Agent For Treatment Of Breast Cancer Research Articles

Impact of camel milk lactoferrin peptides against breast cancer cells: in silico and in vitro study.

Breast cancer remains a significant global health concern, necessitating the exploration of novel therapeutic strategies. Despite advancements in cancer therapeutics, effective treatments with minimal side effects remain elusive. Natural sources, such as camel milk, harbor bioactive compounds such as lactoferrin peptides, which hold promise as anticancer agents. This study investigated the potential of camel milk-derived lactoferrin peptides against breast cancer cells through a combined in silico and in vitro approach. By integrating computational modeling with experimental assays, we aimed to elucidate the anticancer mechanisms of these peptides and provide insights for their optimization as anticancer therapeutics. In silico analysis involving pepetid design, and validation, then molecular docking and molecular dynamics (MD) simulations was used to explore peptide-protein interactions and stability. Peptides were synthesized and tested for anticancer activity using MTT assays on MCF-7 cells, with HDFa normal cells used as controls. Results of this study showed that camel milk-derived lactoferrin peptides, particularly PEP66, exhibited strong anticancer activity against MCF-7 breast cancer cells, with the lowest IC50 value (52.82μg/mL) compared to other peptides. In silico molecular docking and dynamics simulations revealed that PEP66 formed stable interactions with key residues in the HER2 catalytic site, indicating its potential as an effective anticancer agent. The selectivity index (SI) of PEP66 (3.19) also suggested lower toxicity to normal cells compared to cancer cells, reinforcing its therapeutic potential. Hydrogen bonding analysis highlighted key residues involved in stabilizing peptide-protein complexes, while molecular dynamics simulations demonstrated the stability of these interactions over time. Notably, PEP66 exhibited the highest stability and formed significant interactions with essential residues in the HER2 catalytic site, suggesting its potential as an effective anticancer agent. Camel milk-derived lactoferrin peptides show promise as anticancer agents against breast cancer cells. The multidisciplinary approach employed in this study provides valuable insights into the mechanisms underlying their activity, paving the way for rational design strategies to enhance their efficacy. Further experimental validation is warranted to validate the anticancer potential of these peptides and advance their development as novel therapeutic agents for breast cancer treatment.

Unleashing the potential of Genistein and its derivatives as effective therapeutic agents for breast cancer treatment.

Breast cancer remains one of the leading causes of cancer-related deaths among women worldwide. Genistein (Gen), a phytoestrogen soy isoflavone, has emerged as a promising agent in the prevention and treatment of breast cancer due to its ability to function as a natural selective estrogen receptor modulator (SERM). This review explores the multifaceted mechanisms through which Gen and its derivatives exert their anticancer effects, including modulation of the PI3K/Akt signaling pathway, regulation of apoptosis, inhibition of angiogenesis, and impacts on DNA methylation and enzyme functions. We discuss the dual roles of Gen in both enhancing and inhibiting estrogen receptor (ER)-dependent pathways., highlighting its complex interactions with ERα and ERβ. Furthermore, the review examines the synergistic effect of combining Gen with conventional chemotherapeutic agents such as doxorubicin, cisplatin, and selenium, as well as other natural compounds like lycopene. Clinical studies suggest that while isoflavones may not significantly influence breast cancer progression in general, the high consumption of soy isoflavones is associated with reduced recurrence rates in breast cancer survivors. Importantly, Gen's ability to modulate key signaling pathways and enhance the efficacy of existing treatments improves its potential as a valuable adjunct in breast cancer therapy. In conclusion, Gen and its derivatives offer a novel and promising approach for treatment of breast cancer. Continued research into their mechanisms of action and clinical applications will be essential in optimizing their therapeutic potential and translating these findings into effective clinical interventions.

Molecular insights from structural dynamics of HER2-inhibitor complexes pave the way for new breast cancer drugs

The human epidermal growth factor receptor 2 (HER2) is closely associated with the development and progression of breast cancer, making it a critical target for therapeutic interventions. In this study, we employed a comprehensive computational drug discovery strategy to identify potential inhibitors of HER2. Our approach combined virtual screening, re-docking procedures, molecular dynamics (MD) simulations, and free energy landscape analysis using principal component analysis (PCA). From the extensive PubChem library, we initially screened 733 compounds for their binding potential to HER2, using docking scores as a primary filter. These scores ranged notably from −11.172 to −7.028 kcal/mol, indicating substantial binding capacities. Following this screening, we selected four promising compounds (PubChem CID 166029206, 166544027, 21031510, and 11712721) along with a control compound (70I) for in-depth analysis. Utilizing the Amber software suite for MD simulations, we conducted 200-nanosecond simulations to assess the interactions and binding efficiencies of these selected compounds with HER2. We analysed the molecular interactions through various parameters such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), and hydrogen bond formation patterns, free binding energy calculations. The PCA-based free energy landscape analysis revealed that these compounds consistently occupied a distinct low-energy basin, indicating their high stability and strong binding affinity for the HER2. This detailed analysis provided insights into the stability and conformational dynamics of these potential inhibitors when bound to the HER2. Our findings pave the way for further experimental validation and development of these compounds as therapeutic agents in breast cancer treatment.

Pharmacoinformatics, Molecular Dynamics Simulation, and Quantum Mechanics Calculation Based Phytochemical Screening of Croton bonplandianum Against Breast Cancer by Targeting Estrogen Receptor-α (ERα)

Breast cancer progression is strongly influenced by estrogen receptor-α (ERα), a ligand-activated transcription factor that regulates hormone binding, DNA interaction, and transcriptional activation. ERα plays a key role in promoting cell proliferation in breast tissue, and its overexpression is associated with the advancement of breast cancer through estrogen-mediated signaling pathways. Targeting ERα is, therefore, a promising therapeutic strategy for breast cancer. However, there are currently no phytochemical-based drug candidates approved for effectively inhibiting breast cancer progression driven by elevated ERα expression. This study aims to identify phytochemical inhibitors from Croton bonplandianum against ERα using pharmacoinformatics approaches. Eighty-three bioactive compounds from C. bonplandianum were retrieved from the IMPPAT (Indian Medicinal Plants, Phytochemistry, and Therapeutics) database and screened through molecular docking for their binding affinity to ERα. The top candidates were further evaluated through molecular dynamics simulations, ADME analysis, toxicity assessment, and quantum mechanics-based DFT calculations. The thermodynamic properties and HOMO-LUMO energy gap values indicated that the selected compounds were both stable and active. Among them, 2,3-oxidosqualene (CID-5366020) and 5,8,11-eicosatriynoic acid, trimethylsilyl ester (CID-91696396) demonstrated the most potent inhibitory activity against ERα. These findings suggest that these compounds have significant potential as therapeutic agents for breast cancer treatment by targeting ERα.

Investigation of Apoptotic and Anticancer Effects of 2-substituted Benzothiazoles in Breast Cancer Cell Lines: EGFR Modulation and Mechanistic Insights.

Benzothiazole derivatives, a class of heterocyclic compounds, exhibited diverse biological activities influenced by substituents in the thiazole ring. This study aimed to synthesize these compounds with two functional groups to investigate their potential as anticancer agents, particularly against breast cancer. While previous research demonstrated the efficacy of 2-substituted benzothiazoles against glioma and cervical and pancreatic cancer cells, there is a gap in studies targeting breast cancer. The synthesized compounds were tested in vitro using MCF-7, MDA-MB-231, and MCF-10A cell lines, with Doxorubicin as the positive control. Various assays were conducted, including Annexin V/PI, cell cycle analysis, wound healing, and measurement of mitochondrial membrane potential. Protein expression of EGFR and transcription levels of apoptosis-related genes (Bax and Bcl-xL) and cancer progression-related genes (JAK, STAT3, ERK, AKT, mTOR) were analyzed. Additionally, the balance between antioxidants and oxidants was evaluated by measuring TAS and TOS levels. Our findings revealed that benzothiazole compounds significantly inhibited breast cancer cell growth by reducing cell motility, disrupting mitochondrial membrane potential, and inducing cell cycle arrest in the sub-G1 phase. These compounds increased reactive oxygen species accumulation, leading to cell death. Furthermore, they decreased EGFR protein levels, increased Bax gene transcription, and downregulated the expression of genes such as JAK, STAT3, ERK, AKT, and mTOR. In conclusion, benzothiazole derivatives exhibited potent inhibitory effects on breast cancer in vitro by promoting apoptosis, downregulating EGFR activity, and modulating key signaling pathways, including JAK/STAT, ERK/MAPK, and PI3K/Akt/mTOR. These results highlighted the potential of benzothiazole derivatives as novel therapeutic agents for breast cancer treatment.

Dendrosomal Curcumin Showed Cytotoxic Effects on Breast Cancer Cell Line by Inducing Mitochondrial Apoptosis Pathway and Cell Division Arrest

Background: Mutations in the p53 gene have been linked to the initiation and progression of breast cancer, as well as resistance to chemotherapy. Therefore, the development of novel treatment approaches is essential to combat this disease. Objectives: This study aimed to evaluate the effects of dendrosomal curcumin (DNC) on the breast cancer cell line MDA-MB231. Methods: MDA-MB231 cells were treated with 20 μM DNC, and the apoptosis rate and cell proliferation cycles were assessed using flow cytometry. Additionally, after RNA extraction and cDNA synthesis, the expression levels of Lnc-DANCR, EZH2, Noxa, bcl-2, bax, PUMA, p21, and p53 genes were analyzed using RT-PCR. Protein expression levels of P53, P21, Bcl-2, and Bax were evaluated through western blotting. Results: Dendrosomal curcumin induced apoptosis in MDA-MB231 cells and caused cell cycle arrest at the SubG1 phase. Dendrosomal curcumin treatment downregulated Lnc-DANCR, EZH2, bcl-2, and p53 gene expression, while upregulating bax, Noxa, PUMA, and p21 gene expression in a time-dependent manner. Bax and P21 protein levels were significantly upregulated following DNC treatment, whereas Bcl-2 and P53 protein levels were downregulated in DNC-treated breast cancer cells. Conclusions: In summary, dendrosomal nanocurcumin demonstrated potent anti-tumor effects against breast cancer cells, suggesting its potential as a therapeutic agent in breast cancer treatment.

Anti-tumor property of Argemone mexicana leaves methanol extracts against 7, 12- Dimethylbenz[a]anthracene (DMBA) induced mammary tumors in experimental rats

Background: Breast cancer is a complex and multistage process. Many natural compounds are available for an effective and efficient alternative method against breast cancer. This study focused on the anti-cancer activity of Argemone mexicana leaf extract on Dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in experimental rats. Materials and Methods: Argemone mexicana Leaves (AML) were collected, extracted by soxhlet apparatus with methanol solvent, and analyzed by Gas Chromatography and Mass-Spectroscopy (GCMS). Healthy Female Sprague-Dawley rats (7-8 weeks and 100 ± 20 g) were divided in five groups and used to induce mammary tumors by DMBA [25 mg/kg/ Subcutaneous (s.c.)]. After developing a palpable nodule (10-12 weeks after DMBA), the rats were treated with AML extract [200 and 400 mg/kg/Body Weight (b.w.)] and Tamoxifen (TAM 10 mg/kg) orally for 12 weeks. Body weight, tumor weight and volume measurements, lipid peroxidation, antioxidant and tumor marker [Carcinoembryonic Antigen (CEA)] levels, and histological investigations were assessed. Results: Following AML treatment, there was a reduction in weight and volume (P< 0.01) of breast tumor, as well as a significant decrease in levels of lipid peroxidation and tumor marker CEA (P < 0.001) and improved Superoxide Dismutase (SOD), Reduced glutathione (GSH), and caspase levels (P < 0.001). In cytological results, AML improved the cellular architecture, and significant restoration in histopathological examinations revealed a tumor with minimal glandular epithelium proliferation, a decrease in mitotic figures, and nuclear alterations. Conclusion: The study suggests that AML extract has a chemoprotective effect against DMBA-induced mammary tumors in experimental animals, specifying its possibility as a therapeutic agent for breast cancer treatment.

Efficient Delivery of Gold Nanoparticles and miRNA-33a Via Cationic PEGylated Niosomal Formulation to MCF-7 Breast Cancer Cells

To overcome the challenges associated with the co-delivery of AuNPs (gold nanoparticles) and miRNA as an anti-breast cancer combination therapy, niosomal systems were developed using Span 60, cholesterol, and a cationic lipid (CTAB), and the formulations were optimized using Box-Behnken experimental design. The niosomal formulations with the smallest size were selected for further optimization of size, surface charge, entrapment efficiency, and stability. To achieve this, AuNPs and DSPE-PEG2000 (2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000)were added to the formulation. The optimized niosomal formulation could effectively encapsulate AuNPs with an entrapment efficiency of 34.49% ± 0.84 and a spherical particle size of 153.6 ± 4.62 nm. The incorporation of PEG and CTAB led to notable enhancements in the overall characteristics of the delivery system. To evaluate the effectiveness of the combination therapy, various assessments such as cytotoxicity, apoptosis, and gene expression properties were conducted. The results demonstrated that the combination delivery using the new C-PEG-Nio-AuNPs (cationic pegylated niosomal gold nanoparticles) system and miRNA had the lowest IC50, the highest apoptosis rate, and the most significant upregulation of miRNA and BAX/BCL2 expression in MCF-7 cell growth. In conclusion, this innovative co-delivery approach represents a promising breakthrough in the development of therapeutic agents for breast cancer treatment. By combining multiple therapeutic agents within a single delivery system, this method has the potential to enhance treatment efficacy, reduce side effects, and improve patient outcomes.Graphical

Glucose-capped fisetin silver nanoparticles induced cytotoxicity and ferroptosis in breast cancer cells: A molecular perspective

Breast cancer is a prevalent malignancy that poses a significant health threat globally among the women population. In this study, we sought to investigate the cytotoxic and apoptotic effects of glucose-capped fisetin silver nanoparticles (GF-Ag NPs) against the MDA-MB-231 breast cancer cell line. GF-Ag NPs were synthesized and characterized using UV–Vis spectroscopy, X-ray diffractometer, Transmission electron microscopy, Dynamic light scattering, and Photoluminescence. The UV–Vis spectroscopy showed a surface plasmon resonance peak at 432 nm corresponds to Ag. The X-ray diffractometer revealed face-centric cubic nanocrystallites indicating the reduction of Ag+ ions by glucose. Transmission electron microscopy revealed that the glucose-capped fisetin silver nanoparticles had a spherical structure with an average particle size of ∼55 ± 2 nm. The elemental composition analysis with Energy Dispersive X-Ray Analysis indicates 47.04 % of carbon, 3.48 % of oxygen, and 49.48 % of silver. The FT-IR spectra of GF-AG NPs when compared to spectra of fisetin, glucose, and fisetin Ag NPs revealed distinct peak shifts. Diving deeper into cell-based studies, we observed distinct morphological alterations in cells treated with glucose-capped fisetin silver nanoparticles, which included cell shrinkage, detachment, membrane blebbing, and distorted shape. Moreover, the MTT assay demonstrated a significant reduction in cell viability with an IC50 (half-maximal inhibitory concentration) of 11.275 ± 0.197 μg/mL. MDA-MB-231 cells treated with glucose-capped fisetin silver nanoparticles showed signs of apoptosis, decreased mitochondrial membrane potential, and elevated Reactive oxygen species (ROS) production. Gene expression profiling was performed using reverse transcriptase polymerase chain reaction (RT-PCR). The gene expression analysis revealed an upregulation of SLC7A11, SLC40A1, NRF2F, NOX2, and NOX5 genes that are associated with various crucial cellular events. Our study highlights the potential of glucose-capped fisetin silver nanoparticles as a therapeutic agent for breast cancer treatment.

Repositioning fluphenazine as a cuproptosis-dependent anti-breast cancer drug candidate based on TCGA database

Breast cancer is one of the most prevalent malignancies among women. Enhancing the prognosis is an effective approach to enhance the survival rate of breast cancer. Cuproptosis, a copper-dependent programmed cell death process, has been associated with patient prognosis. Inducing cuproptosis is a promising approach for therapy. However, there is currently no anti-breast cancer drug that induces cuproptosis. In this study, we repositioned the clinical drug fluphenazine as a potential agent for breast cancer treatment by inducing cuproptosis. Firstly, we utilized the Cancer Genome Atlas (TCGA) database and Connectivity Map (CMap) database to identify 22 potential compounds with anti-breast cancer activity through inducing cuproptosis. Subsequently, our findings demonstrated that fluphenazine effectively suppressed the viability of MCF-7 cells. Fluphenazine also significantly inhibited the viability of triple negative breast cancer cells MDA-MB-453 and MDA-MB-231. Furthermore, our study revealed that fluphenazine significantly down-regulated the expression of potential prognostic biomarkers associated with cuproptosis, increased copper ion levels, and reduced intracellular pyruvate accumulation. Additionally, it up-regulated the expression of FDX1 at both the mRNA and protein levels, which has been reported to play a crucial role in the induction of cuproptosis. These findings suggest that fluphenazine has the potential to be used as an anti-breast cancer drug by inducing cuproptosis. Therefore, this research provides an insight for the development of novel cuproptosis-dependent anti-cancer agents.

Total triterpenoids from apple peels exert pronounced anti-breast-cancer activity in vivo and in vitro.

Apples are among the most nutritionally valuable fruits and have a history of use in traditional Chinese medicine. Triterpenoids, the primary bioactive compounds found in apples, demonstrate significant antitumor activity. Following enrichment and optimization, the total content of major triterpenoids in total triterpenoids from apple peels (ATT) reached 5.76 g kg-1. The growth of MDA-MB-231 xenograft tumors was significantly inhibited after treatment with ATT. Network pharmacology analysis conclusively identified a close association between the antitumor effect of ATT and the phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) signaling pathway. Experimental validation using MDA-MB-231 cells and a xenograft nude mouse model confirmed that ATT suppressed tumor cell proliferation effectively by modulating the PI3K-Akt signaling pathway, which was consistent with the findings from network pharmacology. The total triterpenoids from apple peels also induced cell apoptosis by mediating the PI3K-Akt signaling pathway. The total triterpenoids from apple peels can inhibit tumor cell proliferation and induce cell apoptosis effectively through the PI3K-Akt signaling pathway, suggesting that ATT holds promise as a prospective therapeutic agent for breast cancer treatment. © 2024 Society of Chemical Industry.

Upregulation of YPEL3 expression and induction of human breast cancer cell death by microRNAs

MicroRNAs (miRNAs), molecules comprising 18–22 nucleotides, regulate expression of genes post-transcriptionally at the 3′ untranslated region of target mRNAs. However, the biological roles and mechanisms of action of miRNAs in breast cancer remain unelucidated. Thus, in this study, we aimed to investigate the functions and possible mechanisms of action of miRNAs in breast cancer to suppress carcinogenesis. Using miRNA databases, we selected miR-34a and miR-605-5p to downregulate MDM4 and MDM2, respectively, because these ubiquitin E3 ligases degrade p53 and promote carcinogenesis. Results showed that miR-34a and miR-605-5p suppressed MDM4 and MDM2 expression, respectively. Moreover, they reduced the expression of yes‑associated protein 1 (YAP1), a well-known oncogene involved in Hippo signaling, but upregulated the mRNA and protein expression of yippee-like 3 (YPEL3). To elucidate whether these miRNAs promote cellular senescence and death through YPEL3 upregulation, we examined their effects on cellular proliferation, SA-β-gal activity, and mitochondrial activity in human breast cancer MCF-7 cells. Given their upregulating effect on YPEL3 expression, miR-34a and miR-605-5p increased the number of β-galactosidase-positive cells and depolarized live cells (by 10%–12%). These data suggest that miR-34a and miR-605-5p promote cellular senescence and cell death. Thus, they may act as tumor suppressors by inducing Hippo signaling and may serve as novel therapeutic agents in breast cancer treatment.

Unlocking nature’s potential: anticancer potential of Helichrysum sanguineum (L.) Kostel on breast cancer cells and its chemical composition

ABSTRACT Helichrysum sanguineum (L.) Kostel (H. sanguineum), a member of the Asteraceae family, has been traditionally employed for various medicinal purposes owing to its rich phytochemical composition. This study investigates the anticancer properties of various extracts of H. sanguineum (ethanol, acetonitrile, hexane, and chloroform) against breast cancer cells, shedding light on its chemical constituents and their potential therapeutic effects. In vitro assays demonstrate the profound inhibitory effects of H. sanguineum extract on human fibroblast and breast cancer cells. Furthermore, we elucidate the underlying mechanisms of action, revealing its ability to induce apoptosis and cell cycle arrest in breast cancer cells. The cytotoxicity and apoptosis outcomes in breast cancer cells varied across different extracts, yet no adverse effects were observed on healthy cells at equivalent concentrations. Furthermore, all extracts initially promoted breast cancer cell proliferation, with the chloroform extract notably reducing cancer cell proliferation even at low concentrations. GC-MS analysis identifies the major chemical constituents of the extract, including flavonoids, terpenoids, and phenolic compounds, which likely contribute to its anticancer activity. Our findings highlight the potential of H. sanguineum extract as a natural agent for breast cancer treatment and the need for further exploration of its mechanisms and clinical applications.

Investigation of the immunological effects of escitalopram oxalate in the breast cancer co-culture model.

During breast cancer treatment, approximately half of the patients are prescribed psychotropic medication, such as selective serotonin reuptake inhibitors (SSRIs). Escitalopram oxalate is an SSRI used as an antidepressant. In this study, by creating a breast cancer microenvironment with THP-1, MCF-7 and MDA-MB-231 breast cancer co-culture models were created. MCF-7, MDA-MB-231, and THP-1 cell lines to determine the concentration range of the cytotoxic effect of escitalopram oxalate MTS and MTT test were used. IC50 values were determined by the xCELLigence real-time cell analysis (RTCA) system. Apoptotic activities and cytokine levels were determined by flow cytometry. In the xCELLigence real-time analysis made according to the results, the IC50 value of escitalopram oxalate was measured as 13.7 μM for MCF-7 and 10.9 μM for MDA-MB-231. The IC50 value was measured as 54.6 μM for MCF-7 and 58.4 μM for MDA-MB-231 in xCELLigence analysis with tamoxifen. According to the MTS test results, the IC50 value of tamoxifen for THP-1 was 92.03 μM and the IC50 value for escitalopram oxalate was 95.32 μM. In the co-culture model, the immunological effects of escitalopram oxalate on MCF-7 cells were 2.8%, 11.1%, 15.6%, 10.6%, and 12.1% for interleukin (IL)-1β, IL-6, IL-8, IL-10, and TNF-α, respectively, while MDA effects on MB-231 cells, respectively, were 2.1%, 15.9%, 16.2%, 8.8%, and 11.8%. According to the results obtained, it was concluded that the immunological effects of escitalopram oxalate are more effective than tamoxifen and that it can be used as an adjunctive agent in breast cancer treatment.

Synergistic cytotoxicity effect by combination of N-hexane fraction of the herbs (Peperomia pellucida) with doxorubicin against breast cancer cells (MCF-7)

Doxorubicin is the first-line chemotherapy agent for breast cancer treatment. However, it's reported to cause cardiotoxicity and induce chemoresistance in breast cancer cells. Doxorubicin is able to induce Pgp (P-glycoprotein) overexpression through NF-kB activation resulting in efflux of chemotherapeutic agents in MCF-7 cells. One of the approaches being developed for cancer treatment is combination therapy by combining two or more anticancer agents that may reduce side effects and provide better effects than single therapy. Peperomia pellucida is reported to have anticancer activity and is widely used as a traditional medicine. This study aimed to investigate the cytotoxic activity of the n-hexane fraction of Peperomia pellucida (NFP) and its combination with doxorubicin (D) against MCF-7 cells. The selectivity of NFP was evaluated using vero cells as a comparator. The phytochemical properties of NFP were evaluated using TLC and LC-MS/MS methods. The cytotoxic activity was determined using the MTT assay. Combination Index (CI) calculations were performed to determine the effect of the combination. This study found that NFP contained about 30 identified compounds and had an IC50 of 96.68 ppm, while doxorubicin had an IC50 of 2.10 ppm. The combination of 24.2 ppm (1/4 IC50) of NFP with 0.26 ppm (1/8 IC50) of doxorubicin had a synergistic cytotoxic effect (CI=0.6) against MCF-7 cells. NFP was selective for MCF-7 cells with a selectivity index of 21.83. The results suggest that NFP may have the potential to enhance the therapeutic efficacy of doxorubicin in breast cancer treatment.

Lactic Acid Bacteria-Derived Postbiotics as Adjunctive Agents in Breast Cancer Treatment to Boost the Antineoplastic Effect of a Conventional Therapeutic Comprising Tamoxifen and a New Drug Candidate: An Aziridine-Hydrazide Hydrazone Derivative.

Breast cancer is associated with high mortality and morbidity rates. As about 20-30% of patients exhibiting ER-positive phenotype are resistant to hormonal treatment with the standard drug tamoxifen, finding new therapies is a necessity. Postbiotics, metabolites, and macromolecules isolated from probiotic bacteria cultures have been proven to have sufficient bioactivity to exert prohealth and anticancer effects, making them viable adjunctive agents for the treatment of various neoplasms, including breast cancer. In the current study, postbiotics derived from L. plantarum and L. rhamnosus cultures were assessed on an in vitro breast cancer model as potential adjunctive agents to therapy utilizing tamoxifen and a candidate aziridine-hydrazide hydrazone derivative drug. Cell viability and cell death processes, including apoptosis, were analyzed for neoplastic MCF-7 cells treated with postbiotics and synthetic compounds. Cell cycle progression and proliferation were analyzed by PI-based flow cytometry and Ki-67 immunostaining. Postbiotics decreased viability and triggered apoptosis in MCF-7, modestly affecting the cell cycle and showing a lack of negative impact on normal cell viability. Moreover, they enhanced the cytotoxic effect of tamoxifen and the new candidate drug toward MCF-7, accelerating apoptosis and the inhibition of proliferation. This illustrates postbiotics' potential as natural adjunctive agents supporting anticancer therapy based on synthetic drugs.

THE APPLICATION OF BIOANALYTICAL METHOD OF TAMOXIFEN AND ITS ACTIVE METABOLITES FOR THERAPEUTIC DRUG MONITORING IN BREAST CANCER PATIENTS: A REVIEW

Breast cancer is the most common cancer around the world and in Indonesia. The most widely used agent for breast cancer treatment is tamoxifen, with a fixed dose of 20 mg per day. Tamoxifen is metabolized by cytochrome P450 3A4 (CYP3A4) and 2D6 (CYP2D6) to endoxifen and 4-hydroxytamoxifen, which have 30-to 100-fold more potent antiestrogenic activity than tamoxifen. High variations of CYP3A4 and CYP2D6 genes can lead to interpatient variability in its metabolites concentration. The dose can be increased to 40 or 60 mg per day based on individual needs. Therapeutic drug monitoring (TDM) is required to measure the concentration of tamoxifen and its metabolites to decide the individualized dose. The measurement of drug levels should use a sensitive, selective, accurate, precise, and reliable bioanalytical method. Various bioanalytical methods have been developed in several matrices: urine, scalp hair, serum, plasma, dried blood spot (DBS), and volumetric absorptive microsampling (VAMS) samples, with different sample preparations, and frequently using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The bioanalytical method of tamoxifen and its metabolites in the DBS sample was more suitable in the TDM application due to the low invasive sampling technique, more stable sample, and rapid sample preparation. Therefore, it is more time-and cost-efficient than the other methods.

Metabolic Profiling, in vitro Cytotoxicity and in silico Investigation of Lycium shawii Roem. Extract

Background: Breast cancer is a prevalent global health concern. Traditional medicine often incorporates the use of medicinal plants to address various diseases. Methods: The cytotoxicity, oxidative stress and cell migration effects of saponin and phenol extracts were evaluated through MTT assay, ROS analysis and wound-healing assay. Following the identification of the active extract, it underwent GC-MS analysis and in silico investigations. Result: Our results revealed significant inhibition of cell proliferation in MDA-MB-231 (IC50:407.3 μg/mL) and HUVECs (IC50:500 μg/mL), which was achieved only with the ethyl acetate extract (Fraction 2). Fraction 2 extract induced notable morphological changes and significantly inhibited time-dependent migration in MDA-MB-231 cells. Additionally, it elevated cellular ROS levels compared to the control cells. In molecular docking analysis, out of the 51 chosen secondary metabolites from L. shawii, stigmast-5-en-3-ol, (3α,24S) (-10.0 kcal/mol) and lup-20(29)-ene-3,28-diol (-9.5 kcal/mol) were found to be the best docked to their respective targets-6CHZ and 4MAN, respectively. Therefore, this plant holds promise as a potential therapeutic agent for breast cancer treatment.

Targeting Breast Cancer with N-Acetyl-D-Glucosamine: Integrating Machine Learning and Cellular Assays for Promising Results.

Breast cancer is a common cancer with high mortality rates. Early diagnosis is crucial for reducing the prognosis and mortality rates. Therefore, the development of alternative treatment options is necessary. This study aimed to investigate the inhibitory effect of N-acetyl-D-glucosamine (D-GlcNAc) on breast cancer using a machine learning method. The findings were further confirmed through assays on breast cancer cell lines. MCF-7 and 4T1 cell lines (ATCC) were cultured in the presence and absence of varying concentrations of D-GlcNAc (0.5 mM, 1 mM, 2 mM, and 4 mM) for 72 hours. A xenograft mouse model for breast cancer was established by injecting 4T1 cells into mammary glands. D-GlcNAc (2 mM) was administered intraperitoneally to mice daily for 28 days, and histopathological effects were evaluated at pre-tumoral and post-tumoral stages. Treatment with 2 mM and 4 mM D-GlcNAc significantly decreased cell proliferation rates in MCF-7 and 4T1 cell lines and increased Fas expression. The number of apoptotic cells was significantly higher than untreated cell cultures (p < 0.01 - p < 0.0001). D-GlcNAc administration also considerably reduced tumour size, mitosis, and angiogenesis in the post-treatment group compared to the control breast cancer group (p < 0.01 - p < 0.0001). Additionally, molecular docking/dynamic analysis revealed a high binding affinity of D-GlcNAc to the marker protein HER2, which is involved in tumour progression and cell signalling. Our study demonstrated the positive effect of D-GlcNAc administration on breast cancer cells, leading to increased apoptosis and Fas expression in the malignant phenotype. The binding affinity of D-GlcNAc to HER2 suggests a potential mechanism of action. These findings contribute to understanding D-GlcNAc as a potential anti-tumour agent for breast cancer treatment.

Propranolol inhibits EMT and metastasis in breast cancer through miR-499-5p-mediated Sox6

PurposeThis study will focus on 4T1 cells, a murine mammary adenocarcinoma cell line, as the primary research subject. We aim to investigate the inhibitory effects and mechanisms of propranolol on epithelial–mesenchymal transition (EMT) in breast cancer cells, aiming to elucidate this phenomenon at the miRNA level.MethodsIn this study, the EMT inhibitory effect of propranolol was observed through in vitro and animal experiments. For the screening of potential target miRNAs and downstream target genes, second-generation sequencing (SGS) and bioinformatics analysis were conducted. Following the screening process, the identified target miRNAs and their respective target genes were confirmed using various experimental methods. To confirm the target miRNAs and target genes, Western Blot (WB), reverse transcription polymerase chain reaction (RT-PCR), and immunofluorescence experiments were performed.ResultsIn this study, we found that propranolol significantly reduced lung metastasis in 4T1 murine breast cancer cells (p < 0.05). In vitro and in vivo experiments demonstrated that propranolol inhibited the epithelial–mesenchymal transition (EMT) as evidenced by Western Blot analysis (p < 0.05). Through next-generation sequencing (SGS), subsequent bioinformatics analysis, and PCR validation, we identified a marked downregulation of miR-499-5p (p < 0.05), suggesting its potential involvement in mediating the suppressive effects of propranolol on EMT. Overexpression of miR-499-5p promoted EMT, migration, and invasion of 4T1 cells, and these effects were not reversed or attenuated by propranolol (Validated via Western Blot, wound healing assay, transwell migration, and invasion assays, p < 0.05). Sox6 was identified as a functional target of miR-499-5p, with its downregulation correlating with the observed EMT changes (p < 0.05). Silencing Sox6 or overexpressing miR-499-5p inhibited Sox6 expression, further promoting the processes of EMT, invasion, and migration in 4T1 cells. Notably, these effects were not alleviated by propranolol (validated via Western Blot, wound healing assay, transwell migration, and invasion assays, p < 0.05). The direct interaction between miR-499-5p and Sox6 mRNA was confirmed by dual-luciferase reporter gene assay.ConclusionThese results suggest that propranolol may have potential as a therapeutic agent for breast cancer treatment by targeting EMT and its regulatory mechanisms.