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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]

Previous data show that the knockdown of the MYBL1 gene in the MDA-MB-231 cell line leads to the downregulation of VCPIP1 gene expression. In addition, MYBL1 and VCPIP1 genes are co-expressed and dysregulated in some of the same triple negative breast cancer patient samples. We propose that the co-expression of the two genes is attributed to the MYBL1 transcription factor regulation of the VCPIP1 gene. We identify the MYBL1 transcription factor binding site upstream of the VCPIP1 start site and show that the MYBL1 protein can bind to the sequence identified in the VCPIP1 promoter region. Combined with the results from the knockdown study, these data support the ability of MYBL1 to regulate the VCPIP1 gene. The VCPIP1 gene functions as a deubiquitinating enzyme involved in DNA repair, protein positioning, and the assembly of the Golgi apparatus during mitotic signaling. The transcriptional regulation of VCPIP1 by the MYBL1 gene could implicate MYBL1 in these processes, which might contribute to tumor processes in TNBC. Although both genes are involved in cell cycle regulatory mechanisms, converging signaling mechanisms have not been identified. In a separate study, we performed sequence alignment of the MYBL1 transcript variants and identified an exon unique to the canonical variant. Probes that specifically target the unique MYBL1 exon show that the exon is overexpressed in tumor cell lines compared to non-tumor breast cells. We are classifying this unique MYBL1 exon as a tumor-associated exon. [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]

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. [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]

Background: TRIB3 has been reported to mediate breast cancer (BC) proliferation and metastasis by interacting with AKT1, and blocking the interaction between TRIB3 and AKT1 can inhibit the progression of BC. Besides, inhibiting TRIB3 to turn "cold tumor" hot has also been proved to be an effective therapeutic strategy for BC. Thus, this study aim to find drugs that can bind to TRIB3 to inhibit BC progression, and further elucidate its mechanism. Methods: The possible inhibitors of TRIB3 were screened by high-throughput molecular docking, CETSA, and CO-IP assay. Then, the effect of TRIB3 inhibitor anti BC was assessed by CCK-8 assay, flow cytometry, plate colony formation assay, and transwell assay; and the RNA-seq was empolyed to study the potential mechanism of Parishin B (PB) anti-BC. Finally, the effect of TRIB3 inhibitor on BC lung metastasis in vivo was evaluated. Results: PB was screened as a possible inhibitor of TRIB3, and CETSA and CO-IP assay indicated that PB could target TRIB3 and block TRIB3-AKT1 interaction. In addition, PB exhibited good anti-BC activity without drug toxicity in normal breast cells by experiments in vitro , and RNA-seq analysis suggested PB could inhibit the proliferation and invasion of BC cells related with cell cycle. It was also proved that PB could inhibit BC lung metastasis in vivo. Conclusion: The study demonstrated PB can bind to TRIB3 to inhibit BC proliferation and lung metastasis by blocking TRIB3-AKT1 interaction and regulating cell cycle, providing a therapeutic agent for the treatment of BC. [ABSTRACT FROM AUTHOR]

Esophageal cancer (EC) is one of the most common highly malignant tumors of the digestive system, with a poor prognosis under current treatment regimens. Nucleolin (NCL) is overexpressed in many tumors, and drugs specifically targeting NCL may offer a promising strategy for treating esophageal cancer. Here, we designed and prepared a novel aptamer-conjugated drug targeting NCL by AS1411 aptamer-human serum albumin (HSA)-the apoprotein of lidamycin (LDP)-active enediyne chromophore (AE), in order to achieve targeted treatment of esophageal cancer. The experimental results revealed that AS1411-HSA-LDP effectively binds to esophageal cancer cells and could be efficiently internalized by esophageal cancer cells. In the KYSE520 xenograft tumor nude mouse model, AS1411-HSA-LDP could be targeted and enriched in the tumor location for a long time. AS1411-HSA-LDP-AE exhibited a strong cell-killing activity in esophageal cancer cells, inhibited cell migration and invasion, and induced cell apoptosis. The animal studies confirmed that AS1411-HSA-LDP-AE exhibited a strong anti-tumor effect. These findings suggested that the novel NCL-targeting aptamer-drug conjugate constructed based on lidamycin exhibited a strong anti-tumor effect, providing a promising strategy for the targeted treatment of esophageal cancer. [ABSTRACT FROM AUTHOR]

Theranostics is a way of treating illness that blends medicine with testing. Specific characteristics should be present in the best theranostic agents for cancer: (1) the drugs should be safe and non-toxic; (2) they should be able to treat cancer selectively; and (3) they should be able to build up only in the cancerous tissue. Liposomes (LPs) are one of the most efficient drug delivery methods based on nanotechnology. Stealth LPs and commercial LPs have recently had an impact on cancer treatment. Using the valuable information from each imaging technique, along with the multimodality imaging functionality of liposomal therapeutic agents, makes them very appealing for personalized monitoring of how well therapeutic drugs are working against cancer in vivo and for predicting how well therapies will work. On the other hand, their use as nanoparticle delivery systems is currently in the research and development phase. Nanoscale delivery system innovation has made LP-nanoparticle hybrid structures very useful for combining therapeutic and imaging methods. LP-hybrid nanoparticles are better at killing cancer cells than their LP counterparts, making them excellent options for in vivo and in vitro drug delivery applications. Hybrid liposomes (HLs) could be used in the future as theranostic carriers to find and treat cancer targets. This would combine the best features of synthetic and biological drug delivery systems. Overarchingly, this article provided a comprehensive overview of the many LP types used in cancer detection, therapy, and theranostic analysis. An evaluation of the pros and cons of the many HLs types used in cancer detection and treatment has also been conducted. The study also included recent and significant research on HLs for cancer theranostic applications. We conclude by outlining the potential benefits and drawbacks of this theranostic approach to the concurrent detection and treatment of different malignancies, as well as its prospects. [ABSTRACT FROM AUTHOR]

Introduction: Oncolytic herpes simplex viruses (oHSVs) are a type of biotherapeutic utilized in cancer therapy due to their ability to selectively infect and destroy tumor cells without harming healthy cells. We sought to investigate the functional genomic response and altered metabolic pathways of human cancer cells to oHSV-1 infection and to elucidate the influence of these responses on the relationship between the virus and the cancer cells. Methods: Two datasets containing gene expression profiles of tumor cells infected with oHSV-1 (G207) and non-infected cells from the Gene Expression Omnibus (GEO) database were processed and normalized using the R software. Common differentially expressed genes between datasets were selected to identify hub genes and were further analyzed. Subsequently, the expression of hub genes was verified by real-time polymerase chain reaction (qRT-PCR) in MDA-MB-231 (a breast cancer cell line) infected with oHSV-1 and non-infected cells. Results: The results of our data analysis indicated notable disparities in the genes associated with the proteasome pathway between infected and non-infected cells. Our ontology analysis revealed that the proteasome-mediated ubiquitin-dependent protein catabolic process was a significant biological process, with a p-value of 5.8E−21. Additionally, extracellular exosomes and protein binding were identified as significant cellular components and molecular functions, respectively. Common hub genes with degree and maximum neighborhood component (MNC) methods, including PSMD2, PSMD4, PSMA2, PSMD14, PSMD11, PSMC3, PSMC2, PSMD8, and PSMA4, were also identified. Analysis of gene expression by qRT-PCR and differential gene expression revealed that GADD45g genes can be effective genes in the proliferation of oncolytic HSV-1 virus. Conclusion: The transcriptome changes in tumor cells infected by oHSV-1 may be utilized to predict oncolytic efficacy and provide rational strategies for designing next-generation oncolytic viruses. [ABSTRACT FROM AUTHOR]

The microbiome-gut-testis axis has emerged as a significant area of interest in understanding testicular cancer, particularly testicular germ cell tumors (TGCTs), which represent the most common malignancy in young men. The interplay between the gut and testicular microbiomes is hypothesized to influence tumorigenesis and reproductive health, underscoring the complex role of microbial ecosystems in disease pathology. The microbiome-gut-testis axis encompasses complex interactions between the gut microbiome, systemic immune modulation, and the local microenvironment of the testis. Dysbiosis in the gut or testicular microbiomes may contribute to altered immune responses, inflammation, and hormonal imbalances, potentially playing a role in the pathogenesis of TGCTs. Concurrently, seminal microbiomes have been linked to variations in sperm quality, fertility potential, and possibly cancer susceptibility, underscoring the need for further evaluation. This review explores the emerging role of the microbiome-gut-testis axis in the context of testicular cancer, highlighting its implications for disease onset, progression, treatment efficacy, and toxicity. Identifying potential microbial biomarkers, followed by microbiota modulation to restore a balanced microbial community, might offer a novel supportive strategy for improving treatment efficacy in refractory TGCT patients while reducing chemotherapy-induced toxicity. We suggest a better understanding of the association between dysregulated microbial environments and TGCTs emphasizes potential pathways by which the gut microbiome might influence testicular cancer. [ABSTRACT FROM AUTHOR]

Although curcumin is a well-known natural polyphenol with many biological activities, its clinical application has been limited by low aqueous solubility and stability. Therefore, curcumin derivatives have been proposed to overcome these limitations and increase anticancer activity. This study tested curcumin derivatives with modified feruloyl moieties (2a and 2a-B) and the β-diketo moiety (2a-B) to better understand their anticancer mechanism against human bladder cancer cells. The anticancer activity of 2a and 2a-B was determined using MTT (hypoxic conditions) and LDH (normoxic conditions) assays. An ELISA-based protein panel was used to find the potential molecular targets, while flow cytometric, colorimetric, fluorescent, and luminescent assays were used to investigate the cell death mechanism. It was shown that compound 2a exerted a more potent cytotoxic effect under hypoxic conditions, while compound 2a-B demonstrated a comparable effect in normoxic and hypoxic conditions. The potential molecular targets modified by 2a and 2a-B depending on oxygen concentration were also proposed. Both compounds alter cell cycle progression by blocking the cell cycle in the G2/M phase and decreasing the percentage of cells in the G0/G1 phase. Compound 2a-B led to phosphatidylserine translocation, increased caspase 3/7 activity, and decreased mitochondrial membrane potential, suggesting a mitochondrial apoptosis pathway. We found that the Akt signaling pathway may modulate the activity of compound 2a-B, as evidenced by enhanced cytotoxic activity in combination with MK-2206, an Akt 1/2/3 inhibitor. Thus, our results provide new insights into the anticancer activity of compounds 2a and 2a-B; however, further studies are needed to better understand their therapeutic potential. [ABSTRACT FROM AUTHOR]

Tea is a significant source of flavonoids in the diet. Due to different production processes, the amount of bioactive compounds in unfermented (green) and (semi-)fermented tea differs. Importantly, green tea has a similar composition of phenolic compounds to fresh, unprocessed tea leaves. It consists primarily of monomeric flavan-3-ols, known as catechins, of which epigallocatechin gallate (EGCG) is the most abundant. Thanks to its antioxidant, antiproliferative, and antiangiogenic properties, EGCG has attracted the scientific community's attention to its potential use in preventing and/or combating cancer. In this review article, we summarize the literature reports found in the Google Scholar and PubMed databases on the anticancer effect of EGCG on selected malignant neoplasms in women, i.e., breast, cervical, endometrial, and ovarian cancers, which have been published over the last two decades. It needs to be emphasized that EGCG concentrations reported as effective against cancer cells are typically higher than those found in plasma after polyphenol administration. Moreover, the low bioavailability and absorption of EGCG appear to be the main reasons for the differences in the effects between in vitro and in vivo studies. In this context, we also decided to look at possible solutions to these problems, consisting of combining the polyphenol with other bioactive components or using nanotechnology. Despite the promising results of the studies conducted so far, mainly in vitro and on animal models, there is no doubt that further, broad-based activities are necessary to unequivocally assess the potential use of EGCG in oncological treatment to combat cancer in women. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is a challenging-to-treat breast cancer subtype, characterized by high recurrence, increased risk of metastasis, and lower survival for patients compared to other breast cancer subtypes. Depending on the clinical advancement of the disease, surgery, radiotherapy, and chemotherapy remain the standard treatment, though they often have limited long-term efficacy. Chemoresistance in TNBC is closely related to the epithelial–mesenchymal transition (EMT), a process where tumor cells gain mesenchymal-like characteristics. This, in turn, increases their metastatic potential and resistance to standard chemotherapeutic treatments. There is a growing interest in small-molecule inhibitors targeting EMT as a potential strategy to overcome resistance and improve TNBC patient outcomes. This review discusses the TNBC progression and drug resistance within the context of EMT, highlighting molecular features, key EMT protein markers, and signaling pathways. It also explores other mechanisms and factors related to chemoresistance in TNBC with an emphasis on treatment advancements. Triple-negative breast cancer (TNBC) is one of the most difficult subtypes of breast cancer to treat due to its distinct clinical and molecular characteristics. Patients with TNBC face a high recurrence rate, an increased risk of metastasis, and lower overall survival compared to other breast cancer subtypes. Despite advancements in targeted therapies, traditional chemotherapy (primarily using platinum compounds and taxanes) continues to be the standard treatment for TNBC, often with limited long-term efficacy. TNBC tumors are heterogeneous, displaying a diverse mutation profile and considerable chromosomal instability, which complicates therapeutic interventions. The development of chemoresistance in TNBC is frequently associated with the process of epithelial–mesenchymal transition (EMT), during which epithelial tumor cells acquire a mesenchymal-like phenotype. This shift enhances metastatic potential, while simultaneously reducing the effectiveness of standard chemotherapeutics. It has also been suggested that EMT plays a central role in the development of cancer stem cells. Hence, there is growing interest in exploring small-molecule inhibitors that target the EMT process as a future strategy for overcoming resistance and improving outcomes for patients with TNBC. This review focuses on the progression and drug resistance of TNBC with an emphasis on the role of EMT in these processes. We present TNBC-specific and EMT-related molecular features, key EMT protein markers, and various signaling pathways involved. We also discuss other important mechanisms and factors related to chemoresistance in TNBC within the context of EMT, highlighting treatment advancements to improve patients' outcomes. [ABSTRACT FROM AUTHOR]

2-arachnadoyl glycerol (2-AG) is one of the most common endocannabinoid molecules with anti-proliferative, cytotoxic, and pro-proliferative effects on different types of tumors. Typically, it induces cell death via cannabinoid receptor 1/2 (CB1/CB2)-linked ceramide production. In breast cancer, ceramide is counterbalanced by the sphingosine-1-phosphate, and thus the mechanisms of 2-AG influence on proliferation are poorly understood. We evaluated the mechanism of the anti-proliferative action by 2-AG and the influence of lysophaosphatidylinositol (LPI) on it in six human breast cancer cell lines of different tumor degree (MCF-10A, MCF-7, BT-474, BT-20, SK-BR-3, and MDA-MB-231) using resazurin test, inhibitor, blocker, and anti-oxidant analysis, and siRNA interference. To avoid acyl migration in 2-AG, we replaced it with the analog 2-arachidonoyl-1,3-difluoropropanol (2-ADFP) newly synthesized by us. Using a molecular docking approach, we showed that at the CB2 receptor, 2-ADFP and 2-AG were very close to each other. However, 2-ADFP demonstrated a stronger affinity towards CB1 in the antagonist-bound conformation. 2-ADFP was anti-proliferative in all the cell lines tested. The toxicity of 2-ADFP was enhanced by LPI. 2-ADFP activity was reduced or prevented by the CB2 and vanilloid receptor 1 (TRPV1) blockers, inositol triphosphate receptor, CREB, and cyclooxygenase 2 inhibitor, and by anti-oxidant addition. Together with the literature data, these results indicate CB2- and TRPV1-dependent COX-2 induction with concomitant cell death induction by the oxidized molecule's metabolites. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSC) are known to be the main source of tumor relapse, metastasis, or multidrug resistance and the mechanisms to counteract or eradicate them and their activity remain elusive. There are different hypotheses that claim that the origin of CSC might be in regular stem cells (SC) and, due to accumulation of mutations, these normal cells become malignant, or the source of CSC might be in any malignant cell that, under certain environmental circumstances, acquires all the qualities to become CSC. Multiple studies indicate that lifestyle and diet might represent a source of wellbeing that can prevent and ameliorate the malignant phenotype of CSC. In this review, after a brief introduction to SC and CSC, we analyze the effects of phenolic and non-phenolic dietary compounds and we highlight the molecular mechanisms that are shown to link diets to CSC activation in colon, breast, and prostate cancer. We focus the analysis on specific markers such as sphere formation, CD surface markers, epithelial–mesenchymal transition (EMT), Oct4, Nanog, Sox2, and aldehyde dehydrogenase 1 (ALDH1) and on the major signaling pathways such as PI3K/Akt/mTOR, NF-κB, Notch, Hedgehog, and Wnt/β-catenin in CSC. In conclusion, a better understanding of how bioactive compounds in our diets influence the dynamics of CSC can raise valuable awareness towards reducing cancer risk. [ABSTRACT FROM AUTHOR]

Cells undergo significant epigenetic and phenotypic change during the epithelial-to-mesenchymal transition (EMT), a process observed in development, wound healing, and cancer metastasis. EMT confers several advantageous characteristics, including enhanced migration and invasion, resistance to cell death, and altered metabolism. In disease, these adaptations could be leveraged as therapeutic targets. Here, we analyze Twist-induced EMT in non-transformed HMLE cells as well as a breast cancer cell line with (MDA-MB-231) and without (MCF7) EMT features to compare differences in metabolic pathways and mitochondrial morphology. Analysis of oxidative and glycolytic metabolism reveals a general EMT-associated glycolytic metabolic phenotype accompanied by increased ATP production. Furthermore, a decrease in mitochondrial size was also associated with EMT-positive cells. However, mitochondrial elongation and spatial dynamics were not consistently altered, as HMLE Twist cells exhibit more rounded and dispersed mitochondria compared to control, while MDA-MB-231 cells exhibit more elongated and clustered mitochondria compared to MCF7 cells. These results provide further insight as to the contextual nature of EMT conferred properties. [ABSTRACT FROM AUTHOR]

Featured Application: The phytochemical sulforaphane has been safely consumed in cruciferous vegetables, wild and cultivated, for centuries. There are multiple applications and copious mechanistic documentation supporting its use in both female- and male-specific conditions, syndromes, diseases, and cancers. All of these relate to the body's hormonal axes in one way or another. More awareness of the specific benefits of sulforaphane on female and male healthspan is warranted for both scientists and the general public. The health-promoting, preventive, protective, and therapeutic applications of the natural compound sulforaphane (SF) produced from its biogenic precursor in broccoli, glucoraphanin, are extremely well established. SF has been the subject of thousands of studies and over 125 clinical trials. The many mechanisms of action of SF in mammalian systems have been extensively documented. SF is the most potent naturally occurring inducer of the Keap1/Nrf2 pathway, which is most well-known for its upregulation of antioxidant and detoxification mechanisms and activation of pathways resulting in the inhibition of inflammation. Much of this regulation involves the various hormonal axes of the body. However, the influence of SF on hormone-mediated health conditions remains unexplored in recent scholarly reviews. This review aims to address this gap by exploring many of these interactions, with a focus on the health and wellness issues specific to both females and males. [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]

Wounds provide an appropriate environment for pathogenic microorganisms to grow, causing tissue damage and inflammation. Remarkable progress has recently been made in nanoparticle formulation for various biological applications over the process of wound recovery. The present study is the first to examine the biosynthesis of silver nanoparticles using Thymus daenensis Celak and investigate its antimicrobial effects on strains causing wound such as Staphylococcus epidermidis, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii, Serratia marcescens, Pseudomonas aeruginosa, and Aspergillus niger. T. daenensis species habitat was first identified in the Daran region, Isfahan, Iran (46° 49′ 2ʺ longitude and 36° 54′ 170ʺ latitude). Flowering branches (leaves, stems, and flowers) of the studied species were then randomly collected from various bases (100 bases per region) in May 2022. Medicinal silver nanoparticles synthesis was confirmed based on UV–Visible, SEM, FTIR, and XRD results. Synthesized silver nanoparticles and the extract's antimicrobial activity were examined through diffusion in agar and determining minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC). UV–Visible results indicated the maximum absorption peak to have been at the 415 nm wavelength. FTIR analysis suggested that synthesized silver nanoparticles' agent groups included aromatic alcohol, primary alcohol, carbonyl, amine, amide, alkyl halide, and carboxylic groups, which was consistent with the extract's spectral pattern. Based on the results XRD, the Debye–Scherrer equation revealed the mean size of silver nanoparticles to be 4.09 nm. Moreover, FESEM analysis demonstrated that silver nanoparticles were rather cube-shaped and uniform with aggregates in 10–50 nm dimensions. Results of ANOVA suggested a significant difference between the growth inhibition halo diameter in T. daenensis extract, synthetic silver nanoparticles, and positive control antibiotics against the microbial strains (P ≤ 0.01). The largest growth-inhibition halo diameter was observed in synthesized silver nanoparticles against P. aeruginosa Gram-negative bacteria at 22.67 mm, indicating a twice as strong performance compared to the rifampin antibiotic. Moreover, synthesized silver nanoparticles demonstrated good inhibitory activity against baumannii (12.00 mm) and Gram-positive bacteria S. epidermidis (22.00 mm) and S. aureus (21.67 mm). On the other hand, the findings indicated that the MIC value of synthesized silver nanoparticles against Gram-negative bacteria P. aeruginosa and S. marcescens was 250 μg/mL, which was 6 times stronger than T. daenensis extract. Hence, silver nanoparticles synthesized from T. daenensis extract could offer possible promising potential as a natural and biocompatible alternative to combat these wound-causing microbial strains. However, further research should be done in the future to gain a complete insight into the toxicity and determine the optimal concentration for clinical applications. [ABSTRACT FROM AUTHOR]

In spite of significant advancements in diagnosis and treatment, cancer remains one of the major threats to human health due to its ability to cause disease with high morbidity and mortality. A multifactorial and multitargeted approach is required towards intervention of the multitude of signaling pathways associated with carcinogenesis inclusive of angiogenesis and metastasis. In this context, plants provide an immense source of phytotherapeutics that show great promise as anticancer drugs. There is increasing epidemiological data indicating that diets rich in vegetables and fruits could decrease the risks of certain cancers. Several studies have proved that natural plant polyphenols, such as flavonoids, lignans, phenolic acids, alkaloids, phenylpropanoids, isoprenoids, terpenes, and stilbenes, could be used in anticancer prophylaxis and therapeutics by recruitment of mechanisms inclusive of antioxidant and anti-inflammatory activities and modulation of several molecular events associated with carcinogenesis. The current review discusses the anticancer activities of principal phytochemicals with focus on signaling circuits towards targeted cancer prophylaxis and therapy. Also addressed are plant-derived anti-cancer vaccines, nanoparticles, monoclonal antibodies, and immunotherapies. This review article brings to light the importance of plants and plant-based platforms as invaluable, low-cost sources of anti-cancer molecules of particular applicability in resource-poor developing countries. [ABSTRACT FROM AUTHOR]

Simple Summary: Metabolic conditions such as obesity, diabetes, and insulin resistance, combined with hormonal imbalances, can disrupt the body's natural growth regulation systems, including the insulin-like growth factor-1 (IGF1) pathway. These disruptions significantly increase the risk of endometrial cancer (EC), a cancer that develops in the lining of the uterus. This review delves into the roles of IGF1 and its variants; IGF1-Ea, IGF1-Eb, and IGF1-Ec, and their interactions with hormones like oestrogen in driving tumour growth and spread. By unravelling these connections, we aim to identify innovative strategies for preventing and treating this cancer, bringing hope for improved patient outcomes and advancing research in hormone-driven cancers. Endometrial cancer (EC) is a common gynaecological malignancy associated with metabolic dysfunctions such as obesity, diabetes and insulin resistance, as well as hormonal imbalances, particularly involving oestrogen and progesterone. These factors disrupt normal cellular metabolism, heightening the risk of developing endometrioid EC (EEC), the most prevalent subtype of EC. The insulin-like growth factor-1 (IGF1) pathway, a key regulator of growth, metabolism, and organ function, is implicated in EC progression. Recent research highlights the distinct roles of IGF1 isoforms, including IGF1-Ea, IGF1-Eb, and IGF1-Ec, in promoting tumour growth, metastasis, and hormone signalling interactions, particularly with oestrogen. This review examines the function and clinical significance of IGF-1 isoforms, emphasising their mechanisms in gynaecological physiology and their contributions to EC pathogenesis. Evidence from other cancers further underscores the relevance of IGF1 isoforms in driving tumour behaviours, offering valuable insights into their potential as biomarkers and therapeutic targets. Understanding these mechanisms provides opportunities for novel approaches to the prevention, diagnosis, and treatment of EC, improving patient outcomes and advancing the broader field of hormone-driven cancers. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) remains a challenging subtype due to its aggressive nature and limited treatment options. This study investigated the potential synergistic effects of Korean mistletoe lectin (Viscum album L. var. coloratum agglutinin, VCA) and cisplatin on MDA-MB-231 TNBC cells using both 2D and 3D culture models. In 2D cultures, the combination of VCA and cisplatin synergistically inhibited cell proliferation, induced apoptosis, and arrested the cell cycle at the G2/M phase. Also, the combination treatment significantly reduced cell migration and invasion. Gene expression analysis showed significant changes in specific genes related to apoptosis (Bax, Bcl-2), metastasis (MMP-2, MMP-9), and EMT (E-cadherin, N-cadherin). Three-dimensional spheroid models corroborated these findings, demonstrating enhanced cytotoxicity and reduced invasion with the combination treatment. Significantly, the 3D models exhibited differential drug sensitivity compared to 2D cultures, emphasizing the importance of utilizing physiologically relevant models in preclinical studies. The combination treatment also reduced the expression of angiogenesis-related factors VEGF-A and HIF-1α. This comprehensive study provides substantial evidence for the potential of VCA and cisplatin combination therapy in TNBC treatment and underscores the significance of integrating 2D and 3D models in preclinical cancer research. [ABSTRACT FROM AUTHOR]

Metformin is an antidiabetic drug with reported potential antiproliferative activity against different cancer types including breast cancer. However, the mechanism of action of how metformin can induce its antiproliferative activity is still unclear. Thus, the current study is a systematic review of the literature aiming to explore the reported antiproliferative mechanisms of metformin against breast cancer. The study included seventeen research articles that describe different mechanisms of action against breast cancer. While the majority of the studies confirm the antiproliferative potential of metformin, albeit at different potencies, there appear to be various mechanisms and factors that can influence this effect. There are a number of questions yet to be answered pertaining the use of metformin as an anti-cancer agent, warranting further investigation into this emerging area of research. [ABSTRACT FROM AUTHOR]

Thrombin binding aptamer (TBA) is one of the best-known G-quadruplex (G4)-forming aptamers that efficiently binds to thrombin, resulting in anticoagulant effects. TBA also possesses promising antiproliferative properties. As with most therapeutic oligonucleotides, chemical modifications are critical for therapeutic applications, particularly to improve thermodynamic stability, resistance in biological environment, and target affinity. To evaluate the effects of nucleobase and/or sugar moiety chemical modifications, five TBA analogues have been designed and synthesized considering that the chair-like G4 structure is crucial for biological activity. Their structural and biological properties have been investigated by Circular Dichroism (CD), Nuclear Magnetic Resonance (NMR), native polyacrylamide gel electrophoresis (PAGE) techniques, and PT and MTT assays. The analogue TBAB contains 8-bromo-2′-deoxyguanosine (B) in G-syn glycosidic positions, while TBAL and TBAM contain locked nucleic acid guanosine (L) or 2′-O-methylguanosine (M) in G-anti positions, respectively. Instead, both the two types of modifications have been introduced in TBABL and TBABM with the aim of obtaining synergistic effects. In fact, both derivatives include B in syn positions, exhibiting in turn L and M in the anti ones. The most appealing results have been obtained for TBABM, which revealed an interesting cytotoxic activity against breast and prostate cancer cell lines, while in the case of TBAB, extraordinary thermal stability (Tm approximately 30 °C higher than that of TBA) and an anticoagulant activity higher than original aptamer were observed, as expected. These data indicate TBAB as the best TBA anticoagulant analogue here investigated and TBABM as a promising antiproliferative derivative. [ABSTRACT FROM AUTHOR]

Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths globally, with a persistently low five-year survival rate of only 14–17%. High rates of metastasis contribute significantly to the poor prognosis of NSCLC, in which inflammation plays an important role by enhancing tumor growth, angiogenesis, and metastasis. Targeting inflammatory pathways within cancer cells may thus represent a promising strategy for inhibiting NSCLC metastasis. This study evaluated the anti-inflammatory and anti-metastatic properties of morin, a bioactive compound derived from a Thai medicinal herb, focusing on its effects on NLRP3 inflammasome-mediated pathways in an in vitro NSCLC model. The A549 and H1299 cell lines were stimulated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP) to activate the NLRP3 pathway. The inhibition effects exhibited by morin in reducing pro-inflammatory secretion in LPS- and ATP-stimulated NSCLC cells were assessed by ELISA, while wound healing and trans-well invasion assays evaluated its impact on cell migration and invasion. RT-qPCR measurement quantified the expression of inflammatory genes, and zymography and Western blotting were used to examine changes in invasive protein levels, epithelial-to-mesenchymal transition (EMT) markers, and underlying molecular mechanisms. Our findings demonstrated the significant ability of morin to decrease the production of IL-1β, IL-18, and IL-6 in a dose-dependent manner (p < 0.05), as well as suppress NSCLC cell migration and invasion. Morin downregulated invasive proteins (MMP-2, MMP-9, u-PAR, u-PA, MT1-MMP) and EMT markers (fibronectin, N-cadherin, vimentin) (p < 0.01) while also reducing the mRNA levels of NLRP3, IL-1β, IL-18, and IL-6. Mechanistic investigations revealed that morin suppressed NLRP3 inflammasome activity and inactivated MAPK pathways. Specifically, it decreased the expression of NLRP3 and ASC proteins and reduced caspase-1 activity, while reducing the phosphorylation of ERK, JNK, and p38 proteins. Collectively, these findings suggest that morin's inactivation of the NLRP3 inflammasome pathway could offer a novel therapeutic strategy for counteracting pro-tumorigenic inflammation and metastatic progression in NSCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: miRNAs are closely associated with the occurrence and development of osteosarcoma, playing a critical role in regulating the cell cycle and programmed cell death of osteosarcoma cells. This review elucidates the mechanisms by which miRNAs influence cancer progression and provides an in-depth analysis of the antitumor potential of natural compounds in regulating osteosarcoma cell apoptosis, ferroptosis, and autophagy through miRNA mediation. Additionally, natural products significantly reduce tumor cell chemoresistance and enhance the efficacy of chemotherapy by modulating miRNA expression. The findings also reveal that natural compounds can regulate miRNA expression via m6A modification, highlighting the important impact of the interplay between m6A modification and miRNAs on tumor development. These findings offer new potential directions and breakthroughs for osteosarcoma treatment. miRNAs are small non-coding RNA molecules that play critical roles in the regulation of gene expression and have been closely associated with various diseases, including cancer. These molecules significantly influence the cell cycle of tumor cells and control programmed cell death (apoptosis). Currently, research on miRNAs has become a major focus in developing cancer therapies. Osteosarcoma, a malignant neoplasm predominantly occurring during adolescence and later in life, is characterized by a high propensity for metastasis. This review explores the role of miRNAs in the initiation and progression of cancer, highlighting their potential as predictive biomarkers for disease. It discusses the mechanisms by which natural products modulate miRNA activity to influence apoptosis, ferroptosis, and autophagy in osteosarcoma cells, aiming to identify new strategies for osteosarcoma treatment. Recent studies on how natural products regulate miRNAs to reduce tumor cell resistance to chemotherapy are also reviewed. Furthermore, the review elaborates on how natural products regulate m6A modifications to influence miRNA expression, thereby exerting antitumor effects. In this process, interactions between m6A modifications and miRNAs have been identified, with both jointly influencing tumorigenesis and cancer progression, offering a new perspective in osteosarcoma treatment. These approaches could help uncover novel regulatory mechanisms in osteosarcoma pathways and provide a theoretical foundation for developing new drugs and identifying novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Resveratrol is a natural polyphenol (stilbenoid), which can be found in grape skin, red wine, blueberries, peanuts and others. The biological properties of resveratrol, in particular antioxidant, anti-inflammatory, anticancer, estrogenic, vasorelaxant and cardioprotective activity, are the main reason for its importance in medicine and pharmacy. Despite all of its advantages, however, there are many problems related to this polyphenolic substance, such as low stability, water insolubility, poor bioavailability and fast metabolism. For this reason, scientists are currently searching for different approaches to dealing with these problematic properties and improving the therapeutic usage of resveratrol. This review summarizes the mechanisms of the biological effects of resveratrol, determined in vitro and in vivo, and the main limitations of the drug. The article emphasizes new approaches for the improvement of resveratrol delivery, in particular nanoencapsulation, formation of nanocrystals, prodrugs and structure analogues. [ABSTRACT FROM AUTHOR]

Background/Objectives: Averrhoa carambola, or star fruit, is a shrub known for its medicinal properties, especially due to bioactive metabolites identified in its roots and fruit with anti-cancer activity. However, the biological effects of its leaves remain unexplored. This study aimed to assess the effects of ethanolic extract from A. carambola leaves on triple-negative breast cancer (TNBC), an aggressive subtype lacking specific therapy. Methods: Phytochemical analysis and HPLC profile and additional cell line evaluation employing MDA-MB-231 were carried out. Results: Phytochemical screening revealed that the ethanolic extract was rich in flavonoids, saponins, and steroids, demonstrating an antioxidant capacity of 45%. 1H NMR analysis indicated the presence of flavonoids, terpenes, and glycoside-like compounds. Cell viability assays showed a concentration-dependent decrease in viability, with an IC50 value of 20.89 μg/mL at 48 h. Clonogenic assays indicated significant inhibition of replicative immortality, with only 2.63% survival at 15 μg/mL. Migration, assessed through a wound healing assay, was reduced to 3.06% at 100 μg/mL, with only 16.23% of cells remaining attached. An additive effect was observed when combining lower concentrations of the extract with doxorubicin, indicating potential synergy. Conclusions: These results suggest that the ethanolic extract of A. carambola leaves contains metabolites with anti-cancer activity against TNBC cells, supporting further research into their bioactive compounds and therapeutic potential. [ABSTRACT FROM AUTHOR]

Opioids are a challenging class of drugs due to their dual role. They alleviate pain, but also pose a risk of dependency, or trigger constipation, particularly in cancer patients, who require the more potent painkillers in more advanced stages of the disease, closely linked to pain resulting from general inflammation, bone metastases, and primary or secondary tumour outgrowth-related nerve damage. Clinicians' vigilance considering treatment with opioids is necessary, bearing in mind extensive data accumulated over decades that have reported the contribution of opioids to immunosuppression, tumour progression, or impaired tissue regeneration, either following opioid use during surgical tumour resection and post-surgical pain treatment, or as a result of other diseases like diabetes, where chronic wounds healing constitutes a challenge. During last few years, an increasing trend for seeking relationships between opioids and epithelial–mesenchymal transition (EMT) in cancer research can be observed. Transiently lasting EMT is desirable during wound healing, but in cancer, or vital organ fibrogenesis, EMT appears to be an obstacle to overcome, forcing to adjust treatment strategies that would reduce the risk for worsening of the disease outcome and patient prognosis. The same opioid may demonstrate promoting or inhibitory effect on EMT, dependently on various conditions in particular clinical cases. We have summarized current findings on this issue to uncover some rules that govern opioid-mediated EMT induction or repression; however, many aspects still remain to be elucidated. [ABSTRACT FROM AUTHOR]

Ciprofloxacin, a widely used second-generation fluoroquinolone for treating bacterial infections, has recently shown notable anticancer properties. This review explores progress in developing ciprofloxacin derivatives with anticancer properties, emphasizing key structural changes that improve their therapeutic effectiveness by modifying the basic group at position 7, the carboxylic acid group at position 3, or both. It further investigates the mechanisms by which these derivatives fight cancer, such as inducing apoptosis, arresting the cell cycle, inhibiting topoisomerase I and II, preventing tubulin polymerization, suppressing interleukin 6, blocking thymidine phosphorylase, inhibiting multidrug resistance proteins, and hindering angiogenesis. Additionally, it outlines their future directions, such as enhancing their efficacy, selectivity, and investigating potential synergy with other chemotherapeutic agents, offering a promising avenue for developing new therapies for cancer. [ABSTRACT FROM AUTHOR]

Background: Tumors, as intricate ecosystems, comprise oncocytes and the highly dynamic tumor stroma. Tumor stroma, representing the non-cancerous and non-cellular composition of the tumor microenvironment (TME), plays a crucial role in oncogenesis and progression, through its interactions with biological, chemical, and mechanical signals. This review aims to analyze the challenges of stroma mimicry models, and highlight advanced personalized co-culture approaches for recapitulating tumor stroma using patient-derived tumor organoids (PDTOs). Methods: This review synthesizes findings from recent studies on tumor stroma composition, stromal remodeling, and the spatiotemporal heterogeneities of the TME. It explores popular stroma-related models, co-culture systems integrating PDTOs with stromal elements, and advanced techniques to improve stroma mimicry. Results: Stroma remodeling, driven by stromal cells, highlights the dynamism and heterogeneity of the TME. PDTOs, derived from tumor tissues or cancer-specific stem cells, accurately mimic the tissue-specific and genetic features of primary tumors, making them valuable for drug screening. Co-culture models combining PDTOs with stromal elements effectively recreate the dynamic TME, showing promise in personalized anti-cancer therapy. Advanced co-culture techniques and flexible combinations enhance the precision of tumor-stroma recapitulation. Conclusions: PDTO-based co-culture systems offer a promising platform for stroma mimicry and personalized anti-cancer therapy development. This review underscores the importance of refining these models to advance precision medicine and improve therapeutic outcomes. [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]

Triple negative breast cancer (TNBC) is characterized by the absence of hormones and growth factor receptors. It is typically responsive to anthracycline/taxol-based conventional chemotherapy. However, major therapeutic limitations include systemic toxicity and acquired resistance to chemotherapeutics. To combat this, nutritional herbs from traditional Chinese medicine (TCM) with limited reported toxicity may represent treatment alternatives for TNBC. Such herbs can effectively target multiple signaling pathways in numerous breast cancer models. The efficacy of various nutritional herbs in a cellular model of TNBC is associated with the downregulation of retinoblastoma (RB) signaling through the cyclin D-CDK4/6-RB axis. Therefore, the present study was designed to examine the effects of Drynaria fortunei (DF) in the same cellular model of TNBC to identify potential mechanistic leads for its efficacy. DF is a nutritional herb that represents a common component of herbal formulations used in TCM. The estrogen receptor-negative, progesterone receptor-negative and human epidermal growth factor receptor-2-negative MDA-MB-231 human breast carcinoma-derived cell line was used as the cellular model for TNBC in the present study. Non-fractionated aqueous extract from the bark of DF represented the test agent. Quantitative end-point biomarkers for the efficacy of DF assessed in the present study included cell cycle progression, RB signaling and caspase 3/7 activity. Treatment with DF at cytostatic concentration induced S phase cell cycle arrest and inhibited RB signaling as evidenced by the downregulated expression of cyclin E, CDK2, E2F1 and RB phosphorylation. DF treatment increased pro-apoptotic caspase 3/7 activity which was inhibited by the pan-caspase inhibitor Z-VAD-FMK. DF treatment also exhibited increased expression of cleaved ADP-ribose) polymerase-1. These data identify potential mechanistic leads for anti-proliferative and pro-apoptotic effects of DF in the present TNBC model. The present experiments validated a mechanism-driven experimental approach to identify efficacious nutritional herbs and/or their bioactive constituents as treatment alternatives for TNBC. [ABSTRACT FROM AUTHOR]

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]