation in vitro. It also remarkably suppressed cell invasion and migration by downregulating MMP2 and MMP9 expression, an effect that was associated with reduced phosphorylation of JAK3/STAT3 and PI3K/AKT, suggesting a potential regulatory role of these signalling cascades. Meanwhile, it significantly inhibited tumor cell VEGF secretion and VEGF-mediated neoangiogenesis by modulating the PI3K/AKT signaling axis. Mouse experiments demonstrated that octacosanol significantly reduced tumor p-AKT, MMP2, and MMP9 levels, indicating its in vivo anti-metastatic effect. It also remarkably decreased tumor microvessel density, alongside reduced VEGF and vascular endothelial marker CD31 expression, further verifying its potent anti-angiogenic activity. This work provides evidence of octacosanol’s dual anti-metastatic and anti-angiogenic effects in lung cancer and offers novel mechanistic insights into its activity against this highly prevalent malignancy. These findings establish a solid foundation for further exploration and development of octacosanol as a promising adjuvant for clinical antitumor therapy. Full article

Background/Objectives: Small cell lung cancer (SCLC) is a highly metastatic and lethal malignancy. Doublet chemotherapy consisting of a platinum compound and etoposide had remained the standard first-line regimen for decades, particularly for the majority of patients, who are diagnosed with extensive-stage disease. Over the past 5 years, results from the IMpower133 trial led to the approval of anti-PD-L1 agent atezolizumab as part of the first-line regimen for extensive-stage SCLC. The accumulation of real-world evidence on atezolizumab efficacy in this context is essential for corroborating trial results and further improving patient outcomes. Herein, we present real-world evidence from a Bulgarian cohort receiving atezolizumab as part of first-line extensive-stage SCLC treatment, comparing these data to the results of IMpower133. Methods: Data were extracted from the electronic health records of patients receiving atezolizumab plus chemotherapy as first-line treatment for extensive-stage SCLC in the period between 1 January 2022 and 31 December 2024. Analysis was conducted via the Danny Platform, an analytic platform for the integration of real-world evidence using embedded machine learning and LLM algorithms. Patients matching IMpower133 inclusion criteria were included in a group for comparison with trial results. Results: A total of 302 patients were included in the analysis. The real-world progression-free survival (PFS) in our study surpassed that in IMpower133 (7.6 versus 5.2 months), in addition to higher PFS rates beyond six months. A lower Objective Response Rate (ORR) (38.7% versus 65.4%) was noted in our real-world cohort, which we attribute to real-world documentation practices. Conclusions: Real-world evidence regarding PFS and treatment response generally align with the efficacy of adding atezolizumab to first-line extensive-stage SCLC treatment reported in the IMpower133 trial, while reflecting differences that may arise in routine clinical practice. Full article

Gastrointestinal malignancies remain among the leading causes of cancer-related morbidity and mortality worldwide, largely due to late diagnosis, aggressive tumor progression, and resistance to conventional therapies. Tumor angiogenesis and the tumor microenvironment (TME) play crucial roles in the initiation, growth, and metastatic dissemination of gastrointestinal cancers. Hypoxia-driven signaling pathways, including hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and inflammatory mediators such as NF-κB and MAPK, are key regulators of these processes. Increasing evidence suggests that natural products derived from medicinal plants and other biological sources may modulate these pathways and exhibit anti-angiogenic, anti-inflammatory, and anti-fibrotic properties. This review summarizes recent findings on natural compounds that influence angiogenesis and tumor microenvironment dynamics through the regulation of molecular pathways involved in hypoxia signaling, extracellular matrix remodeling, fibroblast activation, and inflammatory responses. Compounds such as neotuberostemonine, aloperine, silymarin derivatives, tanshinone IIA, berberine, asiatic acid, and phloretin demonstrate promising biological activities in experimental models by targeting pathways including HIF-1α, PI3K/AKT/mTOR, TGF-β/Smad, and NF-κB signaling. However, further studies focusing on gastrointestinal cancer models and clinical validation are required to translate these preclinical observations into effective therapeutic strategies. Full article

Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), mediates histone H3 lysine 27 trimethylation (H3K27me3), an epigenetic modification associated with transcriptional repression. EZH2 inhibitors (EZH2is) gained attention after the first-in-class drug Tazemetostat received FDA approval for treating epithelioid sarcoma. Preclinical studies suggest that EZH2is could be effective against melanoma, but their general inability to cross the blood–brain barrier (BBB), among others, limits the treatment of secondary brain metastases. Based on these limitations, we designed SG-8, a novel compound derived from TDI-6118 (a known brain-penetrant EZH2i). In silico docking predicted that SG-8 may exhibit high affinity for EZH2 as well as for another PRC2 subunit, Embryonic Ectoderm Development (EED). In addition, in vitro PAMPA assays suggested passive BBB permeability of SG-8. In cell-based assays, SG-8 and the structurally related EZH2i PF-06726304 displayed lower cytotoxicity than Tazemetostat in both primary (A375) and metastatic (Colo-679) human melanoma cells. Western blot analysis showed that SG-8 and PF-06726304 markedly reduced EED protein levels and, to a lesser extent, EZH2 levels, without affecting total H3K27me3, consistent with preserved canonical PRC2 activity. Instead, treatment with both compounds—most prominently SG-8—was associated with reduced phosphorylation levels of EZH2 (Ser21) and its upstream regulator Akt (Ser473), suggesting that modulation of the Akt–EZH2 signaling axis may at least partially contribute to their anti-melanoma activity. Full article

Osteosarcoma is one of the most common malignant tumors that develop in the bone. Currently, surgery is often the best and most used approach, often preceded and followed by chemotherapy, which, however, carries serious short- and long-term side effects. Recently, much attention has been paid to natural compounds capable of inducing tumor cell death, reducing tumor and metastatic activity, and interacting with selective chemotherapy targeting tumor cells. Griffonia simplicifolia, a tropical African plant, has attracted attention because its extracts with bioactive chemicals have demonstrated multiple therapeutic uses. We show the antitumor properties of a Griffonia seed extract, obtained by maceration in a hydroalcoholic mixture (ethanol/water, 70/30, v/v, Gri70), on osteosarcoma cell lines, evaluating cytotoxicity, interaction with a pro-inflammatory signal (interleukin-1β), epigenetic activity of this signal on interleukin-6 gene expression, and interactions with an elective chemotherapeutic agent, doxorubicin. Although the extract did not have strong antiproliferative activity in the cell lines analyzed, we nevertheless observed that it was able to block proliferative and migration signals induced by interleukin-1β, as well as acting epigenetically by blocking the de-methylation of the interleukin-6 promoter and its expression. Furthermore, the extract did not appear to interfere with the antitumor activity of doxorubicin, and the interaction potentiated antimetastatic effects. These results indicate that Gri-70 extract may be useful as adjuvants to enhance the effect of doxorubicin, reducing the adverse effects associated with the increased EMT process of osteosarcoma cells that manage to overcome cell death induction. Indeed, metastasis represents the main cause of poor prognosis. Full article

Although combination therapies with mitogen activated protein kinase inhibitors remain among the most effective treatments for malignant melanoma, they are not universally applicable to all subtypes of this cancer, and their efficacy decreases in the presence of distant metastases. Drug resistance, often associated with elevated autophagy in tumor cells, and adverse effects of the treatment also reduce the survival time of melanoma patients. Therefore, the aim of our research was to assess the cytotoxicity of the combination of a late-stage autophagy blocker chloroquine with thymoquinone, a natural substance with anticancer potential and low toxicity towards healthy cells, in metastatic melanoma cell lines. Using the WST-1 assay, we examined the cytotoxicity of the combination of chloroquine and thymoquinone in melanoma WM9 and WM852 cell lines and assessed the type of their interactions. Additionally, using time-lapse bright field and fluorescent microscopy, we assessed changes in cell morphology during 48 h incubation with the tested compounds and their combinations, as well as their effect on autophagy. We identified an additive and sub-additive cytotoxic effect of thymoquinone/chloroquine combinations against WM9 and WM852 cells. Moreover, we found that thymoquinone combined with chloroquine caused an increase in autophagosome accumulation in WM9 cells, while attenuating the chloroquine’s anti-autophagic effect. A thorough understanding of the mechanism of drug interactions with natural substances is crucial for the development of new effective anticancer therapies. Full article

Background: Malva sylvestris (the common mallow) is an herbaceous species widely used in ethnobotanical practices to treat gastrointestinal, hepatic and urinary inflammation. Objectives: Despite these beneficial effects on human health, the antineoplastic potential of this plant has not yet been fully explored. Thus, in the present study, two human colon cancer cell lines (i.e., HCT-116 and Caco-2) were treated with an extract obtained from M. sylvestris flowers (MFE), whose composition in terms of phytochemicals and microRNAs has been recently published by our research group, to explore its potential bioactivity. Methods/Results: MTT and Trypan blue assays demonstrated that MFE reduced tumour cell growth without causing significant cytotoxicity or apoptosis. Following the diphenylboric acid 2-aminoethyl ester-induced fluorescence of some plant metabolites, microscopy analysis proved that MFE components crossed the cell membranes, accumulating into nuclei. Wound assay and transwell tests documented that MFE was also able to reduce cell motility and invasiveness. In both cell lines qPCR experiments demonstrated that MFE caused the over-expression of factors, like VIMENTIN and E-CADHERIN, which negatively influence epithelial–mesenchymal transition in colon cancers. However, the effects of MFE appeared to be time-, dose- and cell type-dependent. In fact, the treatment induced senescence in P53-null Caco-2 cells (i.e., ROS, β-galactosidase and P21^WAF1/Cip1) and a premise of differentiation (i.e., P27^Kip1) in P53-wild-type HCT-116 cells, also via the CDK2/c-MYC/AKT axis, justifying its antiproliferative property. In parallel, the transfection of tumour cells with pure synthetic miR160b-5p—a microRNA identified in M. sylvestris flowers and predicted to target the human CDK2 transcript—resulted in gene silencing, thereby suggesting its central role in mediating the cross-kingdom effects of MFE on the investigated cancer models. Conclusions: Overall, these findings open new perspectives on the common mallow as a source of potential antimetastatic compounds and on the possible use of its plant microRNAs in the development of gene therapies. Full article

Background: Breast cancer is one of the most frequently diagnosed cancers worldwide, with metastasis contributing to high mortality rates. Current treatments for metastatic disease are limited, emphasizing the urgent need for novel therapeutic approaches. Methods: We conducted a small-molecule drug screen utilizing patient-derived circulating tumor cells (CTCs) as a platform to identify potential anti-cancer agents. We used a dye combination and a high-content imaging microscope to evaluate cellular viability upon compound treatment. Among the 250 small molecules tested, potential hits were identified. The efficacy of these compounds was investigated using in vitro and in vivo studies in mouse breast cancer models. Bulk RNA sequencing of treated cancer cells was performed to identify differentially expressed genes, with Gene Ontology enrichment analyses conducted for their functional characterization. Results: Our screen of a 250 small-molecule library led to the identification of five hits, derivatives of meriolins known to display cyclin-dependent kinase (CDK-2/9) inhibitory activity. Subsequent in vitro and in vivo studies validated the efficacy of these compounds in inhibiting cell cycle, tumor growth, and consequently, metastatic colonization in mouse breast cancer models. Treatment with single agents (15 mg/kg) in breast cancer mouse models demonstrated good tolerability in vivo. Transcriptome profiling of treated cancer cells revealed alterations in pathways associated with cell cycle regulation, providing mechanistic insights into the anti-cancer effects of the compounds. Conclusions: By integrating drug screens, transcriptomic analysis, and in vivo validation, our study contributes to the identification of novel promising candidates for the treatment of breast cancer. Full article

Background/Objectives: Skin-related disorders such as melanoma, premature aging, and chronic wounds significantly impact individuals’ quality of life and psychological well-being. Melanoma, due to its high metastatic potential and poor response to conventional chemotherapeutic agents, remains a major clinical challenge. Additionally, skin aging and impaired wound healing continue to drive the demand for novel therapeutic strategies and bioactive formulations. Methods: In this study, cinnamic acid (CA), a naturally occurring compound with known anti-inflammatory and antioxidant properties, was incorporated into biocompatible Fmoc-FF dipeptide-based nanogels to improve its stability and therapeutic efficacy. The antitumor effects of CA and CA-loaded nanogels were evaluated using human melanoma (SK-MEL-30) cells, while wound healing activity was assessed on human keratinocyte (HaCaT) cells. Results: The results demonstrated that CA exhibited significant activity against melanoma cells and promoted wound healing, with enhanced effects observed when delivered via Fmoc-FF nanogels. Conclusions: These findings suggest that CA-loaded peptide nanogels represent a promising platform for multifunctional treatment approaches targeting various skin disorders. Full article