Search Results (2,683)

Melittin, the principal active peptide of bee venom, exhibits potent cytotoxicity against cancer cells. However, its lipid-level mechanisms remain unclear. Here, we present the first untargeted lipidomic dataset that reveals melittin-induced lipid remodeling in triple-negative breast cancer (TNBC) cells (MDA-MB-231). Cells were exposed to 4 μg/mL of melittin for 15 min, and lipid extracts were analyzed by employing high-resolution LC–MS/MS in both ion modes. Data were processed with XCMS and metaX for peak extraction, normalization, and metabolite annotation, followed by multivariate and KEGG pathway analyses. The results highlight significant alterations in phospholipids, sphingolipids, and acylglycerols, indicative of melittin-mediated disruption of membrane integrity and lipid metabolism. All raw and processed data are publicly accessible at NGDC (accession number PRJCA048975). This dataset not only serves as a comprehensive resource for investigating lipid-based mechanisms underlying melittin’s anticancer effects but also supports its potential in lipid-targeted therapeutic strategies for TNBC. Full article

Poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) copolymer micelles have emerged as promising drug delivery systems for enhancing the solubility and bioavailability of poorly water-soluble benzimidazole drugs. In this study, we prepared and characterized PEG-b-PCL micelles to encapsulate poorly water-soluble anthelmintics such as albendazole (ABZ) and fenbendazole (FBZ), with a focus on comparing their encapsulation behaviour, release profiles, and biological activity in cancer therapy. Drug-loaded micelles were analysed using dynamic light scattering (DLS), which revealed uniform nanosized micelles with a narrow polydispersity index (PDI). The morphology and size of both empty and drug-loaded micelles were examined using transmission electron microscopy (TEM), confirming that the micelles were spherical and consistent in size. Both drugs were efficiently encapsulated within the micellar core, demonstrating a high loading capacity. The release profiles of PEG-b-PCL micelles containing albendazole (ABZ) and fenbendazole (FBZ) at pH 7.4 were also evaluated. FBZ exhibited slower release kinetics compared to ABZ, likely due to its higher lipophilicity and stronger interactions with the hydrophobic PCL core, resulting in enhanced retention within the micelles. In contrast, ABZ had faster release kinetics. Finally, the in vitro MTT assays performed on the highly invasive triple-negative breast cancer (TNBC) cell line revealed the potential of these micelles as effective drug delivery systems. Full article

Background/Objectives: Vernodalin (VD) and crude extracts from Gymnanthemum extensum leaves have previously demonstrated anticancer activity; however, their underlying molecular effects remain incompletely understood. This study investigated the anticancer activities of VD and G. extensum extracts and characterized their associated molecular responses in breast (MDA-MB-231) and ovarian (A2780) cancer cells. Methods:G. extensum leaves were extracted with dichloromethane and ethyl acetate to obtain DEGE and EAGE, respectively. VD was isolated from EAGE and characterized by ¹H-NMR and HPLC. Phytochemical profiles of the extracts were analyzed by GC-MS and HPLC. Cytotoxicity, clonogenic survival, cell cycle progression, migration, and protein expression were evaluated using MTT assay, colony formation assay, flow cytometry, wound healing assay, and Western blotting. Results: GC–MS analysis revealed distinct phytochemical compositions between DEGE and EAGE, although both extracts contained high levels of neophytadiene and phytol. VD, DEGE, and EAGE inhibited cell proliferation and migration in both cancer cell lines. VD suppressed proteins associated with cancer progression, including SMYD3, BRAF, MELK, FOXM1, Cyclin B1, MDR1/ABCB1, and MMP-9, with molecular responses differing between MDA-MB-231 and A2780 cells. DEGE and EAGE exhibited molecular regulatory patterns distinct from those of purified VD, suggesting contributions from multiple phytochemical constituents. Conclusions: VD and G. extensum crude extracts exhibit significant in vitro anticancer activity against breast and ovarian cancer cells and induce distinct molecular responses. The differential effects of DEGE and EAGE may be attributable to differences in their phytochemical constituents. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies, highlighting the need for new anticancer agents. Natural products remain a valuable source of bioactive compounds with diverse mechanisms of action. In this study, a pyrone glucoside, 7-hydroxymaltol-3-O-β-D-glucoside, was isolated from the methanolic leaf extract of Maerua angolensis and evaluated for its anticancer activity against TNBC cells. Structural elucidation was achieved using NMR and LC–MS analyses. Both the crude extract and the isolated compound exhibited dose-dependent cytotoxicity against MDA-MB-468 cells, with IC₅₀ values of 2.94 and 0.78 µg/mL, respectively, while showing reduced toxicity toward MCF10A normal cells. Mechanistic studies revealed induction of apoptosis, evidenced by activation of caspase-9 and caspase-7 and PARP cleavage. Confocal imaging further demonstrated lysosomal disruption and nuclear morphological alterations consistent with stress-associated cell death. Gene expression analysis indicated minimal involvement of the PI3K/AKT/mTOR pathway. Molecular docking showed favorable binding of the compound to AKT1, PARP-1, and caspase-7, suggesting a multi-target mode of action. ADMET analysis indicated low oral bioavailability but a favorable safety profile. These findings highlight the potential of this compound as a lead for TNBC therapy. Full article

Rising triple-negative breast cancer (TNBC) cases and Candida infection risks during chemotherapy demand novel therapies, with metal-oxide nanocomposites emerging as a promising solution. In this study, we synthesized Ag-ZnO and Cu-ZnO nanocomposites as established quantitative links between their physicochemical properties, ion release behaviour, and biological activity, evaluating antifungal effects against Candida albicans (ATCC 90028) and Saccharomyces cerevisiae (ATCC 9763), and their anticancer potential against MDA-MB-231 cells (ATCC HTB-26). The results revealed Ag (~13–19 nm) and Cu (~4–8 nm) nanoparticles dispersed in a ZnO matrix, with XPS confirming mixed Ag⁰/Ag(I)/Ag(III) and Cu(I)/Cu(II) speciation. Ag-ZnO NC exhibited strong antifungal activity (MIC = 25 mg L⁻¹) against both fungi, while Cu-ZnO NC was only effective (MIC = 100 mg L⁻¹) against S. cerevisiae. Aqueous release of Ag⁺ was ~2.6-fold higher than Cu²⁺. Ag-ZnO NC induced marked ROS generation (~6-fold higher than S. cerevisiae) and dehydrogenase inhibition (6.6- and ~20-fold, respectively). ATR-FTIR linked species-specific susceptibility to cell-wall architecture. SEM confirmed membrane destabilization and perforation. In MDA-MB-231, necrotic fractions reached ~9% and >40% for Ag-ZnO and Cu-ZnO, respectively. Both metal oxide nanocomposites (MONCs) act through ion release, revealing a selectivity window, especially for Ag-ZnO. Further studies on non-cancerous cells, ion-release kinetics, uptake and in vivo validation are essential to establish a therapeutic index. Full article

The dynamic crosstalk between the tumor microenvironment (TME) and triple negative breast cancer (TNBC) cells plays a critical role in tumor progression and treatment resistance. Recent studies have highlighted the involvement of IL-20 receptor subunit alpha (IL-20RA) signaling in BC, where its overexpression modulates oncogenic pathways contributing to invasion and metastasis. Epigenetic dysregulation by Bromodomain and Extra-Terminal domain (BET) proteins critically influences key oncogenic pathways and cytokine expression in TNBC. Given that the BET-inhibitor JQ1 blocks TNBC cell growth, in this study we investigated its potential regulatory effects on the IL-20RA pathway. IL-20RA was found expressed across multiple BC cell lines compared to non-tumorigenic cells, with the highest levels detected in MDA-MB-231 and MDA-MB-468 cells. In both cell lines, JQ1 treatment significantly downregulated IL-20RA expression at gene and protein levels, accompanied by a reduction in the oncogenic JAK/STAT signaling pathway, and programmed death-ligand 1 (PD-L1) expression. Parallel in vivo experiments using TNBC xenograft models confirmed these findings, showing reduced IL-20RA and PD-L1 expression alongside decreased phosphorylation of JAK and STAT3. Overall, this study uncovers a novel interplay between BET inhibition and the IL-20RA/STAT3 axis, suggesting JQ1 as a valid therapeutic option for TNBC characterized by high IL-20RA expression. Full article

The glycosidic composition of Psolus phantapus was studied for the first time. Two new glycosides, phantapusosides A (1) and B (2), and the known psolusoside P (3) were isolated and their structures were established by analysis of ¹H, ¹³C NMR, 1D TOCSY, and 2D NMR (¹H,¹H COSY, HMBC, HSQC, ROESY), and HR-ESI mass spectra. These compounds are structurally close to those isolated from other representatives of the genus Psolus: P. fabricii, P. peronii and P. chitonoides. These data confirm the chemotaxonomic significance of triterpene glycosides of sea cucumbers, demonstrating that closely related species biosynthesize structurally similar metabolites. The cytotoxic activity of compounds 1 and 2 was studied against four human breast cancer cell lines (MCF-7, T-47D, MDA-MB-231, MDA-MB-468), as well as the non-tumorigenic mammary epithelial cell line MCF-10A and the pancreatic epithelioid carcinoma cell line PANC-1. The glycosides were selectively active against the TNBC cell lines MDA-MB-231 and MDA-MB-468. Notably, both glycosides inhibited the clonogenic potential of TNBC cell lines more significantly than their metabolic activity (MTT assay) and demonstrated a more pronounced colony-inhibiting effect toward the basal-like cell line MDA-MB-468, making this cell line a promising model for future investigation of the antitumor effects of glycosides. Full article

A critical yet frequently overlooked factor is the tumor’s metabolic profile. Diabetes and chronic moderate hyperglycemia are known risk factors for triple-negative breast cancer (TNBC) that do not respond to hormonal therapy. So, identifying novel therapeutic targets and developing more effective treatments is needed. One of the key pathways involved in the aggressive nature of TNBC is the Toll-like receptor 4 (TLR4) signaling cascade. To this end, curcumin (CUR) has shown effects consistent with modulating inflammatory stress by inhibiting TLR4/MD-2. This study evaluated CUR at concentrations observed in the bloodstream (0.025–25 ng/mL) in MDA-MB-231 TNBC cells under different glucose conditions (normal, moderate, and severe hyperglycemia) and inflammatory states (LPS-induced), using cell viability assays and molecular docking. A zinc complex (Zn–CUR) was also used. Results were validated through cell viability assays. Under severe hyperglycemia, CUR unexpectedly increased cell viability in a dose-dependent manner, while Zn–CUR had no activity across all glucose levels. In LPS-induced inflammation, CUR exhibited a biphasic, dose-dependent response, being protective at mid-level doses but cytotoxic at higher doses, whereas Zn–CUR showed more consistent effects, consistent with modulation of inflammatory stress. Molecular docking suggests that Zn–CUR binds more stably within the MD-2 hydrophobic pocket than CUR, particularly when bound to LPS, with binding energies of −8.7 and −8.3 kcal/mol, respectively. However, better in silico affinity did not always translate into improved cellular effects. These findings indicate that metabolic context significantly influences CUR’s biological activity and that forming a zinc complex offers a safer, more reliable profile. This positions Zn–CUR as a candidate warranting further investigation for TNBC, particularly in the context of hyperglycemia. Full article

Arctigenin (Arc), a novel anti-inflammatory lignan derived primarily from Arctium lappa, has demonstrated promising anticancer activity in multiple cancer types. This study was designed to evaluate the anticancer efficacy of Arc across distinct molecular subtypes of breast cancer in vitro and in vivo and to gain mechanistic insights into its mode of action. In vitro evaluation was conducted in estrogen-receptor-positive MCF-7, human epidermal growth factor receptor 2 (HER2)-positive SKBR3, and triple-negative MDA-MB-231 breast cancer cell lines. In vivo efficacy and safety were evaluated using female severe combined immunodeficient (SCID) mice (5–7 weeks old) bearing MCF-7 or MDA-MB-231 xenografts. Mice received daily oral gavage of Arc at 50 mg/kg body weight for 8 weeks. In vitro, Arc inhibited cell proliferation across all three breast cancer subtypes in a dose-dependent manner. PCR-array analysis of gene expression revealed that Arc targets multiple signaling molecules involved in cell proliferation, cell cycle regulation, apoptosis, migration/invasion, and drug transport, demonstrating a subtype-specific target profile. Arc induced cell-cycle arrest at the G2/M phase in MCF-7 cells and at G0/G1 in MDA-MB-231 cells, accompanied by significant induction of apoptosis in both cell lines. Migration assays further demonstrated marked inhibition of wound closure in Arc-treated cells. In vivo, Arc treatment significantly inhibited tumor growth in both xenograft models, decreased Ki67 expression, and produced no overt toxicity. In summary, Arc exhibits potent anticancer activity against distinct breast cancer subtypes through multi-targeting mechanisms. Given the heterogeneity of breast cancer, Arc appears to be a promising candidate for further preclinical investigation. Full article

Background: Salvadora persica (S. persica), commonly known as ‘Miswak,’ has been used in ethnotraditional applications since ancient times. This study was formulated to examine bioactive phenolics and flavonoids from the hydroethanolic extract of S. persica bark, anticancer activity, and in silico binding interaction analysis with key therapeutic targets of triple-negative breast cancer (TNBC) cells. Methods: UHPLC was used to identify the phytochemicals in S. persica bark extract. Cell death was analyzed by MTT assay in TNBC MDA-MB-231 and MDA-MB-468 cells. Moreover, cellular apoptosis, ROS generation, MMP, and cell cycle checkpoints were also carried out. AutoDock Tools 1.5.7 and PyRx 0.8 tools were used for molecular binding interaction analysis. Results: Phytochemical analysis revealed the presence of total phenolic and total flavonoid content of 26.90 ± 0.46 μg GAE/mg and 54.51 ± 0.42 μg QE/mg of bark extract, respectively. UHPLC analysis confirmed the presence of fumaric acid, chlorogenic acid, rutin, and quercetin in the extract. S. persica significantly reduced cell viability of MDA-MB-231 and MDA-MB-468 cells with an IC₅₀ value of 144 and 128 μg/mL, respectively. S. persica extract elevated ROS generation, loss of MMP, late apoptosis induction, and G2/M-phase cell cycle arrest, while it did not show any significant effect against normal kidney Vero cells. Molecular docking studies revealed that rutin showed strong binding affinity towards EGFR with B.E. = −9.8 and −9.5 Kcal/mol; FGFR1 with B.E. = −7.4 and −7.5 Kcal/mol; FGFR4 with B.E. = −7.5 and −7.9 Kcal/mol; and csGRP78 with B.E. = −9.0 and −9.3 Kcal/mol, using Autodock Vina and PyRx tools, respectively. SwissADME and drug-likeness analysis confirmed acceptable drug-like characteristics and favorable pharmacokinetic profiles of the identified molecules. Conclusions: This study highlighted the potential of phytochemicals from S. persica bark as promising compounds for the development of novel anticancer therapeutics. Full article

Background: Triple-negative breast cancer (TNBC) remains a clinical challenge due to its aggressive nature and the frequent emergence of therapeutic resistance. While the role of protein-coding genes in DNA repair is well-documented, the regulatory contributions of the non-coding genome, specifically long intergenic non-coding RNAs (lincRNAs), remain largely undefined. Objectives: In this study, we characterize the biological significance of LincRNA-BC7, a novel transcript identified within the breast cancer field effect. Methods: Through a combined in silico and in vitro approach, we investigated the transcriptional dynamics of the LincRNA-BC7/miR-663a/BRCA1 axis in response to the PARP inhibitor, Olaparib. Results: Our results demonstrate that Olaparib induces selective cytotoxicity in BRCA1-deficient MDA-MB-231 cells while sparing non-cancerous HEK293 cells, a response accompanied by a significant downregulation of LincRNA-BC7 and a reciprocal upregulation of BRCA1. Bioinformatics analysis through BLASTN, miRBase, and KEGG revealed that LincRNA-BC7 contains highly complementary binding sites for miR-663a, suggesting it functions as a competing endogenous RNA (ceRNA) or “molecular sponge.” Conclusions: By sequestering miR-663a, LincRNA-BC7 appears to modulate the expression of critical signaling nodes within the PI3K-AKT and TP53 pathways, thereby influencing cellular sensitivity to DNA-damaging agents. These findings suggest that LincRNA-BC7 is a key determinant of the aggressive TNBC phenotype and the response to PARP inhibition. Our study establishes the LincRNA-BC7/miR-663a axis as a novel biomarker for precision risk stratification and a promising therapeutic target to enhance treatment outcomes in BRCA1-associated breast cancers. Full article

Vasculogenic mimicry (VM) refers to the capacity of cancer cells from aggressive tumors to form a set of sinuses and channels that mimic normal blood vessels and lack endothelial cells. The rapid growth of a tumor leads to a deficiency in normal vessels, followed by poor oxygen and nutrient supply to tumor cells and VM induction. Understanding the mechanisms behind the development of the VM phenotype is important for the development of new anti-cancer therapies. Previous reports indicate that, during VM formation by melanoma Mel Z cells, about 2000 developmental genes undergo dramatic changes in expression. To identify genes more tightly linked to VM development, we compared the transcriptomes of Mel Z and MDA-MB-231 cells (triple-negative breast cancer cells), which also form VM. Most of the genes that change expression differ substantially between these two cell types. However, we identified 51 up- and 98 downregulated genes common to both cell lines. The non-overlapping groups of these genes are involved in regulating cell adhesion and proliferation. The group of common upregulated genes includes nine genes controlling blood vessel development and tube morphogenesis. Two genes in this group (BAK1 and SERPINE1) rapidly form numerous contacts with nucleoli during VM phenotype formation. We observed that knockdown of the SERPINE1 gene prevents the development of VM in Mel Z cells. Our data indicate that the formation of VM by aggressive cancer cells might be controlled by a special set of genes. Full article

Background: Vasculogenic mimicry (VM) is a tumor-driven vascularization strategy in which aggressive cancer cells form perfusable, endothelium-independent channels that support tumor growth, metastasis, and therapy resistance. VM is prevalent in triple-negative breast cancer (TNBC), but within this group of tumors, VM heterogeneity is underexplored. Likewise, VM competence and its relationship to classical endothelial angiogenesis (EA) remain incompletely understood. Methods: Here, as a proof of concept, we combine functional analysis of three molecularly distinct TNBC cell lines with a panel-wide DepMap transcriptomic survey to characterize VM heterogeneity. Results: Using an in vitro tube formation assay, we show that the VM-competent TNBC cell lines MDA-MB-231 and MDA-MB-231-4175 form robust 3D vessel-like networks in a matrigel matrix, whereas the VM-incompetent line MDA-MB-468 does not. As a control, we use an immortalized endothelial cell line, 3B-11, that forms classical EA vessel-like networks. Moreover, we visualize VM (Laminin-5⁺) and EA (CD31⁺) markers in vessel-like networks of VM-competent TNBC xenografts using immunohistochemical staining and show that while they are distinctly labeled, they can also coexist to form mosaic-like vessels. Then, we use DepMap-based transcription profiles and reveal that VM competence is associated with a distinct signature. Interestingly, VM and EA transcription profiles partially overlap, yet they also remain transcriptionally distinct, with inferred mechanistic divergence, with VM being more associated with cancer cell stemness (CSC), epithelial-to-mesenchymal transition (EMT), and extracellular matrix (ECM) remodeling programs and EA being more associated with vessel strength. In addition, VM-competent TNBC cells display migration patterns and transcriptomic features consistent with endothelial-like mechanosensitivity. Conclusions: Together, these findings indicate that VM is a distinct, heterogeneous, and therapy-relevant state in TNBC that complements classical angiogenesis. Finally, the mechanistic distinction between VM and EA programs made here will motivate future studies on dual-targeting strategies that inhibit both vascularization processes while also motivating future studies on VM for precision treatment in TNBC. Full article

Background: In vitro assays are widely used to optimize emerging radiotherapy strategies before undertaking more resource-intensive in vivo or clinical studies. However, multiple assay types are currently employed, and it remains unclear whether they yield comparable or complementary measures of radiosensitivity, complicating cross-study comparisons. Purpose: This study provides the first direct comparison of two of the most widely used radiosensitivity assays, clonogenic survival and growth inhibition, using commonly reported but non-identical protocols. The goals are to determine whether the assay measurements are correlated and assess their repeatability in breast cancer cell lines. Methods: Five cancer cell lines (4T1, SKBR3, BT474, MCF7, and MDA-MB-231) underwent clonogenic and growth inhibition assays following X-ray irradiation at 2, 4, 6, and 8 Gy. Correlations between assay measurements were assessed using Spearman correlations. The entire experiment was repeated twice for each assay to assess repeatability. Results: At a given radiation dose, no significant correlations were observed between the clonogenic assay measures and the growth inhibition measures. Across cell lines, the radiation dose resulting in 50% growth inhibition for the growth inhibition assay (mean = 3.2 Gy) was significantly higher than the dose resulting in 50% survival for the clonogenic assay (mean 1.3 Gy; p = 0.02). The coefficient of variation between repeat percent of control measurements for growth inhibition assay was trending lower than for clonogenic assay in every experimental condition and was statistically significant at 8 Gy (p = 0.02). However, the coefficient of variation values for D₅₀ measurements were not significantly different between the assays. Conclusions: This procedural comparison demonstrates that clonogenic survival and growth inhibition assays do not yield correlated measurements under the specific conditions tested and instead provide complementary information about cellular radiation response. These findings highlight important practical considerations for assay selection and suggest that the combined use of both assays may provide a more complete characterization of radiosensitivity. Full article

Amaranth proteins have been associated with various health benefits, including anticancer activity. This study aimed to evaluate the cytotoxic effect of proteins and peptides derived from Amaranthus hypochondriacus. A crude extract (CE) and protein fraction (PF) were obtained; peptides were produced by enzymatic hydrolysis, yielding one sample > 30 kDa (P > 30 kDa) and another < 30 kDa (P < 30 kDa). Protein, phenolic, and antinutritional compound content were determined, along with antioxidant capacity and cytotoxic activity against MDA-MB-231 and SiHa cells. CE exhibited the highest protein content of 182.6 mg/g, total phenols 129.40 mg GAE/g, and antioxidant capacity by both methods, 104.50 µM TEAC/g for ABTS•+ and 75.62 µM TEAC/g for DPPH•. PF showed the greatest concentration of saponins and lectins, 80 HU/mg and 60.30 HA/mg, respectively. PF displayed the strongest cytotoxic effect at 72 h in both cell lines, with IC₅₀ of 44.98 µg/mL for MDA-MB-231 cells and 69.24 µg/mL for SiHa cell line. Transmission electron microscopy (TEM) revealed severe structural damage induced by PF in both cell lines. In conclusion, PF from Amaranthus hypochondriacus seeds showed the greatest in vitro cytotoxic effect against both cancer cell lines, principally in MDA-MB-231 cells. Full article