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The present work describes the extraction of a polyprenylated benzophenone-rich extract from Brazilian red propolis (ERPB), the development and validation of an RP-HPLC-UV method to characterize it, and its evaluation against breast cancer cell lines MCF-7 and MDA-MB-231, as well as the normal counterpart MCF-10A. A mixture of gutifferone E and xanthochymol (1+2), and isolated oblongifolin B (3) were used as chemical standards for ERPB and were also evaluated. The concentrations of 1+2 and 3 corresponded to 16.68% and 42.25% of the total content of the extract, respectively, and the validation parameters evaluated were satisfactorily met. The cytotoxic effects of ERPB were assessed, and the obtained IC50 values were 19.58 µg/mL (MCF-10A), 11.56 µg/mL (MCF-7), and 5.22 µg/mL (MDA-MB-231). In conclusion, ERPB exhibits promising cytotoxic effects on the tested breast cell lines. However, further investigation to elucidate its potential therapeutic applications and safety profile should be conducted.

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Introduction: The increasing incidence of cancer diseases necessitates the urgent exploration of new bioactive compounds. One of the trends in drug discovery is marine sponges which is gaining significant support due to the abundant production of natural pharmaceutical compounds obtained from marine ecosystems. This study evaluates the anticancer properties of an organic extract from the Red Sea sponge Callyspongia siphonella (C. siphonella) on HepG-2 and MCF-7 cancer cell lines. Methods: C. siphonella was collected, freeze-dried, and extracted using a methanol-dichloromethane mixture. The extract was analyzed via Liquid Chromatography-Mass Spectrometry. Cytotoxic effects were assessed through cell viability assays, apoptosis detection, cell cycle analysis, mitochondrial membrane potential assays, scratch-wound healing assays, and 3D cell culture assays. Results: Fifteen compounds were identified in the C. siphonella extract. The extract showed moderate cytotoxicity against MCF-7 and HepG-2 cells, with IC50 values of 35.6 ± 6.9 µg/mL and 64.4 ± 8 µg/mL, respectively, after 48 hours of treatment. It induced cell cycle arrest at the G2/M phase in MCF-7 cells and the S phase in HepG-2 cells. Apoptosis increased significantly in both cell lines, accompanied by reduced mitochondrial membrane potential. The extract inhibited cell migration, with notable reductions after 24 and 48 hours. In 3D cell cultures, the extract had IC50 values of 5.1 ± 2 µg/mL for MCF-7 and 166.4 ± 27 µg/mL for HepG-2 after 7 days of treatment, showing greater potency in MCF-7 spheres compared to HepG-2 spheres. Discussion and Conclusion: The anticancer activity is attributed to the bioactive compounds. The C. siphonella extract's ability to induce apoptosis, disrupt mitochondrial membrane potential, and arrest the cell cycle highlights its potential as a novel anticancer agent. Additional research is required to investigate the underlying mechanism by which this extract functions as a highly effective anticancer agent.

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Aim: Metal nanoclusters are emerging nanomaterials applicable for drug delivery. Here, the toxicity and oxidative stress induction of divalent cationic cadmium (Cd2+) was compared with a Cd in the form of nanocluster. Then, it was used for targeted drug delivery into breast cancer cell lines. Methods: Using a green chemistry route, a Cd nanocluster (Cd-NC) was synthesized based on bovine serum albumin. After characterization, its genotoxicity and oxidative stress induction were studied in both in vitro and in vivo. After that, it was conjugated with hyaluronic acid (HA). The efficiency of hyaloronized-Cd-CN (HA-Cd-NC) for loading and releasing crocin (Cro), an anticancer phytochemical, was studied. Finally, it was applied for cell death induction in a panel of breast cancer cell lines. Results: The comet assay results indicated that, unlike Cd2+ and potassium permanganate (KMnO4), no genotoxicity and oxidative stress was induced by Cd-NC in vitro. Then, the pharmacokinetics of this Cd-NC was studied in vivo. The data showed that Cd-NC has accumulated in the liver and excreted from the feces of mice. Unlike Cd2+, no toxicity and oxidative stress were induced by this Cd-NC in animal tissues. Then, the Cd-NC was targeted toward breast cancer cells by adding HA, a ligand for the CD44 cell surface receptor. After that, Cro was loaded on HA-Cd-NC and it was used for the treatment of a panel of human breast cancer cell lines with varying degrees of CD44. The half-maximal drug inhibitory concentration (IC50) of Cro was significantly decreased when it was loaded on HA-Cd-NC, especially in MDA-MB-468 with a higher degree of CD44 at the surface. These results indicate the higher toxicity of Cro toward breast cancers when carried out by HA-Cd-NC. Conclusions: The Cd-NC was completely safe and is a promising candidate for delivering anticancer drugs/phytochemicals into the targeted breast tumors.

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Aim: The study explores the synergistic potential of atorvastatin (ATR) and quercetin (QUER)- loaded solid lipid nanoparticles (SLN) in combating breast cancer. Materials & methods: SLNs were synthesized using a high-shear homogenization method and optimized using Box-Behnken design. The SLNs were characterized and evaluated for their in vitro anticancer activity. Results: The optimized SLN exhibited narrow size distribution (PDI = 0.338 ± 0.034), a particle size of 72.5 ± 6.5 nm, higher entrapment efficiency (<90%), sustained release and spherical surface particles. The in vitro cytotoxicity studies showed a significant reduction in IC50 values on MDA-MB-231 cell lines. Conclusion: We report a novel strategy of repurposing well-known drugs and encapsulating them into SLNs as a promising drug-delivery system against breast cancer.

[Box: see text].

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The mechanical characteristics of the extracellular environment are known to significantly influence cancer cell behavior in vivo and in vitro. The structural complexity and viscoelastic dynamics of the extracellular matrix (ECM) pose significant challenges in understanding its impact on cancer cells. Herein, we report distinct regulatory signatures in the invasion of different breast cancer cell lines into three-dimensional (3D) fibrillar collagen networks, caused by systematic modifications of the physical network properties. By reconstituting collagen networks of thin fibrils, we demonstrate that such networks can display network strand flexibility akin to that of synthetic polymer networks, known to exhibit entropic rubber elasticity. This finding contrasts with the predominant description of the mechanics of fibrillar collagen networks by an enthalpic bending elasticity of rod-like fibrils. Mean-squared displacement analysis of free-standing fibrils confirmed a flexible fiber regime in networks of thin fibrils. Furthermore, collagen fibrils in both networks were softened by the adsorption of highly negatively charged sulfonated polymers and colloidal probe force measurements of network elastic modulus again proofed the occurrence of the two different physical network regimes. Our cell assays revealed that the cellular behavior (morphology, clustering, invasiveness, matrix metalloproteinase (MMP) activity) of the 'weakly invasive' MCF-7 and 'highly invasive' MDA-MB-231 breast cancer cell lines is distinctively affected by the physical (enthalpic/entropic) network regime, and cannot be explained by changes of the network elastic modulus, alone. These results highlight an essential pathway, albeit frequently overlooked, how the physical characteristics of fibrillar ECMs affect cellular behavior. Considering the coexistence of diverse physical network regimes of the ECM in vivo, our findings underscore their critical role of ECM's physical network regimes in tumor progression and other cell functions, and moreover emphasize the significance of 3D in vitro collagen network models for quantifying cell responses in both healthy and pathological states.

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The size of the pores created by external electrical pulses is important for molecule delivery into the cell. The size of pores and their distribution on the cell membrane determine the efficiency of molecule transport into the cell. There are very few studies visualizing the presence of electropores. In this study, we aimed to investigate the size distribution of electropores that were created by high intensity and short duration electrical pulses on MCF-7 cell membrane. Scanning Electron Microscopy (SEM) was used to visualize and characterize the membrane pores created by the external electric field. Structural changes on the surface of the electroporated cell membrane was observed by Atomic Force Microscopy (AFM). The size distribution of pore sizes was obtained by measuring the radius of 500 electropores. SEM imaging showed non-uniform patterning. The average radius of the electropores was 12 nm, 51.60% of pores were distributed within the range of 5 to 10 nm, and 81% of pores had radius below 15 nm. These results showed that microsecond (µs) high intensity electrical pulses cause the creation of heterogeneous nanopores on the cell membrane.

Electroporation is a phenomenon in which permeability of the cell membrane to molecules and ions is increased due to externally applied high electric field pulses. The externally applied electric field pulses create pores on the cell membrane, allowing ions and molecules that normally can not pass through the membrane. The transport of molecules into the cell is related to the size and distribution of the pores created on the membrane. Studies visualizing the presence of electropores are very limited. In this study, we aimed to visualize pores and determine the size distribution of pores created due to the application of external electric field pulses on the cell membrane of human breast cancer cells. The membrane pores created by external electric field were visualized and characterized by different imaging techniques. The size distribution of pores was obtained by measuring the radius of 500 pores created on the cell membrane due to the applied electric fields. The surface of the electropermeabilized cells were very rough due to deformation during electroporation. We observed heterogeneous pore populations that were formed due to application of external electrical pulses on the surface of cell membrane. The average radius of the pores was found to be 12 nm.

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Paclitaxel (PTX) is a chemotherapeutic agent affecting microtubule polymerization. The efficacy of PTX depends on the type of tumor, and its improvement would be beneficial in patients' treatment. Therefore, we tested the effect of slow sulfide donor GYY4137 on paclitaxel sensitivity in two different breast cancer cell lines, MDA-MB-231, derived from a triple negative cell line, and JIMT1, which overexpresses HER2 and is resistant to trastuzumab. In JIMT1 and MDA-MB-231 cells, we compared IC50 and some metabolic (apoptosis induction, lactate/pyruvate conversion, production of reactive oxygen species, etc.), morphologic (changes in cytoskeleton), and functional (migration, angiogenesis) parameters for PTX and PTX/GYY4137, aiming to determine the mechanism of the sensitization of PTX. We observed improved sensitivity to paclitaxel in the presence of GYY4137 in both cell lines, but also some differences in apoptosis induction and pyruvate/lactate conversion between these cells. In MDA-MB-231 cells, GYY4137 increased apoptosis without affecting the IP3R1 protein, changing the morphology of the cytoskeleton. A mechanism of PTX sensitization by GYY4137 in JIMT1 cells is distinct from MDA-MB-231, and remains to be further elucidated. We suggest different mechanisms of action for H2S on the paclitaxel treatment of MDA-MB-231 and JIMT1 breast cancer cell lines.

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Adenosine deaminases acting on RNA 1(ADAR1), an RNA editing enzyme that converts adenosine to inosine by deamination in double-stranded RNAs, plays an important role in occurrence and progression of various types of cancer. Ferroptosis has emerged as a hot topic of cancer research in recent years. We have previously reported that ADAR1 promotes breast cancer progression by regulating miR-335-5p and METTL3. However, whether ADAR1 has effects on ferroptosis in breast cancer cells is largely unknown. In this study, we knocked down ADAR1 using CRISPR-Cas9 technology or over-expressed ADAR1 protein using plasmid expressing ADAR1 in MCF-7 and MDA-MB-231 breast cancer cell lines, then detected cell viability, and levels of ROS, MDA, GSH, Fe2+, GPX4 protein and miR-335-5p. We showed that the cell proliferation was inhibited, levels of ROS, MDA, Fe2+, and miR-335-5p were increased, while GSH and GPX4 levels were decreased after loss of ADAR1, compared to the control group. The opposite effects were observed after ADAR1 overexpression in the cells. Further, we demonstrated that ADAR1-controlled miR-335-5p targeted Sp1 transcription factor of GPX4, a known ferroptosis molecular marker, leading to inhibition of ferroptosis by ADAR1 in breast cancer cells. Moreover, RNA editing activity of ADAR1 is not essential for inducing ferroptosis. Collectively, loss of ADAR1 induces ferroptosis in breast cancer cells by regulating miR-335-5p/Sp1/GPX4 pathway. The findings may provide insights into the mechanism by which ADAR1 promotes breast cancer progression via inhibiting ferroptosis.

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Alkaline phosphatases (APs, EC 3.1.3.1) belong to a superfamily of biological macromolecules that dephosphorylate many phosphometabolites and phosphoproteins and their overexpression is intricated in the spread of cancer to liver and bones, neuronal disorders including Alzheimer's disease (AD), inflammation and others. It was hypothesized that cyclooxygenase-2 (COX-2) selective inhibitors may possess anti-APs potential and may be involved in anticancer proceedings. Three COX-2 inhibitors including nimesulide, piroxicam and lornoxicam were evaluated for the inhibition of APs using in silico and in vitro methods. Molecular docking studies against tissue nonspecific alkaline phosphatase (TNAP) offered the best binding affinities for nimesulide (-11.14 kcal/mol) supported with conventional hydrogen bonding and hydrophobic interactions. MD simulations against TNAP for 200 ns and principal component analysis (PCA) reiterated the stability of ligand-receptor complexes. Molecular expression analysis of TNAP enzyme in the breast cancer cell line MCF-7 exhibited 0.24-fold downregulation with 5 µM nimesulide as compared with 0.26-fold standard 10 µM levamisole. In vitro assays against human placental AP (hPAP) displayed potent inhibitions of these drugs with IC50 values of 0.52 ±â€¯0.02 µM to 3.46 ±â€¯0.13 µM and similar results were obtained for bovine intestinal AP (bIAP). The data when generalized collectively emphasizes that the inhibition of APs by COX-2 inhibitors provides another target to work on the development of anticancer drugs.

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Autophagy is a new window of science that has been noticed due to the importance of specific therapies in cancer. In this study, the effect of lactoferrin (Lf) on the expression level of ATG101, mTOR and AMPK genes in breast cancer cell line MCF7, as well as the interaction between lactoferrin protein and their protein were investigated. The expression level of the genes was measured using a real-time PCR method. PDB, UniProt, KEGG, and STRING databases and ClusPro webserver and PyMol software were used in silico study. The results showed that the expression level of the ATG101 gene in treatment with concentrations of 100, 400, 600, and 800 µg/ml Lf decreased by 0.05, 0.13, 0.54 and 0.77, respectively. The expression level of the mTOR gene in treatment with concentrations of 100, 400, 600, and 800 µg/ml Lf decreased by 0.07, 0.05, 0.13, and 0.49 times respectively. The level of the AMPK gene expression in treatment with concentrations of 100, 400, 600, and 800 µg/ml Lf decreased by 0.05, 0.01, 0.06, and 0.03, respectively. Virtualization of the interaction of Lf protein with ATG101, mTOR and AMPK proteins by Pymol software showed that the N lobe region of Lf interacted with the HORMA domain of ATG101 protein, the fat domain of mTOR protein, and the CTD domain of AMPK protein. Although Lf was not able to increase the expression of autophagy-inducing genes, it may be able to induce autophagy through protein interaction by activating or inhibiting proteins related to autophagy regulation.

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Background Heliotropium bacciferum, often known as wild heliotrope or wild quailplant, is a flowering plant from the borage family. This study examines the anti-metastatic impact of H. bacciferum on Michigan Cancer Foundation-7 (MCF-7) breast cancer cells and its ability to disrupt signaling pathways. Aim To explore the anti-metastatic effect of H. bacciferum on the MCF-7 breast cancer cell line. Materials and methods For this research, MCF-7 breast cancer cells were used. Cells were cultured and subjected to 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, as well as gene expression analysis for glycogen synthase kinase 3 beta (GSK3ß), wingless-related integration site 2 (Wnt2), and ß-catenin. The plant extract was tested to determine if it successfully blocked the signalling pathway or not.  Results The MTT test was performed to study the cytotoxic impact of H. bacciferum. At an increasing concentration of 100 µg/mL, the extract inhibited growth by 55%, whereas at 150 µg/mL, it inhibited growth by 52.5%. Maximum inhibition was seen at 150 µg/mL. H. bacciferum suppressed the GSK3ß and Wnt2 signaling pathways in MCF-7 breast cancer cell lines, acting as an anti-metastatic and anticancer agent. The heliotrine compound in H. bacciferum showed high binding energy to metastatic targets such as GSK3ß, Wnt2, and ß-catenin. Moreover, chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties also support the study. Conclusion In this study, we can infer that H. bacciferum has a favourable anticancer impact on MCF-7 breast cancer cell lines and may be utilised as an anticancer drug against breast cancer cells. It can also be further evaluated for different breast cancers and cell lines.

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Introduction: Evaluating the anticancer property of Padina boergesenii mediated bimetallic nanoparticles. Methods: The present study focuses on synthesizing Se-ZnO bimetallic nanoparticles from an aqueous algal extract of brown algae Padina boergesenii.Synthesized Se-ZnO NPs were characterized by UV, FTIR, SEM-EDS and HRTEM for confirmation along with the anticancer activity by MTT assay. Results: The UV gave an absorbance peak at 342 and 370 nm, and the FTIR showed functional groups involved in synthesizing Se-ZnO NPs. The TEM micrographs indicated the crystalline nature and confirmed the size of the Se-ZnO NPs to be at an average size of 26.14 nm. Anticancer efficacy against the MCF-7 breast and HepG2 (hepatoblastoma) cell lines were also demonstrated, attaining an IC50 value of 67.9 µg and 74.9 µg/ml respectively, which caused 50% cell death. Discussion: This work aims to highlight an effective method for delivering bioactive compounds extracted from brown algae and emphasize its future therapeutic prospects. The potential of Selenium-Zinc oxide nanoparticles is of great interest due to the biocompatibility and low toxicity aspects of selenium combined with the cost-effectiveness and sustainability of zinc metal. The presence of bioactive compounds contributed to the stability of the nanoparticles and acted as capping properties.

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To improve breast cancer treatment and to enable new strategies for therapeutic resistance, therapeutic targets are constantly being studied. Potential targets are proteins of DNA repair and replication and genomic integrity, such as Flap Endonuclease 1 (FEN1). This study investigated the effects of FEN1 inhibitor FEN1-IN-4 in combination with ionizing radiation on cell death, clonogenic survival, the cell cycle, senescence, doubling time, DNA double-strand breaks and micronuclei in breast cancer cells, breast cells and healthy skin fibroblasts. Furthermore, the variation in the baseline FEN1 level and its influence on treatment prognosis was investigated. The cell lines show specific response patterns in the aspects studied and have heterogeneous baseline FEN1 levels. FEN1-IN-4 has cytotoxic, cytostatic and radiosensitizing effects, expressed through increasing cell death by apoptosis and necrosis, G2M share, senescence, double-strand breaks and a reduced survival fraction. Nevertheless, some cells are less affected by the cytotoxicity and fibroblasts show a rather limited response. In vivo, high FEN1 mRNA expression worsens the prognosis of breast cancer patients. Due to the increased expression in breast cancer tissue, FEN1 could represent a new tumor and prognosis marker and FEN1-IN-4 may serve as a new potent agent in personalized medicine and targeted breast cancer therapy.

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Beauvericin (BEA) is a cyclic depsipeptide secondary metabolite of Fusarium species. It causes chemical hazards in food products and exists in an environment containing soil and various food types. On the other hand, the purified BEA has various biological activities and is regarded as a potential candidate for pharmaceutical research. This study was performed to assess the anti-proliferation activity of BEA against human breast cancer cells by regulating the estrogen receptor-alpha (ERα)/p38 pathway. TA and BA assays verified that BEA is a completed ER antagonist. Additionally, BEA suppressed cell proliferation in the anti-proliferation assay involving ER-positive human breast cancer cells co-treated with BPA and BEA. In respect to an anti-proliferation activity, the BPA-induced phosphorylation of p38 protein was inhibited in the presence of BEA. These results suggested that BEA exerts inhibitory potentials on endocrine disrupting effect and possibly acts as a natural therapeutic material for human estrogen hormonal health.

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Breast cancer (BC) is the most prevalent malignancy in women and the second most common disease worldwide, affecting approximately one million individuals annually. Despite the efficacy of conventional chemotherapy, medication resistance and adverse effects limit its effectiveness, leading researchers to explore alternative treatments, including herbal remedies. Saffron, a well-known spice derived from the Crocus sativus L. plant, has shown potential as a BC treatment. The active components of saffron exhibit anti-cancer properties by inducing apoptosis, inhibiting cell division, and modulating signaling pathways implicated in cancer development, such as PI3K/AKT, NF-κB, and MAPK. Clinical findings suggest that saffron can alleviate chemotherapy-induced symptoms, reduce serum tumor marker levels, and enhance quality of life. Preliminary clinical trials are investigating the safety and efficacy of saffron in treating BC, with recent evidence indicating that recommended doses of saffron supplementation are well-tolerated and safe. This review provides an overview of the anti-tumor effects of saffron and its unique chemical composition in BC. However, further research and clinical studies are imperative to fully comprehend the potential of saffron in adjuvant therapy for BC patients.

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Breast cancer is the most prevalent and aggressive type of cancer, causing high mortality rates in women globally. Many drawbacks and side effects of the current chemotherapy force us to develop a robust chemotherapeutic system that can deal with off-target hazards and selectively combat cancer growth, invasiveness, and cancer-initiating cells. Here, a pH-responsive cross-linked nanocarrier (140-160 nm) endowed with poly-ß-thioester functionality (CBAPTL) has been sketched and fabricated for noncovalent firm encapsulation of anticancer drug, parthenolide (PTL) at physiological pH (7.4), which enables sustain release of PTL at relevant endosomal pH (∼5.0-5.3). For this, a bolaamphiphilic molecule integrated with ß-thioester and acrylate functionality was synthesized to fabricate the pH-responsive poly-ß-thioester-based cross-linked nanocarrier via Michael addition click reactions in water. The poly-ß-thioester functionality of CBAPTL hydrolyzes at endosomal acidic conditions, thus leading to the selective release of PTL inside the cancer cell. Cross-linked nanocarriers exhibit high serum stability, dilution insensitivity, and targeted cellular uptake at tumor microenvironment (TME), contrasting normal cells. In vitro study using human MCF-7 breast cancer cells demonstrated that CBAPTL exhibited selective cytotoxicity, reduced clonogenic potential, increased reactive oxygen species (ROS) generation, and arrested the progression of the cell cycle at the G0/G1 phase efficiently. CBAPTL induced apoptosis via downregulating pro-proliferative protein Bcl-2 and upregulating proapoptotic proteins p53, BAD, p21, and cleaved PARP-1. CBAPTL inhibited proliferating signaling by suppressing AKT phosphorylation and p38 expression. CBAPTL also blocked the invasion and migration of MCF-7 cells. CBAPTL effectively inhibits primary and secondary mammosphere formation, thereby preventing cancer-initiating cells' growth. Conversely, CBAPTL has negligible effect on human red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs). These findings highlight the superior efficacy of CBAPTL compared to PTL alone in suppressing cancer cell growth, inducing apoptosis, and preventing invasiveness of MCF-7 cells. Thus, CBAPTL could be considered a possible selective chemotherapeutic cargo against breast cancer without affecting normal cells.

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In our study, we explored how parasitic nematodes, specifically Heligmosomoides polygyrus, influence the immune response, focusing on their potential role in tumor growth. The study aimed to understand the mechanisms by which these parasites modify immune cell activation, particularly in macrophages, and how this might create an environment conducive to tumor growth. Our methods involved analyzing the effects of H. polygyrus excretory-secretory antigens on macrophage activation and their subsequent impact on breast cancer cell lines EMT6 and 4T1. We observed that these antigens significantly increased the expression of genes associated with both pro-inflammatory and anti-inflammatory molecules, such as inducible nitric oxide synthase, TNF-α, (Tumor Necrosis Factor) Il-6 (Interleukin), and arginase. Additionally, we observed changes in the expression of macrophage surface receptors like CD11b, F4/80, and TLR4 (Toll-like receptor 4). Our findings indicate that the antigens from H. polygyrus markedly alter macrophage behavior and increase the proliferation of breast cancer cells in a laboratory setting. This study contributes to a deeper understanding of the complex interactions between parasitic infections and cancer development, highlighting the need for further research in this area to develop potential new strategies for cancer treatment.

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BACKGROUND: Breast cancer clinical outcome relies on its intrinsic molecular subtype and mortality is almost exclusively due to metastasis, whose mechanism remains unclear. We recently revealed the specific contribution of plasma membrane cholesterol to the invasion of malignant MCF10CAIa but not premalignant MCF10AT and normal MCF10A cell lines in 2D, through invadopodia formation and extracellular matrix (ECM) degradation. In the present study, we address the impact of breast cancer subtypes, mutations and aggressiveness on cholesterol implication in breast cancer cell invasion and 3D spheroid invasion and growth. METHODS: We used nine breast cancer cell lines grouped in four subtypes matching breast tumor classification. Four of these cell lines were also used to generate 3D spheroids. These cell lines were compared for cell invasion in 2D and 3D, spheroid growth in 3D, gelatin degradation, cortactin expression, activation and subcellular distribution as well as cell surface cholesterol distribution and lipid droplets. The effect of plasma membrane cholesterol depletion on all these parameters was determined in parallel and systematically compared with the impact of global matrix metalloproteinase (MMP) inhibition. RESULTS: The six invasive cell lines in 2D were sensitive to partial cholesterol depletion, independently of their subtype, aggressiveness or mutation. Nevertheless, the effect was stronger in the three cell lines able to degrade gelatin. 3D spheroid invasion was also reduced after cholesterol depletion in all breast cancer subtypes tested. Notably, targeting cholesterol was more powerful than MMP inhibition in reducing invasion in both 2D and 3D culture models. Moreover, cholesterol depletion in the six invasive cell lines impaired cortactin distribution in the perinuclear region where invadopodia localized. Breast cancer cell line aggressiveness relied on cholesterol-enriched domains at the ECM-free side and intracellular lipid droplets. Furthermore, the three gelatin-degrading cell lines were characterized by increased cholesterol-enriched submicrometric domains at their ECM-contact side. CONCLUSION: Together, our data suggest cell surface cholesterol combined with lipid droplet labeling as a breast cancer cell aggressiveness marker. They also open the way to test other cholesterol-targeting drugs in more complex models to further evaluate whether cholesterol could represent a strategy in breast cancer therapy.

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In this study we presented a novel series of NNO tridentate ligands generating imino, amido and oxo donor pocket for Pd(II) coordination. All the compounds were meticulously characterized by elemental analysis and advanced spectroscopic techniques, including FTIR, proton and carbon NMR. The synthesized compounds underwent rigorous evaluation for their potential as anti-cancer agents, utilizing the aggressive breast cancer cell lines MDA-MB (ATCC) and MCF-7 as a crucial model for assessing growth inhibition in cancer cells. Remarkably, the MTT assay unveiled the robust anti-cancer activity for all palladium complexes against MDA-MB-231 and MCF-7 cells. Particularly, complex [Pd(L1)(CH3CN)] exhibited exceptional potency with an IC50 value of 25.50 ± 0.30 µM (MDA-MB-231) and 20.76 ± 0.30 µM (MCF-7), compared to respective 27.00 ± 0.80 µM and 24.10 ± 0.80 µM for cisplatin, underscoring its promising therapeutic potential. Furthermore, to elucidate the mechanistic basis for the anti-cancer effects, molecular docking studies on tyrosine kinases, an integral target in cancer research, were carried out. The outcome of these investigations further substantiated the remarkable anticancer properties inherent to these innovative compounds. This research offers a compelling perspective on the development of potent anti-cancer agents rooted in the synergy between ligands and Pd(II) complexes and presenting a promising avenue for future cancer therapy endeavors.

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Obstacles to the successful treatment of breast cancer patients with chemotherapeutic agents can be overcome with effective new strategies. It is still unclear how folic acid affects the onset and spread of breast cancer. The purpose of this study was to determine how folic acid affected the apoptotic and autophagic pathways of the breast cancer cell lines MCF-7 and MDA-MB-231. In the present study, folic acid was applied to MCF-7 and MDA-MB-231 breast cancer cell lines at different concentrations and for different durations. MTT analysis was used to investigate cytotoxic activity. All groups underwent the Tunel staining procedure to identify apoptosis and the immunofluorescence staining approach to identify the autophagic pathway. 24-hour folic acid values were accepted as the most appropriate cytotoxic dose. In MCF-7, cell cycle arrest was observed in the S phase and MDA-MB-231 G1/G0 phases. When apoptotic TUNEL staining was evaluated in both cell lines, folic acid significantly increased apoptosis. While a significant difference was observed between the groups in terms of Beclin 1 immunoreactivity in the MDA-MB-231 cell line, there was no significant difference in the MCF-7 cell line. In addition, statistical significance was not observed LC3 immunoreactivity in both cell lines. In the study, it was observed that folic acid induced autophagy at the initial stage in the MDA-MB-231 cell line but had no inductive effect in the MCF-7 cell line. In conclusion, our findings showed that folic acid has a potential cytotoxic and therapeutic effect on MCF-7 and MDA-MB-231 breast cancer cell lines.

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