Anti-breast Cancer Activity Research Articles

Anti-breast cancer effects of dairy protein active peptides, dairy products, and dairy protein-based nanoparticles

Breast cancer is the most frequently diagnosed and fatal cancer among women worldwide. Dairy protein-derived peptides and dairy products are important parts of the daily human diet and have shown promising activities in suppressing the proliferation, migration, and invasion of breast cancer cells, both in vitro and in vivo. Most of the review literature employs meta-analysis methods to explore the association between dairy intake and breast cancer risk. However, there is a lack of comprehensive summary regarding the anti-breast cancer properties of dairy protein-derived peptides, dairy products, and dairy protein-based nanoparticles as well as their underlying mechanisms of action. Therefore, the present study discussed the breast cancer inhibitory effects and mechanisms of active peptides derived from various dairy protein sources. Additionally, the characteristics, anti-breast cancer activities and active components of several types of dairy products, including fermented milk, yogurt and cheeses, were summarized. Furthermore, the preparation methods and therapeutic effects of various dairy protein-containing nanoparticle delivery systems for breast cancer therapy were briefly described. Lastly, this work also provided an overview of what is currently known about the anti-breast cancer effects of dairy products in clinical studies. Our review will be of interest to the development of natural anticancer drugs.

Design, synthesis, and anti-breast cancer activity evaluation of novel 3-cyanopyridine derivatives as PIM-1 inhibitors.

A novel series of cyanopyridines 7a-j were synthesized via a one-pot multicomponent reaction of arylidene 4 with ammonium acetate 5 and respective methylaryl/heterylketones 6a-j in ethanol using vanillin as a natural starting material. Moreover, the regioselective alkylation reaction was studied by the treatment of cyanopyridines 7a-f and 7j with CH3I in the presence of K2CO3 in DMF to afford O-methylcyanopyridines 8a-g (major) and N-methylcyanopyridines 9a-g (minor), whereas bipyridine 7h gave bipyridinium iodide salt 10. All of the designed cyanopyridines were evaluated as anti-breast cancer (MCF-7) cell lines via PIM Kinase inhibitory activity, and the results displayed that some of them showed high activities, especially compounds 7h and 8f, which showed excellent activities against MCF-7 with IC50 values of 1.89 and 1.69 μM, respectively, more potent than the reference drug doxorubicin. Mechanistically, compounds 7h and 8f exhibited strong in vitro PIM-1 kinase inhibitory activity with an IC50 of 0.281 and 0.58 μM, respectively, compared to the reference staurosporine. Moreover, compound 7h arrested the tumor cells at the S phase and caused cell death mainly by inducing early and late apoptosis. Molecular docking studies against PIM-1 revealed good binding modes of the synthesized compound and showed agreement with the biological results.

In vitro pharmacological evaluation of Methanolic leaf extract of Calotropis procera for antifungal and anti-breast cancer activities.

Medicinal plants remained the primary choice worldwide from several centuries due to many therapeutic effects in the management of infectious and non-infectious diseases. Therefore, exploration of new medicinalplants as a green medicine has the major concern of many research groups. Microbial infections and different types of cancers in human are among the common health problems both in developing as well as in developed countries. Medicinal plants as a source of anti-microbial and anti-cancer agents are still in their initial stage in modern medicine. So current research work was planned to explore the anti-fungal and anticancer potential of Calotropis procera. C. procera leaves were collected from local area of Faisalabad, Pakistan, and phytochemical, anti-microbial, and anti-cancer activities were studied following reference methods. In vitro anti-microbial study of methanolic extracts of C. procera leaves against different strains of fungal was performed. Results showed that plant extract in a dose of 5 mg/mL have significant (P<0.05) antifungal activity. Moreover, the methanolic leaf extract of C. procera displayed strong anti-cancer activity in breast cancer cells (MCF-7), with a cytotoxic activityat 200μg/mL comparable to that found for Taxol as standard drug. Findings of current research work showed that the leaf extracts of C. procera has strong potential as an antibacterial, antifungal and anti-cancer agent. However, characterization and purification of phytochemicals is required to develop drug from natural resources.

Comprehensive single-cell and bulk transcriptomic analyses to develop an NK cell-derived gene signature for prognostic assessment and precision medicine in breast cancer.

Natural killer (NK) cells play crucial roles in mediating anti-cancer activity in breast cancer (BRCA). However, the potential of NK cell-related molecules in predicting BRCA outcomes and guiding personalized therapy remains largely unexplored. This study focused on developing a prognostic and therapeutic prediction model for BRCA by incorporating NK cell-related genes. The data analyzed primarily originated from the TCGA and GEO databases. The prognostic role of NK cells was evaluated, and marker genes of NK cells were identified via single-cell analysis. Module genes closely associated with immunotherapy resistance were identified by bulk transcriptome-based weighted correlation network analysis (WGCNA). Following taking intersection and LASSO regression, NK-related genes (NKRGs) relevant to BRCA prognosis were screened, and the NK-related prognostic signature was subsequently constructed. Analyses were further expanded to clinicopathological relevance, GSEA, tumor microenvironment (TME) analysis, immune function, immunotherapy responsiveness, and chemotherapeutics. Key NKRGs were screened by machine learning and validated by spatial transcriptomics (ST) and immunohistochemistry (IHC). Tumor-infiltrating NK cells are a favorable prognostic factor in BRCA. By combining scRNA-seq and bulk transcriptomic analyses, we identified 7 NK-related prognostic NKRGs (CCL5, EFHD2, KLRB1, C1S, SOCS3, IRF1, and CCND2) and developed an NK-related risk scoring (NKRS) system. The prognostic reliability of NKRS was verified through survival and clinical relevance analyses across multiple cohorts. NKRS also demonstrated robust predictive power in various aspects, including TME landscape, immune functions, immunotherapy responses, and chemotherapeutic sensitivity. Additionally, KLRB1 and CCND2 emerged as key prognostic NKRGs identified through machine learning and external validation, with their expression correlation with NK cells confirmed in BRCA specimens by ST and IHC. We developed a novel NK-related gene signature that has proven valuable for evaluating prognosis and treatment response in BRCA, expecting to advance precision medicine of BRCA.

Comprehensive Review of the Potential Anti-Breast Cancer Properties of Various Medicinal Plants

Breast cancer is the most frequent cancer in women throughout the globe, and its management can be difficult due to its complex etiology. Treatment with chemotherapy, surgical procedures, radiation treatment, and hormone therapy are among the most frequently utilized treatments. However, complications and resistance to multiple drugs can cause challenges. This overview addresses how organic medicinal products obtained from edibles and plants can assist with treatment of Breast cancer. The article scrutinizes the ways by which natural substances may exert beneficial impact in the prevention and management of breast carcinoma as well as offers knowledge regarding the therapeutic plant, including its family, part used, kind of extraction, and molecular mechanisms in breast carcinoma. Following an exhaustive analysis of the various plants, we discovered that Peganum normata, Ammi visnaga, Camellia sinensis, Curcuma longa, and Allium sativam L. had potential anti-breast cancer activities. These data were gathered from PubMed, Scopus, and Google Scholar.

First report on exploration of structural features of natural compounds (NPACT database) for anti-breast cancer activity (MCF-7): QSAR-based virtual screening, molecular docking, ADMET, MD simulation, and DFT studies.

The online version contains supplementary material available at 10.1007/s40203-024-00266-5.

8018 Improving Anti-Breast Cancer Activities by Optimizing Torsion Angle Energies

Abstract Disclosure: D.R. Zak: None. E.C. Fink: None. G.R. Hancock: None. K.S. Young: None. S.W. Fanning: None. Overexpression of estrogen receptor alpha (ER-alpha) is found in 70% of breast cancer tumors. Normally, ER-alpha remains inactive and sequestered in the cytoplasm until estrogen binds to the ligand-binding domain (LBD) to enable nuclear translocation, coregulator recruitment, and subsequent activation of proliferative ER-alpha-dependent transcriptomic profiles. The majority of breast cancers are treated successfully with ER-targeted endocrine therapies, but hotspot ER-alpha LBD mutants are selected for, namely Y537S and D538G causing therapeutic resistance, relapse, and aggressive metastatic disease. The selective estrogen receptor modulator (SERM) lasofoxifene (laso) and selective estrogen receptor degrader (SERD) elacestrant (RAD1901) are chemically distinctive and show great promise in the ER-alpha mutant setting with potent anti-tumor effects and improved side effect profiles compared to the standard-of-care SERD fulvestrant (ICI). To elucidate the structural-transcriptional relationships of these ligands, we created a laso/RAD1901 chemical hybrid T6I-29 that demonstrated both canonical and unexpected therapeutic mechanisms of action. However, it possesses reduced anti-proliferative potency compared to ICI. We hypothesized that minor chemical changes to T6I-29 could improve potency while maintaining its favorable pharmaceutical profiles. To address this hypothesis, we performed quantum mechanical calculations of a series of T6I-derivatives. The addition of a methyl linker within the scaffold core significantly improved the torsion angle energies of the ligand binding pose. Multiple derivatives were synthesized based on these computations. The new compound T6I-B2 exerted profound anti-proliferative effects on breast cancer cells and adopted a unique ligand binding pose within the LBD. This approach shows that T6I-SERM potency can be improved by optimizing ligand torsion angle energies. Presentation: 6/3/2024

Artemisitene induces apoptosis of breast cancer cells by targeting FDFT1 and inhibits the growth of breast cancer patient-derived organoids

Artemisitene (ATT) is a natural bioactive compound with anti-breast cancer activity. However, the direct target and clinical efficacy of ATT on breast cancer are still unclear. The current study aimed to identify the target protein and underlying mechanism of ATT in anti-breast cancer. Moreover, patient-derived organoids (PDOs) were employed to assess the clinical efficacy of ATT on breast cancer. Herein, molecular docking, molecular dynamics simulation, cellular thermal shift assay (CETSA) combined with Western blot, surface plasmon resonance (SPR) were applied to confirm the interactional target of ATT in breast cancer cells. Bioinformatics analysis, Western blot, flow cytometry, plasmid construction and lentivirus infection, chromatin immunoprecipitation (ChIP) assay, and quantitative real-time PCR (RT-qPCR) were performed to reveal the potential mechanism of ATT in treating breast cancer. PDOs were established to evaluate the clinical therapeutic efficiency of ATT on breast cancer. We found that ATT interacted with Farnesyl-diphosphate farnesyltransferase 1 (FDFT1) in breast cancer cells. Knockdown of FDFT1 induced NEDD4 expression and apoptosis in breast cancer cells. Overexpression of FDFT1 could rescue ATT-induced apoptosis, while interfering with FDFT1 expression decreased the level of RelA (NF-κB p65 subunit) in the nucleus in breast cancer cells. Knockdown of FDFT1 induced NEDD4 expression by regulating TNFR1/NF-κB pathway. Overexpression of FDFT1 could reverse the activation of ATT-induced TNFR1/NF-κB/NEDD4 pathway in breast cancer cells. Interestingly, the ChIP assay revealed that p65 could regulate NEDD4 transcription. Furthermore, ATT exhibited a broad-spectrum inhibitory effect on the growth of breast cancer PDOs with different pathological subtypes, and showed an excellent safety profile in comparison with that of conventional chemotherapy drugs. In summary, this work demonstrated that ATT targets FDFT1 to induce apoptosis of breast cancer cells through regulating TNFR1/NF-κB/NEDD4 pathway and suppresses breast cancer PDOs growth, which supported ATT as an effective and potential drug candidate for breast cancer treatment.

Dysprosium-containing Cobalt Sulfide Nanoparticles as Anticancer Drug Carriers.

Among various materials designed for anticancer drug transport, sulfide nanoparticles are uniquely intriguing owing to their spectral characteristics. Exploration of newer nanoscale copper sulfide particles with dysprosium doping is reported herein. It leads to a change in the physicochemical properties of the sulfide nanoparticles and hence the difference in drug release and cytotoxicity. We intend to purport the suitably engineered cobalt sulfide and dysprosium-doped cobalt sulfide nanoparticles that are magnetic and NIR-absorbing, as drug delivery vehicles. The drug loading and release are based on the supramolecular drug complex formation on the surface of the nanoparticles. The nanomaterials are synthesized employing hydrothermal procedures, coated with a biocompatible poly-β-cyclodextrin, and characterized using the methods of diffractometry, microscopy, spectroscopy, thermogravimetry and magnetometry. The sustained drug release is investigated in vitro. 5-Fluorouracil is loaded in the nanocarriers. The empty and 5-fluorouracil-loaded nanocarriers are screened for their anti-breast cancer activity in vitro on MCF-7 cells. The size of the nanoparticles is below 10 nm. They show soft ferromagnetic characteristics. Further, they show broad NIR absorption bands extending up to 1200 nm, with the dysprosium-doped material displaying greater absorbance. The drug 5-fluorouracil is encapsulated in the nanocarriers and released sustainably, with the expulsion duration extending over 10 days. The IC50 of the blank and the drug-loaded cobalt sulfide are 16.24 ± 3.6 and 12.2 ± 2.6 μg mL-1, respectively. For the drug-loaded, dysprosium-doped nanocarrier, the IC50 value is 9.7 ± 0.3 μg mL-1. The ultrasmall nanoparticles possess a size suitable for drug delivery and are dispersed well in the aqueous medium. The release of the loaded 5-fluorouracil is slow and sustained. The anticancer activity of the drug-loaded nanocarrier shows an increase in efficacy, and the cytotoxicity is appreciable due to the controlled release. The nanocarriers show multi-functional characteristics, i.e., magnetic and NIR-absorbing, and are promising drug delivery agents.

Zn2+ enhanced the anti-breast cancer activity of fucoidan based nanoparticles by activating the cGAS-STING pathway

The incidence rate of breast cancer remains high, and lung metastasis often leads to treatment failure. Immunotherapy based on the cyclic guanosine monophosphate synthesis (cGAS) − interface gene stimulatory factor (STING) pathway is expected to bring benefits to the treatment of breast cancer. This study provided a delivery system based on fucoidan (Fu) and polyvinylpyrrolidone (PVP) for the potential molecule resveratrol (Res). The study confirmed that Fu and PVP were assembled into nanoparticles through hydrogen bonding and effectively loaded Res (Fu/PVP/Res). Interestingly, the adsorption of Zn2+ (Fu/PVP/Res Zn2+) was expected to provide impetus for the treatment of breast cancer. The results in vitro confirmed that Fu/PVP/Res Zn2+ significantly inhibited the proliferation of breast cancer 4T1 cells, induced the accumulation of mitochondrial reactive oxygen species (ROS) and the damage of mitochondrial membrane potential (MMP), and further induced the cytoplasmic release of mtDNA, which was the direct cause of the activation of cGAS-STING pathway. In vivo studies confirmed that Fu/PVP/Res Zn2+ treatment inhibited the growth of 4T1 transplanted tumors. Excitingly, Fu/PVP/Res Zn2+ treatment also prevented lung metastasis of in situ tumors. The in vivo mechanism confirmed that Fu/PVP/Res Zn2+ treatment activated the cGAS-STING pathway and induced abnormal expression of tumor apoptosis factors such as Bax/Bcl-2. In conclusion, our research provided potential for the treatment of breast cancer.

New Pyrazole/Pyrimidine-Based Scaffolds as Inhibitors of Heat Shock Protein 90 Endowed with Apoptotic Anti-Breast Cancer Activity.

Background/Objectives: Supported by a comparative study between conventional, grinding, and microwave techniques, a mild and versatile method based on the [1 + 3] cycloaddition of 2-((3-nitrophenyl)diazenyl)malononitrile to tether pyrazole and pyrimidine derivatives in good yields was used. Methods: The newly synthesized compounds were analyzed with IR, 13C NMR, 1H NMR, mass, and elemental analysis methods. The products show interesting precursors for their antiproliferative anti-breast cancer activity. Results: Pyrimidine-containing scaffold compounds 9 and 10 were the most active, achieving IC50 = 26.07 and 4.72 µM against the breast cancer MCF-7 cell line, and 10.64 and 7.64 µM against breast cancer MDA-MB231-tested cell lines, respectively. Also, compounds 9 and 10 showed a remarkable inhibitory activity against the Hsp90 protein with IC50 values of 2.44 and 7.30 µM, respectively, in comparison to the reference novobiocin (IC50 = 1.14 µM). Moreover, there were possible apoptosis and cell cycle arrest in the G1 phase for both tested compounds (supported by CD1, caspase-3,8, BAX, and Bcl-2 studies). Also, the binding interactions of compound 9 were confirmed through molecular docking, and simulation studies displayed a complete overlay into the Hsp90 protein pocket. Conclusions: Compounds 9 and 10 may have apoptotic antiproliferative action as Hsp90 inhibitors.

Synthesis of quinoline fused 1,2,3-triazole derivatives via continuous CuAAC and C[sbnd]H arylation; anti-breast cancer, anti-EGFR and HER2 activities, computational studies

Some new quinoline linked fused 1,2,3-triazole hybrids (5a-5o) were synthesized via Cu(I) catalyzed azide-alkyne cycloaddition followed by intramolecular CH arylation in one pot. Further, these derivatives were screened for their anti-breast cancer activity against MCF-7, MDA-MB-468 and MDA-MB-231 cell lines and results were compared with the 5-fluorouracil (5-FU). Out of all, compounds 5a, 5c, 5f, 5g and 5j displayed higher activity than the 5-FU against three cancer cell lines. Compound 5a was more effective in inhibiting both tyrosine kinase EGFR and HER2 enzymes than the Erlotinib and Lapatinib. Furthermore, compound 5j demonstrated greater potency than the Erlotinib against EGFR. Molecular docking studies revealed the important binding features of most potent compounds 5a, 5c, 5f, 5g and 5j with EGFR (PDB ID-4HJO) and HER2 (PDB ID-3RCD) and results were found to be supportive with corresponding IC50 data. Finally, in silico pharmacokinetic studies revealed that compounds 5a, 5c, 5f, 5g and 5j followed Ghose, Egan, Muegge, Lipinski and Veber rules without any deviation.

2-(1H-indol-3-yl)ethyl]-(4-nitrobenzylidene)amine: Investigating the inhibition of breast cancer: Synthesis, structure, in-silico–Computational predictions & potent antibacterial properties

The synthesis and characterization of a novel Schiff base compound, [2-(1H-indol-3-yl)ethyl]-(4-nitrobenzylidene)amine (2IE4NBA), are described and characterized by 1H, 13C NMR, FT-IR, and UV–VIS spectroscopic analysis. The crystal structure was determined by monoclinic space group P21/c, with lattice parameters a = 15.8372(8) Å, b = 11.0720(5) Å, c = 8.5464(4) Å, β = 97.780(2) °, and Z = 4. The intermolecular interactions in the Schiff base 2IE4NBA were theoretically examined by Hirshfeld surface analysis. The optimized structure, HOMO and LUMO energy gap, mulliken population analysis, and molecular Electrostatic Potential (MEP) of the compound were calculated by Density Functional Theory (DFT) calculation with the B3LYP/6–311 G basis set method. In addition, we compared calculated and experimental spectral values. Molecular docking studies indicated that the synthesized compound, 2IE4NBA, interacts with the binding pocket of mutated TP53 with a binding affinity of -8.0 kcal/mol. The docking results demonstrated favourable molecular-level interactions with the anticancer drug target, exhibiting strong interactions with active site residues. In vitro studies revealed that the compound exhibited the best minimum inhibitory concentration (MIC) value against Staphylococcus aureus and demonstrated an effect on MDA-MB-231 cancer cell lines. This study investigated its potential as a breast cancer therapeutic agent. 2IE4NBA exhibited promising anti-breast cancer activity against the MDA-MB-231 breast cancer cell line, as confirmed by MTT assay.

The Antibacterial and Anti-Breast Cancer Activities of Caulerpa racemosa from the Minahasa Peninsula Water and North Sulawesi, Indonesia

The Antibacterial and Anti-Breast Cancer Activities of Caulerpa racemosa from the Minahasa Peninsula Water and North Sulawesi, Indonesia

Development of New N- and S-substituted-imidazolidin-4-one Analogues with Potent Anti-breast Cancer Activity: In vitro Molecular Docking Assessment

: 2-Thioxoimidazolidin-4-one derivatives 3, 4, 7, 8, and 9 have been synthesized from 3- (benzylideneamino)-2-thioxoimidazolidin-4-one (2) as a starting material. Compounds 3, 4, 7, 8, and 9 were obtained via the reaction of compound (2) with ethyl chloroacetate, methyl acrylate, and chlorophenacyl bromide, respectively. Elemental analysis and several spectroscopy techniques were used to confirm the synthesized compounds. The synthesized compounds, particularly compounds 7 and 8, exhibited significant cytotoxic influences on MCF-7 cells, surpassing staurosporine. Compounds 7 and 8 can induce apoptosis in those treated MCF-7 cells. Studying molecular docking approved that compounds 7 and 8 bind in two and three dimensions to the aromatase binding pockets. Molecular modeling indicates compounds 7 and 8 have a strong affinity for human topoisomerase II beta, establishing its promise as a multifaceted antitumor agent for breast cancer.

Improving Water Solubility and Skin Penetration of Ursolic Acid through a Nanofiber Process to Achieve Better In Vitro Anti-Breast Cancer Activity.

Woman's breast cancer has always been among the top ten causes of cancer death, and nearly 2% to 5% of locally advanced breast cancers develop a fungating breast wound. Fungal breast cancer leads to skin ulcers, wound ruptures, and other bacterial infections in patients. Ursolic acid (UA), a natural pentacyclic triterpene compound, is widely distributed in many fruits. Previous studies demonstrated that UA has anti-breast cancer, antifungal, and improved wound-healing effects. UA, however, had poor water solubility and low bioavailability, restricting its clinical application. Nanofibers have the advantages of rapid dissolution, improved stability, and bioavailability of active ingredients. We had successfully prepared ursolic acid nanofibers (UANFs) and effectively improved their water solubility and skin penetration. UANFs can increase water solubility by improving the physicochemical properties, including increased surface area, intermolecular bonding with excipients, and amorphous transformation. Furthermore, UANFs had better anti-breast cancer activity than raw UA. UANFs inhibited the expression of phospho-signal transducer and activator of transcription 3 (STAT3) and phospho-extracellular regulated protein kinases (ERK)1/2, and induced cleaved caspase-3 protein expression, but had no effect on the raw UA treatment. In summary, UANFs enhanced the skin absorption of UA and improved its anti-breast cancer efficacy. We expect that UANFs can be used as an anti-breast cancer treatment and reduce the discomfort of breast cancer patients during dressing changes, but more detailed efficacy and safety trials still need to be conducted in further studies.

Synthesis, anticancer, α-glucosidase inhibition, molecular docking and dynamics studies of hydrazone-Schiff bases bearing polyhydroquinoline scaffold: In vitro and in silico approaches

A series of hydrazone-Schiff base derivatives of polyhydroquinoline (PHQ) nucleus have been synthesized, structurally deduced by NMR (13C- and 1H-) and HR-ESI-MS spectroscopic methods and finally subjected for anti-cancer and α-glucosidase inhibitory activities. The MTT assay's results exposed that these eight compounds (2j, 2u, 2t, 2w, 2s, 2r, 2x, and 2d) presented notable activity against breast cancer MDA-MB-231 cells having IC50 in the range of 11.4 ± 0.2 to 15.1 ± 0.4 µM, while the remaining fourteen compounds displayed significant to good anti-breast cancer activity. In case of α-glucosidase inhibition, eight compounds (2n, 2j, 2e, 2o, 2w, 2q, 2v, and 2l) exhibited superior inhibition against α-glucosidase enzyme with IC50 values ranging from 8.72 ± 0.14 to 16.16 ± 0.17 µM, compare with the standard acarbose. Additionally, the remaining eighteen derivatives showed significant to least inhibitory activity. The in silico docking, and molecular dynamic displayed the minimal divergence in MM-PBSA values for 2n, 2j, 2e, and 2o which suggests a strong and stable interaction with the protein's amino acid backbone. Pharmacokinetic profiles and anti-glucosidase ability suggested them as potential drug candidates for further studies.

Oleanolic acid derivative self-assembled aggregates based on heparin and chitosan for breast cancer therapy

Oleanolic acid is an active ingredient from natural products with anti-breast cancer activity. However, the poor solubility in water and low bioavailability have limited its effectiveness in clinic. To improve the anticancer activity of oleanolic acid, we synthesized a novel oleanolic quaternary ammonium (QDT), which, driven by electrostatic interactions, was introduced into heparin and coated with chitosan to obtain a QDT/heparin/chitosan nanoaggregate (QDT/HEP/CS NAs). QDT/HEP/CS NAs showed the negative zeta potential (−35.01 ± 4.38 mV), suitable mean particle size (150.45 ± 0.68 nm) with strip shape, and high drug loading (36 %). The coated chitosan had strong anti-leakage characteristics toward QDT under physiological conditions. More importantly, upon sustained release in tumor cells, QDT could significantly decrease the mitochondrial membrane potential and induce apoptosis of breast cancer cells. Further in vivo antitumor study on 4 T1 tumor-bearing mice confirmed the enhanced anticancer efficacy of QDT/HEP/CS NAs via upregulation of caspase-3, caspase-9 and cytochrome C, which was attributed to the high accumulation in tumor via the enhanced permeability and retention effect. Moreover, QDT/HEP/CS NAs significantly enhanced the biosafety and biocompatibility of QDT in vitro and in vivo. Collectively, the development of QDT/HEP/CS NAs with high antitumor activity, favorable biodistribution and good biocompatibility provided a safe, facile and promising strategy to improve the anti-cancer effect of traditional Chinese medicine ingredients.

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.

Physicochemical, ADMET Properties, and Molecular Docking Studies of N-benzoyl-N’-naphtylthiourea Derivatives for Anti-Breast Cancer Activity

Background: N-benzoyl-N'-naphthylthiourea (BNTU) is a thiourea-derived compound that is predicted to have anti-breast cancer activity. However, their physicochemical properties, ADMET, and receptor-specific targets for their anti-breast cancer activity have not been reported. Objective: This study aimed to predict the physicochemical properties, ADMET, and anti-breast cancer activity of BNTU and its derivatives by in silico approach. Methods: The physicochemical and ADMET properties were predicted using the pkCSM online program and ProTox-II online tool. While the anti-breast cancer activity was predicted using the molecular docking method through the Molegro Virtual Docker (MVD) program on the HER-2 receptor. The parameter observed in the molecular docking method was the bond energy value or rerank score (RS). Compounds with small RS values were predicted to have a great activity. Results: Most BNTU derivatives had lower RS values than BNTU, especially 4TBBNTU, and 4CFBNTU, although their RS values were still higher than lapatinib and TAK-285. As for the reference ligand hydroxyurea, the RS value of BNTU and its derivatives was much lower. The physicochemical and pharmacokinetic properties (ADMET) of lapatinib and TAK-285 were not better than that of BNTU and its derivatives. Conclusion: Five compounds that deserve to be synthesized and tested for anti-breast cancer activity in vitro and in vivo are 4TBBNTU, 3CFBNTU, 4CFBNTU, 4OCBNTU, and the lead compound BNTU.