Search Results (4,030)

In recent years, metallodrugs have been playing an important role, showing to be more efficient in the treatment of several diseases, such as cancer. Indeed, it is important to synthesize novel molecules to be used as more effective agents against cancer. In the present paper, the synthesis of two new molecules belonging to Casiopeínas^® is reported. These compounds present a β²-aminoacidate derivative as the secondary ligand. The novel metal complexes were characterized by high-resolution mass spectrometry, FT-IR, UV-Vis, EPR, effective magnetic moment and cyclic voltammetry measurements, and single crystal X-ray diffraction analysis. Furthermore, these compounds were evaluated in vitro against the cancer lines MCF-7 (breast cancer) and A549 (lung cancer). Full article

Biologically active compounds of natural origin, such as betulin, are a source of obtaining new medicinal substances. The presence of chemically active hydroxyl groups in the betulin structure at C-3 and C-28 positions enables esterification with dicarboxylic acid anhydrides or carboxylic acids. As a result of a four-step synthesis, difunctional betulin derivatives were obtained, which were evaluated for their antiproliferative activity against the following human cell lines: leukemia (MV4-11), (A549), breast cancer (MCF-7), prostate adenocarcinoma (PC-3), colon cancer (HCT116), pancreatic cancer (MiaPaca-2), and melanoma (Hs294T). The target 3-carboxyacyl-28-alkynyloyl betulin derivatives showed significant antiproliferative activity against MV4-11 cells. For 3-carboxyacylbetulins and their selected alkynyl derivatives, studies to investigate the effect on the cell cycle and apoptosis process, as well as drug similarity analysis, were performed. Full article

Breast cancer (BC) is a widespread malignancy that affects the lives of millions of women each year, and its resulting financial and healthcare hardships cannot be overstated. These issues, in combination with side effects and obstacles associated with the current standard of care, generate considerable interest in new potential targets for treatment as well as means for BC prevention. One potential preventive compound is Withaferin A (WFA), a traditional medicinal compound found in winter cherries. WFA has shown promise as an anticancer agent and is thought to act primarily through its effects on the epigenome, including, in particular, the methylome. However, the relative importance of specific genes’ methylation states to WFA function remains unclear. To address this, we utilized human BC cell lines in combination with CRISPR-dCas9 fused to DNA methylation modifiers (i.e., epigenetic editors) to elucidate the importance of specific genes’ promoter methylation states to WFA function and cancer cell viability. We found that targeted demethylation of promoters of the tumor suppressors p21 and p53 within MDA-MB-231/MCF7 cells resulted in around 1.7×/1.5× and 1.2×/1.3× increases in expression, respectively. Targeted methylation of the promoter of the oncogene CCND1 within MDA-MB-231/MCF7 cells resulted in 0.5×/0.8× decreases in gene expression. These changes to p21, p53, and CCND1 were also associated with decreases in cell viability of around 25%/50%, 5%/35%, and 12%/16%, respectively, for MDA-MB-231/MCF7 cells. When given in combination with WFA in both p53 mutant and wild type cells, we discovered that targeted methylation of the p21 promoter was able to modulate the anticancer effects of WFA, while targeted methylation or demethylation of the promoters of p53 and CCND1 had no significant effect on viability decreases from WFA treatment. Taken together, these results indicate that p21, p53, and CCND1 may be important targets for future in vivo studies that may lead to epigenetic editing therapies and that WFA may have utility in the prevention of BC through its effect on p21 promoter methylation independent of p53 function. Full article

Quercetin, a flavonoid, has well-proven cytotoxicity potential, but its therapeutic efficacy is hampered by hydrophobicity, stability issues, and lower bioavailability. The present research aims to address these issues and formulation barriers by formulating a quercetin-loaded micellar nanogel. Quercetin was encapsulated in PF 68 micelles to enhance its solubility, loading, and stability to better its therapeutic potential. The nanogel was further characterized regarding for pH, spreadability, and in vitro cytotoxicity against human breast cancer cells (MCF-7). The resulting micelles exhibited a particle size of 180.26 ± 2.4 nm, surface charge of −13.5 mV, entrapment efficiency of 78.4 ± 1.2%, and in vitro release of 96.11 ± 0.75% up to 8 h. This in vitro cytotoxicity study on MCF-7 cell lines reveals the improved TGI and GI 50 values of micellar nanogel formulation compared to quercetin. The overall study results demonstrated that the developed micellar nanogel system might serve as a promising nanocarrier to enhance the cytotoxic potential of quercetin in cancer therapy. Full article

Peripheral tissues such as skin and adipose tissue play a crucial role in the intracrine formation of sex steroid hormones, complementing the endocrine and paracrine systems. These mechanisms involve the conversion of dehydroepiandrosterone (DHEA) and its sulfated form—DHEAS—into potent androgenic and estrogenic hormones. In vitro studies using tissue-specific cell lines are essential for unraveling the complex intracrine synthesis of these hormones. This study examined the formation of DHEA, androstenedione (A4), testosterone (T), dihydrotestosterone (DHT), and estradiol (E2) from DHEAS in four cell lines: MCF-7 breast cancer cells, HaCaT keratinocytes, human dermal fibroblasts (HDF), and 3T3-L1 preadipocytes and mature adipocytes, using liquid chromatography–mass spectrometry (LC-MS/MS). MCF-7 cells converted DHEAS to DHEA, A4, T, E2, and DHT, while HaCaT cells produced all these steroids except DHT. Mature 3T3-L1 adipocytes produced DHEA, A4, T, and DHT. By contrast, HDF and 3T3-L1 preadipocytes converted DHEAS only to DHEA and A4. This study highlights the vital role of peripheral tissues, such as skin and adipose tissue, for the intracrine formation of sex hormones and underlines the crucial role of in vitro cell culture models to analyze such effects. The data shed light on the significant impact of androgen metabolism in skin and adipose tissue, which is of great relevance for aging, wound healing, obesity, and lipid metabolism. Full article

Marine organisms are a vital source of biologically active compounds. Organic extracts from the muscle of the Pacific white shrimp (L. vannamei) have shown antiproliferative effects on tumor cells, including breast adenocarcinoma. This study aimed to analyze these extracts’ composition and confirm their specificity for breast adenocarcinoma cells without harming normal cells. An organic chloroform extract from L. vannamei muscle was divided using a solvent partition procedure with methanol and hexane. The methanolic partition was fractionated through an open preparative liquid chromatography column to isolate compounds with biological activity, that were later tested on MDA-MB-231 (breast adenocarcinoma), and recently tested on MCF10-A (non-cancerous breast epithelial cells). Cells incubated with these fractions were assessed for viability and morphological changes using fluorescence confocal microscopy. Fractions F#13 and F#14 reduced MDA-MB-231 cancer cell viability at 100 µg/mL without affecting non-cancerous MCF-10A cells, inducing apoptosis-related changes in cancer cells. These fractions contained EPA and DHA free fatty acids, specifically F#13 contained free and esterified astaxanthin as well. The high levels of free linoleic acid 18:2 ω-6, EPA, and DHA (in a 2:1 ratio, EPA:DHA), along with free and esterified astaxanthin in F#13, significantly reduced breast adenocarcinoma cell viability, nearly to that achieved by cisplatin, a chemotherapy drug. Full article

Triple-negative breast cancer (TNBC) represents the most aggressive breast carcinoma subtype lacking efficient therapeutic options. A promising approach in cancer treatment is the pharmacological inhibition of murine double minute 2 (MDM2)-p53 interaction inducing apoptosis in p53 wild-type tumors. However, the role of MDM2 in TNBC with primarily mutant p53 is not well understood. We here selected the clinical-stage MDM2 inhibitors Idasanutlin and Milademetan and investigated their anti-tumoral effects in TNBC. When we analyzed anti-tumor activity in the TNBC cell lines MDA-MB-231, MDA-MB-436, and MDA-MB-468, cellular viability was efficiently reduced, with half maximal inhibitory concentration (IC₅₀) values ranging between 2.00 and 7.62 µM being up to 11-fold lower compared to the well-characterized non-clinical-stage MDM2 inhibitor Nutlin-3a. Furthermore, caspase-3/7 activity was efficiently induced. Importantly, the IC₅₀ values for MDM2 inhibition were equally observed in HCT116 p53^+/+ or HCT116 p53^−/− cells. Finally, the IC₅₀ was significantly higher in non-malignant MCF-10A cells than in TNBC cells. Taken together, Idasanutlin and Milademetan show a potent anti-tumor activity in TNBC cell culture models by efficiently inducing tumor cell death via apoptosis. This effect was observed despite an inactivating p53 mutation and was apparently independent of p53 expression. Our data suggest that MDM2 is a promising target in TNBC and clinical-stage MDM2 inhibitors should be further evaluated for their potential therapeutic application. Full article

Lectins are proteins that specifically recognize carbohydrates on cell membranes, triggering several cellular events such as apoptosis of cancer-transformed cells; however, the mechanisms of action remain incompletely understood. Our research group has reported that a concentrated fraction of Tepary bean lectins (Phaseolus acutifolius; TBLF) exhibits the concentration-dependent induction of apoptosis in colon cancer cells by caspase activation. It is well established that an increase in cytoplasmic calcium ([Ca²⁺]_i) initiates intracellular signals involved in processes such as exocytosis, gene transcription, apoptosis, cell cycle regulation, and muscle contraction, among others. Furthermore, dysregulated calcium signaling has been implicated in various diseases, including certain neurological disorders and cancer. In this study, we aim to demonstrate the effects of native TBLF lectins and a recombinant lectin (rTBL-1) on calcium mobility in breast cancer cells (MCF-7) and non-cancerous cells (MCF-12F). Both TBLF and rTBL-1 increased intracellular calcium concentrations and mobilized calcium from intracellular stores in a concentration-dependent manner; however, the two cell lines exhibited differential responses. While MCF-12F cells restored cytoplasmic calcium concentration, MCF-7 cells maintained a high intracellular calcium concentration. This strongly suggests that lectins can elicit differential cellular responses in cancer and non-cancer cells due to variations in their intrinsic mechanisms of calcium homeostasis. Finally, we demonstrated that TBLF and rTBL-1 can differentially alter Metabolic Cellular Activity (MCA) as a direct measure of cell viability (CVi) in both cell lines. These findings strengthen the evidence of the therapeutic potential of Tepary bean lectins. Undoubtedly, further studies will be necessary to elucidate the mechanisms underlying their applications. Full article

Background: Thieno[2,3-c]pyridines and their analogs are not well explored for their anticancer properties. Hence, our research aimed to establish the anticancer potential of thieno[2,3-c]pyridines through cell-based assays and in silico evaluations. Methods: Thieno[2,3-c]pyridine derivatives 6(a–k) were synthesized and characterized using FT-IR, ¹H-NMR, ¹³C-NMR, and HRMS. All the synthesized compounds were screened initially for their anticancer activity against MCF7 and T47D (breast cancer), HSC3 (head and neck cancer), and RKO (colorectal cancer) cell lines using MTT assay. Apoptosis and cell cycle analyses were conducted using Annexin V/propidium iodide (PI) double staining for apoptosis assessment and PI staining for cell cycle analysis to investigate the mechanisms underlying the reduced cell viability. In silico molecular docking was accomplished for the synthesized compounds against the Hsp90 and determined pharmacokinetics properties. Results: From the screening assay, compounds 6a and 6i were identified as potential inhibitors and were further subjected to IC₅₀ determination. The compound 6i showed potent inhibition against HSC3 (IC₅₀ = 10.8 µM), T47D (IC₅₀ = 11.7 µM), and RKO (IC₅₀ = 12.4 µM) cell lines, all of which indicated a broad spectrum of anticancer activity. Notably, 6i was found to induce G2 phase arrest, thereby inhibiting cell cycle progression. Molecular docking results indicated crucial molecular interactions of the synthesized ligands against the target Hsp90. Conclusion: The compound 6i induced cell death via mechanisms that are different from apoptosis. Thus, the synthesized thieno[2,3-c]pyridine derivatives can be suitable lead compounds to be optimized to obtain potent anticancer agents through Hsp90 inhibition. Full article

Breast Cancer (BrCa) exhibits a high phenotypic heterogeneity, leading to the emergence of aggressive clones and the development of drug resistance. Considering the BrCa heterogeneity and that metabolic reprogramming is a cancer hallmark, we selected seven BrCa cell lines with diverse subtypes to provide their comprehensive metabolome characterization: five lines commonly used (SK-Br-3, T-47D, MCF-7, MDA-MB-436, and MDA-MB-231), and two patient-derived xenografts (Hbcx39 and Hbcx9). We characterized their endometabolomes using ¹H-NMR spectroscopy. We found distinct metabolite profiles, with certain metabolites being common but differentially accumulated across the selected BrCa cell lines. High levels of glycine, lactate, glutamate, and formate, metabolites known to promote invasion and metastasis, were detected in all BrCa cells. In our experiment setting were identified unique metabolites to specific cell lines: xanthine and 2-oxoglutarate in SK-Br-3, 2-oxobutyrate in T-47D, cystathionine and glucose-1-phosphate in MCF-7, NAD⁺ in MDA-MB-436, isocitrate in MDA-MB-231, and NADP⁺ in Hbcx9. The unique and enriched metabolites enabled us to identify the metabolic pathways modulated in a cell-line-specific manner, which may represent potential candidate targets for therapeutic intervention. We believe this study may contribute to the functional characterization of BrCa cells and assist in selecting appropriate cell lines for drug-response studies. Full article

Cardiovascular diseases and cancer are leading global causes of morbidity and mortality, necessitating advances in diagnosis and treatment. Doxorubicin (Doxo), a potent chemotherapy drug, causes long-term heart damage due to cardiotoxicity. Small extracellular vesicles (sEVs) carry bioactive molecules—such as proteins, lipids, and nucleic acids—that can modulate gene expression and signaling pathways in recipient cells, including cardiomyocytes. Through the delivery of cytokines, microRNAs, and growth factors, sEVs can influence cell survival, which plays a critical role in the development of cardiotoxicity. This study investigates the role of sEVs derived from breast cancer cells treated or not with Doxo and their potential to induce cardiomyocyte damage, thereby contributing to cardiotoxicity. We isolated sEVs from MCF-7 cells treated or not to Doxo using ultracentrifugation and characterized them through Nanoparticle Tracking Analysis (NTA), Scanning Electron Microscopy (SEM), and Western Blotting (WB) for the markers CD63, CD81, and TSG101. We analyzed cytokine profiles using a Multiplex Assay and Cytokine Membrane Array. We exposed Guinea pig cardiomyocytes to different concentrations of sEVs. We assessed their viability (MTT assay), shortening, reactive oxygen species (ROS–DHE dye) production, mitochondrial membrane potential (JC-1 dye), and calcium dynamics (FLUO-4 dye). We performed statistical analyses, including t-tests, ANOVA, Cohen’s d, and η² to validate the robustness of the results. Treatment of MCF-7 cells with 0.01 μM Doxorubicin resulted in increased sEVs production, particularly after 48 h of exposure (~1.79 × 10⁸ ± 2.77 × 10⁷ vs. ~5.1 × 10⁷ ± 1.28 × 10⁷ particles/mL, n = 3, p = 0.0019). These sEVs exhibited protein profiles in the 130–25 kDa range and 93–123 nm sizes. They carried cytokines including TNF-α, IL-1β, IL-4, IFN-γ, and IL-10. Exposure of cardiomyocytes to sEVs (0.025 μg/mL to 2.5 μg/mL) from both Doxo-treated and untreated cells significantly reduced cardiomyocyte viability, shortened cell length by up to 20%, increased ROS production, and disrupted calcium homeostasis and mitochondrial membrane potential, indicating severe cellular stress and cardiotoxicity. These findings suggest that Doxo enhances sEVs production from breast cancer cells, which plays a key role in cardiotoxicity through their cytokine cargo. The study highlights the potential of these sEVs as biomarkers for early cardiotoxicity detection and as therapeutic targets to mitigate cardiovascular risks in chemotherapy patients. Future research should focus on understanding the mechanisms by which Doxorubicin-induced sEVs contribute to cardiotoxicity and exploring their diagnostic and therapeutic potential to improve patient safety and outcomes in cancer therapy. Full article

In the field of medicinal chemistry, the introduction of silylated groups is an important strategy to alter the activity, selectivity, and pharmacokinetics of compounds based on the diverse traits of silicon, including atomic size, electronegativity, and hydrophobicity. The hydroxy group on C-9 or C-9 and C-10 of hydroxystearic acids have been functionalized as t-butyl dimethyl silyl ether. The target compounds have been fully characterized and tested for in vitro cytotoxicity in tumor cells HT29, HCT116, CaCo2, HeLa, MCF7, U2OS, and Jurkat J6 and normal I407 cells. In particular, the silyl derivative of (R)-9-hydroxystearic acid was more active in colon cancer cells. Analyses of cell proliferation, oxidative cell status, histones post-translational modifications, protein phosphorylation, gene expression, and DNA damage were performed to obtain information on the antitumor properties of the new molecules in comparison with the unmodified (R)-9-hydroxystearic acid’s previously studied effects. Our results suggest that the incorporation of a silyl functionality may be a useful tool for the structural development of new pharmaceutically active compounds against colon cancer. Full article

Numerous emerging chemotherapeutic agents incorporate N-heterocyclic fragments in their structures, with the quinoline skeleton being particularly significant. Our recent works have focused on glycoconjugates of 8-hydroxyquinoline (8-HQ), which demonstrated enhanced bioavailability and solubility compared to their parent compounds, although they fell short in selectivity. In this study, our objective was to improve the selectivity of glycoconjugates by replacing the oxygen atom with nitrogen by substituting the 8-HQ moiety with 8-aminoquinoline (8-AQ). The 8-AQ derivatives were functionalized through the amino group and linked to sugar derivatives (D-glucose or D-galactose) that were modified with an azide, alkylazide, or propargyl group at the anomeric position by copper(I)-catalyzed 1,3-dipolar azido-alkyne cycloaddition (CuAAC). The resulting glycoconjugates, as well as their potential metabolites, were evaluated for their ability to inhibit the proliferation of cancer cell lines (including HCT 116 and MCF-7) and a healthy cell line (NHDF-Neo). Two of the synthesized glycoconjugates (17 and 18) demonstrated higher cytotoxicity than their oxygen-containing counterparts and showed improved selectivity for cancer cells, thus enhancing their anticancer potential. Furthermore, it was found that glycoconjugates exhibited greater cytotoxicity in comparison to their potential metabolites. Full article

Cancer remains a leading cause of morbidity and mortality worldwide, highlighting the urgent need for novel therapeutic agents. This study investigated the synthesis and biological evaluation of O-alkyl (E)-chalcone derivatives (4a–4v) as potential anticancer agents. The compounds were synthesized via aldol condensation of substituted aldehydes and acetophenones, with structures confirmed by IR, NMR, and mass spectrometry. In vitro cytotoxicity assays revealed varying effectiveness, with compounds 4a, 4b, 4q, and 4v exhibiting potent activity against MDA-MB-231 and MCF-7, showing IC₅₀ values between 2.08 and 13.58 µM, besides HCT-116 and HeLa cancer cell lines (IC₅₀ values between 6.59 and 22.64 µM). Notably, compound 4b displayed remarkable selectivity, with an IC₅₀ of 54.59 µM against the non-cancerous WI-38 cell line. Additionally, protein kinase inhibition assays indicated that compounds 4b and 4q effectively inhibited EGFR and VEGFR-2, with 4b outperforming the standard inhibitor erlotinib. Molecular docking studies of compound 4q showed strong binding affinities in the ATP-binding pockets of EGFR, HER2, VEGFR2, and CDK2. In silico analyses further highlighted the favorable pharmacokinetic properties of compound 4q, underscoring its potential as a selective tyrosine kinase inhibitor. These findings suggest the therapeutic promise of O-alkyl (E)-chalcone derivatives in cancer treatment. Full article

Cancer-related deaths primarily occur due to metastasis, a process involving the migration and invasion of cancer cells. In most solid tumors, metastasis occurs through collective cell migration (CCM), guided by “cellular leaders”. These leader cells generate forces through actomyosin-mediated protrusion and contractility. The cytoskeletal mechanisms employed by metastatic cells during the migration process closely resemble the use of the actin cytoskeleton in endocytosis. In our previous work, we revealed that tumor cells exhibiting high metastatic potential (MP) are more adept at encapsulating 100–200 nm nanoparticles than those with lower MP. The objective of this study was to investigate whether nanoparticle encapsulation could effectively differentiate leader tumor cells during their CCM. To achieve our objectives, we employed a two-dimensional CCM model grounded in the wound-healing (“scratch”) assay, utilizing two breast cancer cell lines, MCF7 and MDA-MB-231, which display low and high migratory potential, respectively. We conducted calibration experiments to identify the “optimal time” at which cells exhibit peak speed during wound closure. Furthermore, we carried out experiments to assess nanoparticle uptake, calculating the colocalization coefficient, and employed phalloidin staining to analyze the anisotropy and orientation of actin filaments. The highest activity for low-MP cells was achieved at 2.6 h during the calibration experiments, whereas high-MP cells were maximally active at 3.9 h, resulting in 8% and 11% reductions in wound area, respectively. We observed a significant difference in encapsulation efficiency between leader and peripheral cells for both high-MP (p < 0.013) and low-MP (p < 0.02) cells. Moreover, leader cells demonstrated a considerably higher anisotropy coefficient (p < 0.029), indicating a more organized, directional structure of actin filaments compared to peripheral cells. Thus, nanoparticle encapsulation offers a groundbreaking approach to identifying the most aggressive and invasive leader cells during the CCM process in breast cancer. Detecting these cells is crucial for developing targeted therapies that can effectively curb metastasis and improve patient outcomes. Full article