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Background: Ferroptosis is a recently studied form of programmed cell death characterized by lipid peroxides accumulation in the cells. This process occurs when a cell's antioxidant capacity is disturbed resulting in the inability of the cell to detoxify the toxic peroxides. Two major components that regulate ferroptosis are cysteine and iron. Objective: This study aimed to determine the effect of cysteine deficiency and iron chelation on triple-negative breast cancer (TNBC) ferroptosis in a lipid-enriched microenvironment. Design: The study has a laboratory-based experimental design. This study used the MDA-MB-231 cell line in various in vitro cell culture systems to investigate the research question. Methods: For the first part of the study, we subjected MDA-MB-231 cells to grow in cysteine-absent adipocyte-conditioned media. In the second half, we treated MDA-MB-231 cells with iron chelator, deferoxamine. BODIPY imaging and western blot were carried out to observe ferroptosis in the cells under the 2 conditions. Results: The results showed that cysteine absence in the conditioned media was able to reduce the formation of lipid droplets, which increased the greater access to free fatty acids to undergo oxidation, therefore inducing ferroptosis. On the contrary, cells when treated with deferoxamine along with erastin (ferroptosis-inducing drug), showed an increase in cell iron content was observed, later inducing ferroptosis. Conclusion: Our results show an alternative function of cysteine and deferoxamine, one regulating lipid droplets and the other inducing ferroptosis, although an inhibitor of the same, respectively. Plain Language Summary: Absence of Cysteine and Iron Chelation Induces Ferroptosis in Triple-Negative Breast Cancer Cells The lack of this nonessential amino acid was however able to sensitize triple-negative breast cancer cells to ferroptosis, even in the presence of adipocytes. Iron chelator such as deferoxamine was also affected by the absence of cysteine, wherein they aggravated the situation by increasing the intracellular iron content, therefore promoting ferroptosis. Treatment with System xc inhibitor (erastin or sulfasalazine) and deferoxamine showed similar results. [ABSTRACT FROM AUTHOR]

This study aims to assess the potential mechanism of rutin to treat triple-negative breast cancer (TNBC) based on network pharmacology followed by in vitro experiments. The potential rutin targets were predicted, and the DisGeNET database was used to obtain the disease targets. The intersection targets were identified with Venny 2.1 software, with the String database subsequently used as input to produce the "drug-target-disease" visual network employing Cytoscape 3.7.2. Gene ontology. Kyoto Encyclopaedia of Genes and Genomes analyses were performed for intersection targets, while AutoDock Vina was used for molecular docking and visualization. Cell viability was assessed using the Colorimetric CCK-8 test, and apoptosis was analyzed using PI/Annexin V. The predicted core targets were confirmed by qPCR and western blotting assays. EGFR, IL6, TNF, and INS were found as the primary targets. The molecular docking analysis revealed the rutin interaction with the core targets. The in vitro results confirmed that rutin inhibited the growth of the MDA-MB-231 cell line. Rutin also induced cell death and decreased the expressions of IL6, TNF, INS, and EGFR. Rutin's multi-target effects and molecular mechanism for treating TNBC were confirmed through preliminary results. The results provide a theoretical base for rutin's possible function in breast cancer treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] • The synthesized Ir(III) complexes (1–3) showed the growth inhibition of breast cancer cell lines with lower IC 50 than cisplatin. • Lipophilicity of complexes 1-3 was coresponding to their cytotoxicity potency. • DFT/TDDFT and NTOs pointed out the MMCT, MLCT and XLCT transitions in absorption bands. • The luminescence of Ir(III) complexes were quenched towards Fe(III) concentrations with 1:1 stoichiometric binding. Three phosphorescent iridium(III) complexes consisting bis-diphosphine ligands were prepared and characterized by single-crystal XRD, CHN analysis, spectroscopic techniques, cyclic voltammetry, and DFT. The synthesized complexes were the three monomeric [Ir(ppy) 2 (L 1)Cl] (1), [Ir(ppy) 2 (L 2)]Cl (2) and [Ir(ppy) 2 (L 3)]Cl (3) where L 1 = bis-(diphenylphosphino)methane (dppm), L 2 = bis-(diphenylphosphino)propane (dppp) and L 3 = bis-(diphenylphosphino)benzene (dppbe). Complexes 1 – 3 gave an absorption band between 240 to 380 nm in both CH 2 Cl 2 and DMSO, which is assigned as a charge transfer transition based on theoretical calculation. They showed a blue-green emission at 460–520 nm in DMSO with an absolute quantum efficiency of 0.013–0.046 at room temperature. The selective photo-induced electron transfer (PET) by Fe3+ in DMSO, was studied to obey the Rehm-Weller principle. The 1:1 binding soichiometry between 1 – 3 and Fe3+ was established by Job's plot. The binding constants (K a) were determined using the Benesi-Hildebrand plot. All the complexes are extremely more potent than cisplatin for in vitro antiproliferative activity towards the human breast cancer cells, HCC1937, MCF-7, and MDA-MB-231. The values of IC 50 were in the range of 0.077–0.485 μM, and 1 exhibited the most effective IC 50 against MDA-MB-231 cell line, the triple-negative breast cancer cell. Their lipophilicities (log P) were also examined to explain the penetration ability of the studied complexes towards cell barriers, and transport to the molecular target. [ABSTRACT FROM AUTHOR]

In the present study, a versatile biomaterial of chitosan polymer/ginger (Zingiber officinale Roscoe) extract/ZnO bionanocomposite (CS/GE/ZnO) was formulated. The physicochemical characteristics of the CS/GE/ZnO were examined using a variety of techniques, including Brunauer–Emmett–Teller (BET), elemental analysis (CHN), transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectrum (FTIR), and field emission scanning electron microscopy (FESEM). The elemental analysis indicated that CS/GE/ZnO comprised 22.82% carbon, 4.17% hydrogen, 2.32% nitrogen, and 70.69% oxygen. The BET analysis indicated that CS/GE/ZnO possesses a specific surface area of 11.41 m2/g and a total pore volume of 0.0596 cm3/g. The CS/GE/ZnO exhibits a mesoporous structure with a mean pore diameter (20.91 nm). By analyzing the cytotoxicity and antioxidant properties of the CS/GE/ZnO biomaterial on a breast cancer cell line (MDA-MB-231), its biological activity was determined. In contrast to the standard ascorbic acid (78.08%), the CS/GE/ZnO biomaterial demonstrated an exceptional DPPH radical scavenging efficiency of 78.66%. An IC50 value of 103 μg/mL was determined through MTT assay research on breast cancer investigations involving CS/GE/ZnO and the MDA-MB-231 cell line. The CS/GE/ZnO biomaterial demonstrates efficacy as a chemotherapeutic agent against breast cancer cells, as evidenced by the results. The performance and structure of the CS/GE/ZnO biomaterial indicate potential advancements in nanomaterials for biomedical applications. [ABSTRACT FROM AUTHOR]

The lack of targeted therapy for triple-negative breast cancer (TNBC) is among the mainsprings of its poor prognosis. This study aimed to elucidate the role of the androgen receptor (AR) and its splice variant 7 (ARv7) in TNBC patients. Further, the molecular impact of their blockers, Enzalutamide and EPI-001, on the TNBC cell line MDA-MB-231 was investigated. Thereby, immunohistochemical expression of AR/ARv7 was assessed for TNBC Egyptian patients. Moreover, bioinformatics analysis of AR/ARv7 RNA status was carried out on TNBC patients from The Cancer Genome Atlas Breast Carcinoma project (TCGA-BRCA). Data from both groups was correlated with patients' clinicopathological features. Besides, scratch wound healing assay and ELISA were employed to assess the effect of AR/ARv7 blockers on several metastasis markers in MDA-MB-231 cell line. In the Egyptian-TNBC patients, AR expression was associated with worse 7-year DFS (40.6 ± 18.6 %). In addition, ARv7 showed cytoplasmic and nuclear patterns, and both cytoplasmic and nuclear ARv7+ patients demonstrated a worse 7-year DFS (22.7 ± 17.7 % and 20 ± 17.9 %) and overall survival (63.6 ± 14.5 % and 40 ± 21.8 %). Importantly, 80 % of the nuclear ARv7+ patients developed distant metastasis. The data of the TCGA-TNBC patients showed a tendency for poor outcomes in the high ARv7-expressing patients. Molecularly, in MDA-MB-231, both inhibitors modulated metastasis and epithelial to mesenchymal transition (EMT) markers ROCK1, ROCK2, c-Myc, E-cadherin and N-cadherin, with EPI-001 downregulating NF-ĸB level as well. We concluded that ARv7 indicated poor prognosis in the studied cohorts and that blocking of AR/ARv7 abated metastasis and key regulators of EMT in MDA-MB-231, at least in part by targeting ROCK/NF-ĸB/c-Myc axis. [Display omitted] • The Role of AR and Arv7 in TNBC needs clarification. • Their role was investigated in TNBC patients (NCI and TCGA-BRCA cohorts). • We investigated targeting AR/ARV7 by Enzalutamide and EPI-001 in TNBC cell model. • ARv7 predicts worse prognosis in NCI and TCGA-TNBC patients. • Blocking AR/ARV7 decreases EMT and metastasis through ROCK/NF-ĸB /c-Myc axis. [ABSTRACT FROM AUTHOR]

Background: It is worthwhile to establish a prognostic prediction model based on microenvironment cells (MCs) infiltration and explore new treatment strategies for triple-negative breast cancer (TNBC). Methods: The xCell algorithm was used to quantify the cellular components of the TNBC microenvironment based on bulk RNA sequencing (bulk RNA-seq) data. The MCs index (MCI) was constructed using the least absolute shrinkage and selection operator Cox (LASSO-Cox) regression analysis. Single-cell RNA sequencing (scRNA-seq), spatially resolved transcriptomics (SRT), and multiplex immunofluorescence (mIF) staining analyses verified MCI. The mechanism of action of the MCI was investigated in tumor-bearing mice. Results: MCI consists of the six types of MCs, which can precisely predict the prognosis of the TNBC patients. scRNA-seq, SRT, and mIF analyses verified the existence and proportions of these cells. Furthermore, combined with the spatial distribution characteristics of the six types of MCs, an MCI-enhanced (MCI-e) model was constructed, which could predict the prognosis of the TNBC patients more accurately. More importantly, inhibition of the insulin signaling pathway activated in the cancer cells of the MCIhigh the TNBC patients significantly prolonged the survival time of tumor-bearing mice. Conclusions: Overall, our results demonstrate that MCs infiltration can be exploited as a novel indicator for the prognosis and therapeutic regimen selection of the TNBC patients. [ABSTRACT FROM AUTHOR]

Background: Up to 23% of breast cancer patients recurred within a decade after trastuzumab treatment. Conversely, one trial found that patients with low HER2 expression and metastatic breast cancer had a positive response to trastuzumab-deruxtecan (T-Dxd). This indicates that relying solely on HER2 as a single diagnostic marker to predict the efficacy of anti-HER2 drugs is insufficient. This study highlights the interaction between histamine N-methyltransferase (HNMT) and HER2 as an adjunct predictor for trastuzumab response. Furthermore, modulation of HER2 expression by HNMT may explain why those with low HER2 expression still respond to T-Dxd. Methods: We investigated the impact of HNMT protein expression on the efficacy of anti-HER2 therapy in both in vivo and ex vivo models of patient-derived xenografts and cell line-derived xenografts. Our analysis included Förster resonance energy transfer (FRET) to assess the interaction strength between HNMT and HER2 proteins in trastuzumab-resistant and sensitive tumor tissues. Additionally, we used fluorescence lifetime imaging microscopy (FLIM), cleaved luciferase, and immunoprecipitation to study the interaction dynamics of HNMT and HER2. Furthermore, we evaluated the influence of HNMT activity on the binding of anti-HER2 antibodies to their targets through flow cytometry. We also observed the nuclear translocation of HNMT/HER2-ICD cells using fluorescent double staining and DeltaVision microscopy. Finally, ChIP sequencing was employed to identify target genes affected by the HNMT/HER2-ICD complex. Results: This study highlights HNMT as a potential auxiliary biomarker for diagnosing HER2 + breast cancer. FRET analysis demonstrated a significant interaction between HNMT and HER2 protein in trastuzumab-sensitive tumor tissue (n = 50), suggesting the potential of HNMT as a predictor of treatment response. Mechanistic studies revealed that the interaction between HNMT and HER2 contributes to increased HER2 protein expression at the transcriptional level, thereby impacting the efficacy of anti-HER2 therapy. Furthermore, a subset of triple-negative breast cancers characterized by HNMT overexpression was found to be sensitive to HER2 antibody–drug conjugates such as T-Dxd. Conclusions: These findings offer crucial insights for clinicians evaluating candidates for anti-HER2 therapy, especially for HER2-low breast cancer patients who could gain from T-Dxd treatment. Identifying HNMT expression could help clinicians pinpoint patients who would benefit from anti-HER2 therapy. [ABSTRACT FROM AUTHOR]

Background: Pharmacological vitamin C (Vit-C), or high-dose Vit-C has recently gained attention as a potential cancer therapeutic. However, the anticancer activity of Vit-C has not been investigated in realistic 3D models of human cancers, especially with respect to breast cancer (BC), and its potential benefits remain under debate. Herein, we investigate the activity and mechanism of action of pharmacological Vit-C on two BC tumor spheroids. Methods: We developed two distinct types of BC tumor spheroids from MDA-MB-231 and MCF-7 cells. The spheroids underwent treatment with a range of concentrations of pharmacological Vit-C (1, 5, 10, 15, and 20 mM). Assessments were conducted to determine the cell viability, H2O2 levels, glutathione-to-glutathione disulfide (GSH/GSSG) ratios, and apoptosis. Both flow cytometry analyses of Annexin V/PI staining and caspase3/7 activity assay were used to check apoptosis. Results: We showed that Vit-C induced dose-dependent cell death in both types of tumor spheroids, primarily driven by elevated H2O2 production and a concomitant oxidative stress imbalance induced by the GSH depletion. The high levels of H2O2 generated by Vit-C triggered the apoptosis of spheroids. In MCF-7 spheroids, Vit-C-induced H2O2 production was higher, with a more pronounced decrease in the GSH/GSSG ratio, indicating greater susceptibility to oxidative stress-induced cell death. However, MDA-MB-231 spheroids exhibited a more severe cytotoxic response. Conclusions: This study reveals that Vit-C induces oxidative stress-mediated cell death in both non-aggressive and aggressive BC spheroids. Unlike traditional in vitro studies, this work provides novel insights into the response of two BC tumor subtypes to Vit-C, demonstrating its potential as a targeted common therapy for BC. [ABSTRACT FROM AUTHOR]

Summary: Breast cancer will overtake all other cancers in terms of diagnoses in 2024. Breast cancer counts highest among women in terms of cancer incidence and death rates. Innovative treatment approaches are desperately needed because treatment resistance brought on by current clinical drugs impedes therapeutic efficacy. The T cell-based immunotherapy known as chimeric antigen receptor (CAR) T cell treatment, which uses the patient's immune cells to fight cancer, has demonstrated remarkable efficacy in treating hematologic malignancies; nevertheless, the treatment effects in solid tumors, like breast cancer, have not lived up to expectations. We discuss in detail the role of tumor-associated antigens in breast cancer, current clinical trials, barriers to the intended therapeutic effects of CAR-T cell therapy, and potential ways to increase treatment efficacy. Finally, our review aims to stimulate readers' curiosity by summarizing the most recent advancements in CAR-T cell therapy for breast cancer. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) exhibits higher susceptibility towards oxaliplatin (OXA) due to a faulty DNA damage repair system. However, the unfavorable physicochemical properties and risk of toxicities limit the clinical utility of OXA. Therefore, to impart kinetic inertness, site-specific delivery, and multidrug action, an octahedral Pt(IV) prodrug was developed by using chlorambucil (CBL) as a choice of ligand. The combination of OXA and CBL exhibited synergistic anti-cancer action in TNBC cell lines. Further, to maximize tumor-specific delivery, intracellular accumulation, and in-vivo performance, the developed prodrug (OXA-CBL) was encapsulated in pH-sensitive PEGylated liposomes into (OXA-CBL/PEG-Liposomes). The fabricated liposomes had smaller particle size < 200 nm and higher drug loading (~ 4.26 ± 0.18%). In-vitro release displayed pH-dependent sustained release for up to 48 h. Cellular internalization revealed maximal uptake via clathrin-mediated endocytosis. The cytotoxicity assay showed reduced IC50 in the 4T1 (~ 1.559-fold) and MDA-MB-231 (~ 1.539-fold) cell lines than free OXA-CBL. In-vivo efficacy in 4T1-induced TNBC model revealed a marked increase in % tumor inhibition rate, while diminished % tumor burden in OXA-CBL/BSA-NPs treated animals. Toxicity assessment displayed no signs of systemic and hemolytic toxicity. Overall, delivery of Pt (IV) prodrug as a pH-sensitive PEGylated liposomes offers a safer and efficient system to manage TNBC. [ABSTRACT FROM AUTHOR]

3-Amino-1-(3,4-dimethoxyphenyl)-8-methoxy-1H-benzo[f]chromene-2-carbonitrile (3-ABC, 4) was prepared and affirmed through the spectral data and single crystal X-rays diffraction. The molecule spatial attributes were revealed by the three-dimensional Hirshfeld surface, which is validated by comprehensive statistical evaluations. The key interactions that contribute to the crystal's stability and properties, such as π–π stacking and H⋯X contacts, were highlighted. The dominant forces in the crystal were explained by energy framework calculations and density functional theory analyses, which also show the geometric optimization aspects and molecular reactivity indicators. The focus is on the investigation of frontier molecular orbitals, aromaticity, and π–π stacking abilities. The research concluded by identifying electron density distributions, aromatic features, and possible reactivity sites, offering a complete picture of the compound's structural and electronic landscape. Compound 4 was screened for its antimicrobial capability against three Gram-positive, three Gram-negative bacteria, and three fungi, utilizing the reference antibiotic drug Ampicillin, Gentamycin, and Ketoconazole. Compound 4 exhibited favorable antimicrobial activities that were lower/resembled the reference antimicrobial agents with an IZ range of 15–31 mm. In addition, MIC, MBC, and MFC were assessed and screened for the target molecule 4, unveiling its revealing antimicrobial activities. Lastly, the molecular docking evaluation was implemented for the molecules interaction with the DHFR protein. The compounds exhibit significant interactions with the EGFR protein's active site. [ABSTRACT FROM AUTHOR]

Breast cancer is a substantial source of morbidity and mortality worldwide. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are the primary biomarkers which inform breast cancer treatment. Although endocrine therapy for ER+ patients is widely available, there is a need for increased access to low‐cost, rapid, and accurate ER testing methods. In this work, we designed a near‐infrared optical nanosensor using single‐walled carbon nanotubes (SWCNT) as the transducer and an anti‐ERα antibody as the recognition element. We evaluated the nanosensor in vitro prior to testing with 26 breast cancer samples which were collected by scraping the cut surface of fresh, surgically resected tumors. Twenty samples were ER+, and six ER−, representing 13 unique patients. We found that the nanosensor can differentiate ER− from ER+ patient biopsies through a shift in its center wavelength upon sample addition. Receiver operating characteristic area under the curve analyses determined that the strongest classifier with an AUC of 0.94 was the (7,5) SWCNT after direct incubation and measurement, and without further processing. We anticipate that further testing and development of this nanosensor may push its utility toward field‐deployable, rapid ER subtyping with the potential for additional molecular marker profiling. [ABSTRACT FROM AUTHOR]

Metastasis remains a leading cause of cancer-related mortality, irrespective of the primary tumour origin. However, the core gene regulatory program governing distinct stages of metastasis across cancers remains poorly understood. We investigate this through single-cell transcriptome analysis encompassing over two hundred patients with metastatic and non-metastatic tumours across six cancer types. Our analysis revealed a prognostic core gene signature that provides insights into the intricate cellular dynamics and gene regulatory networks driving metastasis progression at the pan-cancer and single-cell level. Notably, the dissection of transcription factor networks active across different stages of metastasis, combined with functional perturbation, identified SP1 and KLF5 as key regulators, acting as drivers and suppressors of metastasis, respectively, at critical steps of this transition across multiple cancer types. Through in vivo and in vitro loss of function of SP1 in cancer cells, we revealed its role in driving cancer cell survival, invasive growth, and metastatic colonisation. Furthermore, tumour cells and the microenvironment increasingly engage in communication through WNT signalling as metastasis progresses, driven by SP1. Further validating these observations, a drug repurposing analysis identified distinct FDA-approved drugs with anti-metastasis properties, including inhibitors of WNT signalling across various cancers. [ABSTRACT FROM AUTHOR]

Background: Environmental nanoplastics pose a potential health risk due to human exposure, necessitating studies on their cellular effects. This study aims to assess the toxic and antibacterial properties of polystyrene nanoplastics (PS-NH2) on MDA-MB-231 breast cancer cells and HFF-2 fibroblast cells, while also evaluating their oxidative stress responses. Additionally, the study explores the anti-tumor effects and apoptosis induction by PS-NH2. The primary objectives were to determine the cytotoxicity, antibacterial efficacy, and oxidative stress response of PS-NH2 at different concentrations and sizes. The study also aimed to investigate the mechanism of cell death, including apoptosis, necrosis, cell cycle arrest, and changes in antioxidant enzyme activity (SOD and GPx). Methods: Nanoplastic properties were characterized using FTIR, FESEM, and zeta potential analysis. Antibacterial effects were assessed using the agar dilution method, while the MTT assay determined cytotoxicity in MDA-MB-231 and HFF-2 cells. Apoptosis, necrosis, cell cycle arrest, and antioxidant enzyme activities (SOD, GPx) were also evaluated. Results: FTIR analysis confirmed the amino-functionalization of PS-NH2 with a wide peak at 3386 cm-1, and zeta potential indicated a neutral charge. PS-NH2 showed no antibacterial activity against E. coli or Staphylococcus aureus at sizes of 90, 200, and 300 nm. Cytotoxicity assays revealed dose-dependent decreases in cell viability for both cell lines. SOD and GPx activity decreased significantly with increasing PS-NH2 concentrations. Both cell lines underwent apoptosis, with cell accumulation in the G1 and sub-G1 phases, indicating apoptotic cell death. Conclusions: PS-NH2 exhibits dose- and size-dependent cytotoxicity in MDA-MB-231 and HFF-2 cells. Smaller particle sizes and higher concentrations of PS-NH2 enhance oxidative stress, leading to apoptosis and cell cycle arrest. [ABSTRACT FROM AUTHOR]

Chromosome instability is a prevalent vulnerability of cancer cells that has yet to be fully exploited therapeutically. To identify genes uniquely essential to chromosomally unstable cells, we mined the Cancer Dependency Map for genes essential in tumor cells with high levels of copy number aberrations. We identify and validate KIF18A, a mitotic kinesin, as a vulnerability of chromosomally unstable cancer cells. Knockdown of KIF18A leads to mitotic defects and reduction of tumor growth. Screening of a chemical library for inhibitors of KIF18A enzymatic activity identified a hit that was optimized to yield VLS-1272, which is orally bioavailable, potent, ATP non-competitive, microtubule-dependent, and highly selective for KIF18A versus other kinesins. Inhibition of KIF18A's ATPase activity prevents KIF18A translocation across the mitotic spindle, resulting in chromosome congression defects, mitotic cell accumulation, and cell death. Profiling VLS-1272 across >100 cancer cell lines demonstrates that the specificity towards cancer cells with chromosome instability differentiates KIF18A inhibition from other clinically tested anti-mitotic drugs. Treatment of tumor xenografts with VLS-1272 results in mitotic defects leading to substantial, dose-dependent inhibition of tumor growth. The strong biological rationale, robust preclinical data, and optimized compound properties enable the clinical development of a KIF18A inhibitor in cancers with high chromosomal instability. Chromosomal instability occurs frequently in cancer, making it an attractive therapeutic target. Here, the authors identify KIF18A as a targetable vulnerability of cancer cells with chromosomal instability and target this using VLS-1272, a selective KIF18A inhibitor. [ABSTRACT FROM AUTHOR]

Doxorubicin is a key treatment for breast cancer, but its effectiveness often comes with significant side effects. Its actions include DNA intercalation, topoisomerase II inhibition, and reactive oxygen species generation, leading to DNA damage and cell death. However, it can also cause heart problems and low blood cell counts. Current trials aim to improve doxorubicin therapy by adjusting doses, using different administration methods, and combining it with targeted treatments or immunotherapy. Nanoformulations show promise in enhancing doxorubicin's effectiveness by improving drug delivery, reducing side effects, and overcoming drug resistance. This review summarizes recent progress and difficulties in using doxorubicin for breast cancer, highlighting its mechanisms, side effects, ongoing trials, and the potential impact of nanoformulations. Understanding these different aspects is crucial in optimizing doxorubicin's use and improving outcomes for breast cancer patients. This review examines the toxicity of doxorubicin, a drug used in breast cancer treatment, and discusses strategies to mitigate adverse effects, such as cardioprotective agents and liposomal formulations. It also discusses clinical trials evaluating doxorubicin-based regimens, the evolving landscape of combination therapies, and the potential of nanoformulations to optimize delivery and reduce systemic toxicity. The review also discusses the potential of liposomes, nanoparticles, and polymeric micelles to enhance drug accumulation within tumor tissues while sparing healthy organs. Representation of the role of Doxorubicin in cancer therapy, highlighting its utilization across diverse nano-formulations and combined strategies aimed at augmenting targeted delivery to tumor cells. Through intricate nano-engineering, these formulations enhance the specificity of Doxorubicin, ensuring its preferential accumulation within cancerous tissues while mitigating systemic toxicity to healthy cells. By harnessing the principles of targeted drug delivery, these approaches seek to amplify the therapeutic efficacy of Doxorubicin, inducing programmed cell death specifically within malignant cells, and thereby minimizing collateral damage to surrounding healthy tissues. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are implicated in inter-organ communication, which becomes particularly relevant during aging and exercise. DNA methylation-based aging clocks reflect lifestyle and environmental factors, while regular exercise is known to induce adaptive responses, including epigenetic adaptations. Twenty individuals with High-fitness (aged 57.7 ± 9.8 years) and twenty Medium-Low-fitness (aged 57.5 ± 9.7 years) subjects provided blood samples. EVs were isolated from the samples using a size exclusion chromatography (SEC)-based method, and their protein content was analyzed by mass spectrometry (MS). Acceleration of the biological age estimator DNAmFitAge (AgeAccelFit) was associated with the protein cargo of EVs, whereas PhenoAge and GrimAge acceleration did not show a significant relationship. This finding suggests that the epigenetic aging-modulating role of exercise may involve inter-organ communication via EVs. Set Enrichment Analysis was performed to identify enriched Gene Ontology (GO) terms for sets of proteins that were either correlated with AgeAccelFit or detected exclusively in individuals with high levels of aerobic fitness. The protein cargo of EVs further suggests that inter-organ communication influences inflammation, the immune system, cellular repair, adhesion, metabolism and coagulation. Our findings help to understand the preventive role of exercise, which could be mediated in part by EVs., Competing Interests: Declarations. Conflict of interest: The authors have no competing interests to declare that are relevant to the content of this article. Ethical approval: Ethical approval was obtained from the Hungarian Ministry of Human Capacities (EMMI) in agreement with the Hungarian Scientific and Research Ethics Committee (ETT TUKEB, 25167–6/2019 EUIG). Consent to participate: Ethical approval was obtained from the Hungarian Ministry of Human Capacities (EMMI) in agreement with the Hungarian Scientific and Research Ethics Committee (ETT TUKEB, 25167–6/2019 EUIG)., (© 2025. The Author(s).)

Reactive oxygen species (ROS) generated by oxidative stress have emerged as critical factors in the pathophysiology of malignancies. This study investigated the antioxidant and anticancer properties of zinc (Zn), selenium (Se), and silver (Ag) nanoparticles (NPs) against the A2780 human ovarian cancer cell line. Here, the bioinformatics approach was used to determine the top differentially expressed genes associated with oxidative stress. The ZnO-, Se-, and Ag-NPs were then synthesized via a green synthesis method and subsequently characterized using techniques, such as FTIR, XRD, DLS, zeta potential analysis, FESEM, and TEM. The antioxidant capacity of the NPs was evaluated using a DPPH scavenging assay and their effect on superoxide dismutase enzyme activity was determined. HDF and A2780 cells were treated with varying concentrations of ZnO-, Se-, and Ag-NPs, and cell viability and colony formation were assessed using MTT and clonogenic assays, respectively. Additionally, qPCR was performed to analyze the expression of the candidate genes NOX4, SOD2, and NR4A4. Characterization techniques confirmed the successful synthesis of pure, crystalline, and spherical NPs. Antioxidant assays demonstrated the significant antioxidant properties of ZnO-, Se-, and Ag-NPs. In vitro studies indicated that ZnO-, Se-, and Ag-NPs effectively inhibited cell proliferation and suppressed colony formation, likely owing to the downregulation of NOX4 and upregulation of SOD2 genes. Our findings suggest that ZnO-, Se-, and Ag-NPs may serve as promising anticancer agents for ovarian cancer and NOX4 downregulation and SOD2 upregulation can be proposed as oxidative stress biomarkers; however, further experimental investigation is required to elucidate the therapeutic potential of NPs and the early detection potential of biomarkers., Competing Interests: Declarations. Conflict of interest: We certify that there is no conflict of interest with any financial organization., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In recent years, there have been significant developments using combined therapies in cancer treatment. The present study aimed to determine the effects of using crizotinib alone and in combination with butyric acid on different types of breast cancer cells. A total of three different breast cancer models were used: MDA-MB-231, a triple negative model; MCF-7, a Luminal A model; and SKBR-3 cell line, a human epidermal growth factor receptor 2 positive model. In the experiments, proliferation rates and cell index values were obtained using the xCELLigence RTCA DP System, and mitotic index, bromodeoxyuridine labeling index and caspase activity were evaluated as cell kinetics parameters. The results showed that while proliferation rates, cell index values, mitotic index and bromodeoxyuridine labeling index decreased, caspase activity values increased. These results demonstrated that the combined application was more effective than the monotherapy application and could be used at lower concentrations than those drugs applied as monotherapy. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common cancer and the main cause of mortality due to cancer in women around the World. Histone deacetylase 6 (HDAC6) is a promising target for the treatment of BC. In the present study, a series of novel 3-carboxy-coumarin sulfonamides, analogs of belinostat, targeting HDAC6 were designed and synthesized. The compounds were synthesized and purified through open-column chromatography. Characterization was performed using spectroscopic techniques, including 1H and 13C NMR, homonuclear and heteronuclear correlation experiments, IR and UV. Molecular docking was carried out using AutoDock Vina implemented in UCSF Chimera version 1.16 against the HDAC6 protein structure (PDB: 5EDU). 2D protein-ligand interaction diagrams were generated with Maestro, and validation was conducted by redocking trichostatin A into the HDAC6 active site. Additionally, the compounds were evaluated in cancer cell lines (MDA-MB-231, MCF-7 and NIH/3T3), and healthy cells using lymphocytes from healthy volunteers. In the in vitro experiments, the compounds evaluated showed cytotoxic activity against the BC cell lines MCF-7 and MDA-MB-231 and the non-malignant cells 3T3/NIH. Compounds 5, 8a-c exhibited antiproliferative activity comparable to that of cisplatin and doxorubicin. Molecular docking studies showed that compounds with the 3-benzoylcoumarin scaffold had favorable affinity with catalytic domain of HDAC6 and whose interactions are similar to those found in belinostat. Compounds 5, 8b, 8c, 4c, and 8a exhibited higher viability against nonmalignant cells (leukocytes), with percentages ranging from 73-87%, demonstrating 3-4-fold lower potency than belinostat against healthy cells. [ABSTRACT FROM AUTHOR]

Combinational therapy to treat triple-negative breast cancer (TNBC) by concomitantly influencing different cellular pathways has attracted attention recently. In the present study, co-delivery of dasatinib and miR30a by means of CRGDK-targeted lipopolyplexes was conducted to enhance the inhibition of cell proliferation and migration. For this purpose, we condensed the cationic copolymer poly(1-vinylimidazole- co -2-aminoethyl methacrylate) with miR-30a to form polyplexes. Next, the polyplexes and dasatinib were loaded in targeted liposomes via a thin-film hydration method to form final lipopolyplexes. Physicochemical properties of the nano-carriers were evaluated, and their influence on cellular uptake, cytotoxicity, cell migration, apoptosis induction, and Notch-1 mRNA levels as well as their transfection efficiency were assessed in the MDA-MB-231 cell line. Targeted dasatinib-loaded lipopolyplexes exhibited superior cell proliferation and migration inhibition and cellular uptake than dasatinib, polyplexes and non-targeted lipopolyplexes. Moreover, in comparison with non-targeted lipopolyplexes and polyplexes, targeted lipopolyplexes significantly transfected MDA-MB-231 cells and downregulated Notch-1 mRNA.