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Background: Breast cancer is the second most common cancer in women worldwide. Developing drugs increase the radiosensitivity effect of tumoral tissue, while protecting normal tissues has gained much attention. Ginsenoside Rg3, one of the active components of ginseng, has been shown to possess various pharmacological effects and antiproliferation activity on cancer cell lines. In this study, we assessed the anti-cancer effect of co-treatment with ginsenoside 20(S)-Rg3 and curcumin on MDA-MB-231 breast cancer cells with and without radiotherapy. Methods: MTT assay was applied using different concentrations of ginsenoside 20(S)-Rg3 (0, 10, 80, 150 µmol/l) and curcumin (0, 10, 30, 50, 90 µg/mL). The inhibitory effect of co-treatment with these herbal drugs with and without 4 Gy radiotherapy on the MDA-MB-231 cell line was examined. Flow cytometry was applied to measure the effect of co-treatment of the drugs on radiation-induced apoptosis. The data were analyzed using ANOVA and Kruskal-Wallis tests. P values<0.05 were considered statistically significant. Results: The results of the MTT assay showed that ginsenoside 20(S)-Rg3 and curcumin had an inhibitory effect on the MDA-MB-231 cell line in a concentration-dependent manner. Ginsenoside 20(S)-Rg3 and curcumin inhibited tumor cell development and proliferation at concentrations of 80 µmol/L and 30 μg/mL, respectively, with 50% cell viability (P=0.018, P=0.01, respectively) at 48 hour incubation time. Conclusion: Ginsenoside 20(S)-Rg3 and curcumin inhibited MDA-MB-231 cell growth in a dose- and time-dependent manner and increased the radiosensitivity of cancer cells. These herbal drugs can be considered as a radiosensitizer in radiotherapy. [ABSTRACT FROM AUTHOR]

Introduction: in Guerrero, a wide variety of pigmented maize is found. However, there are not alternatives to generate added value, as well as positive impact on the producer's economy. Method: in this study, the morphometric (thousand grain weight, test weight, hardness, whole grain parts and color), physicochemical (bromatological analysis, phenolic and anthocyanin content, Xray pattern, thermal and paste properties and the scavenging radical activity), as well as the antiproliferative activity (MDA-MB-231 cell line) from pigmented maize (red, black, purple, and white) were evaluated. Results: the physicochemical properties varied depending on the maize pigmentation. The corn kernels showed adequate morphometric characteristics for the masa and tortilla industry. The maximum viscosity was observed in purple maize starch. The highest value of ΔHgel was observed for black maize (7.88 J g-1). With the exception of purple maize, the analyzed corn kernels showed a high protein content (8.08-8.71 %). The highest content of total phenols (14.7-11.7 mgEAG g-1 extract), monomeric anthocyanins (528 - 154 µg EC3G g-1 extract) and activity against DPPH (CI50 < 200 µg mL-1) and ABTS (CI50 < 236 µg mL-1 radicals were shown by purple maize. The black maize extract showed the highest antiproliferative activity (CI50 = 938 µg mL-1) in the MDA-MB-231 cell line. Discussion or conclusion: Regardless of color, the analyzed corn kernels have characteristics that are useful for the starch and masa and tortilla industries. Pigmented maize, mainly black and purple, are a promising option for obtaining bioactive compounds for the establishment of novel strategies for the prevention and therapy of diseases associated with oxidative stress. [ABSTRACT FROM AUTHOR]

Background: Autophagy has an essential role in cellular energetic balance, cell cycle, and cell death, so the change in autophagy level is crucial in many human diseases such as cancer. Herbal medicine has been widely used to treat cancer. Bowman-Birk protease inhibitor (BBI), a protease inhibitor extracted from soybean, has antitumorigenic, anti-inflammatory, and anti-angiogenic activities. In this study, we evaluated the effect of BBI on the growth of breast cancer cell line and transcript level of autophagy and apoptosis-related genes.Materials and Methods: BBI was purified from soybean by ion-exchange chromatography method. The viability of MDA-MB-231 cells that were treated with BBI was measured by MTT assay, and the transcript level of genes involved in autophagy and apoptosis was measured by real-time-polymerase chain reaction (PCR) technique.Results: The results of BBI purification showed that 100 g of the ethanolic fraction yielded 300-mg BBI with more than 95% purity. MTT results revealed that BBI inhibited the cell growth of MDA-MB-231 cell line in a dose-dependent manner, with an IC50 of 200 μg/mL. The results of real-time reverse transcription-PCR exhibited that BBI altered the expression of Atg5, Beclin1, light chain 3-II, and sequestosome1 and increased the Bax/Bcl2 ratio in MDA-MB-231 cell line.Conclusion: According to our results, BBI could inhibit autophagy and induce apoptosis in MDA-MB-231 cell line. Thus, BBI may be used as a therapeutic drug in the treatment of breast cancer whether alone or with chemotherapeutic drugs. [ABSTRACT FROM AUTHOR]

Two novel silver(I) phenanthroline derivative complexes (P‐235 and P‐239) have been synthesized and characterized by IR, HPLC‐MS, and 1HNMR. The cytotoxicity of two complexes exhibited significant cytotoxicity against human breast cancer (MDA‐MB‐231) cell line (IC50 = 0.48 ± 0.01 and 0.12 ± 0.01 μM) and less toxicity than cisplatin by MTT assays. Furthermore, anticancer mechanistic studies showed that P‐235 and P‐239 induced G2/M phase cell cycle arrest to inhibit the growth of MDA‐MB‐231 cells. Flow cytometry analysis showed that MDA‐MB‐231 cells could be significantly induced to undergo apoptosis by P‐235 and P‐239. And P‐235‐ and P‐239‐induced apoptosis was linked with reactive oxygen species (ROS) production. Further study revealed that P‐235 and P‐239 cause mitochondrial membrane potential depolarization and destroy mitochondrial membrane potential. [ABSTRACT FROM AUTHOR]

Triple-Negative Breast Cancer (TNBC) is a particularly aggressive subtype among breast cancers (BCs), characterized by anoikis resistance, high invasiveness, and metastatic potential as well as Epithelial–Mesenchymal Transition (EMT) and stemness features. In the last few years, our research focused on the function of MCL1, an antiapoptotic protein frequently deregulated in TNBC. Here, we demonstrate that MCL1 inhibition by A-1210477, a specific BH3-mimetic, promotes anoikis/apoptosis in the MDA-MB-231 cell line, as shown via an increase in proapoptotic markers and caspase activation. Our evidence also shows A-1210477 effects on Focal Adhesions (FAs) impairing the integrin trim and survival signaling pathways, such as FAK, AKT, ERK, NF-κB, and GSK3β-inducing anoikis, thus suggesting a putative role of MCL1 in regulation of FA dynamics. Interestingly, in accordance with these results, we observed a reduction in migratory and invasiveness capabilities as confirmed by a decrease in metalloproteinases (MMPs) levels following A-1210477 treatment. Moreover, MCL1 inhibition promotes a reduction in EMT characteristics as demonstrated by the downregulation of Vimentin, MUC1, DNMT1, and a surprising re-expression of E-Cadherin, suggesting a possible mesenchymal-like phenotype reversion. In addition, we also observed the downregulation of stemness makers such as OCT3/4, SOX2, NANOG, as well as CD133, EpCAM, and CD49f. Our findings support the idea that MCL1 inhibition in MDA-MB-231 could be crucial to reduce anoikis resistance, aggressiveness, and metastatic potential and to minimize EMT and stemness features that distinguish TNBC. [ABSTRACT FROM AUTHOR]

Cancer is one of the most common pathologies in the world, leading to a reduced standard of living and even death for centuries. Despite promising developments in treatment methods in recent years, the expected level of treatment and success hasn't yet been achieved due to the side effects and cost of treatment methods and the fact that some drugs are still in the trial phase. This situation has encouraged the scientific community to search for natural agents with lower costs and limited side effects. Abies cilicica, also known as fir, and Aloe vera has been used in both food and traditional medicine from the past to the present. In the literature review, it was found that both A. vera and A. cilicica have many beneficial effects, especially anti-inflammatory, antifungal, and wound-healing properties. This study aimed to investigate the antimicrobial, antioxidant, cytotoxic, and apoptotic/necrotic effects of extracts of A. vera from Asphodelaceae and A. cilicica (Ant. Et Kotschy.) subsp. cilicica Carr. from Pinaceae. The best antimicrobial activity was observed against Escerichia coli with a zone diameter of 20.00 ± 3.59 mm and Klebsiella pneumoniae with a zone diameter of 21 ± 5.35 mm. 2KA showed the best effect on antioxidant activity. 2MA + 2KSA showed significant cytotoxic activity on MDA-MB-231 cancer cells. IC50 values of 1EA + 1KA extract (whole A. cilicica and A. vera dissolved in ethanol) against MDA-MB-231 cell line (IC50 458.29 ± 19.01 µg/ml) and MCF-7 cell line (IC50 596.03 ± 5.56 µg/ml) were determined. According to the data obtained from the study, A. vera and A. cilicica were found to have antimicrobial, antioxidant, and cytotoxic effects both alone and synergistically. It is predicted that they can be used especially in cancer treatment. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer with high heterogeneity and poor therapeutic responses to standard treatments. The use of herbal medicine for treatment of TNBC is gaining in popularity worldwide due to their better anti-tumor efficacy and less side effects compared to chemotherapy agents. Previous studies have shown that crocin, a natural carotenoid from saffron, induced cell apoptosis in a concentration-dependent behavior in TNBC MDA-MB-231 breast cancer cells. To improve anti-cancer properties of crocin, liposome-based formulation was prepared by the thin layer hydration-sonication method. The formulation was characterized based on particle size, zeta potential, morphology, encapsulation efficiency (EE) and cellular uptake. The formulation showed monodisperse distribution with an average size of 80 nm, about 70% EE and 11% loading capacity. The effect of crocin, and crocin-loaded liposomes in combination with doxorubicin (DOX) were evaluated using the MDA-MB-231 cell line. The results showed that crocin significantly increased the cytotoxicity of DOX, and crocin loaded liposome enhanced the cytotoxicity further. Flow cytometric analysis revealed that crocin loaded liposome in combination with DOX increased the number of cells in Sub-G1 and G2/M phases. Real time qPCR analysis showed that survivin, cyclin-B1, Bcl-xl mRNA were significantly down-regulated, while Bax and Bid mRNA levels were up-regulated following treatment with crocin loaded liposome compared to control. This study suggested that formulation of crocin into liposomes can be considered as a promising approach against tumor cells, especially when combining with the chemotherapy agent, DOX. [Display omitted] • Crocin was encapsulated into liposome nanoparticles with an average size of 80 nm. • Liposome encapsulated crocin enhanced doxorubicin efficacy in a concentration-dependent manner. • Crocin loaded liposome induced sub G1 and G2/M cell cycle arrest in breast cancer cells. [ABSTRACT FROM AUTHOR]

In this study, two series of C‐14 derivatives of parthenolide were designed, and synthesized 13 ester derivatives were obtained by oxidation and further esterification of their C‐14 methyl groups. Similarly, the C‐14‐oxidative product suffered from iodination and reacted with amino compounds to afford 3 amine derivatives. Antiproliferative test in vitro exhibited that most of the newly synthesized compounds were more potent than parthenolide toward both human non‐small cell lung cancer A549 cell line and breast cancer MDA‐MB‐231 cell line. Among them, ZA‐5 displayed a significant antiproliferative effect against A549 with an IC50 value of 1.03 μmol L−1 and ZB‐1 had a potency almost equal to that of the positive drug Adriamycin toward MDA‐MB‐231 cells. Finally, a mechanism study showed that ZA‐5 could significantly trigger off apoptosis of A549 cells at the test concentration. [ABSTRACT FROM AUTHOR]

This report discusses the biosynthesis of zinc oxide nanoparticles (ZnO NPs) using Ocimum basilicum leaf extract (OBLE) and their potential as a therapeutic agent due to their ability to induce apoptosis in cancer cells. The structural characterization of the synthesized OBLE@ZnO NPs was determined using X-ray diffraction (XRD) and indicated a hexagonal crystal configuration with a wurtzite-type structure and no impurities. The microstructure of OBLE@ZnO NPs was inhomogeneous and non-linked, with an average grain size of 20.07 ± 0.34 nm. Fourier transform infrared (FTIR) spectra showed a hump at 3430 cm−1, which was attributed to the phenolic or hydroxyl group (-OH) in anthraquinones of OBLE. The UV-visible absorption spectra displayed a strong characteristic peak at 366 nm, confirming the formation of ZnO NPs. The cytotoxic activity of OBLE@ZnO NPs was tested against the MDA-MB-231 cell line, and the results showed excellent cell inhibition with a low IC50 value of 6.54 μg/mL, suggesting their potential for combating breast cancer. [ABSTRACT FROM AUTHOR]

An efficient synthetic strategy was developed for the synthesis of hybrid pharmacophores; encompass the merging of β-lactams, 1,8-naphthyridine and secondary amines/pyridines. With a simple unified synthetic protocol, we prepared a series of substituted 3-chloro-1-((3-(2-(trifluoromethyl)phenyl)-1,8-naphthyridin-2-yl)amino)azetidin-2-one compounds (8a–8j) and evaluated for their antimicrobial, and anticancer activities (against MDA-MB-231 cell line). Notably, compounds 8d, 8g, and 8j were identified as potent anticancer molecules and comparable to Cisplatin. Compounds 8d and 8g were found to have promising antitubercular efficacy even greater than the standards Streptomycin and Ciprofloxacin. Compounds 8a, 8d, 8g, 8i, and 8j also displayed potency against both Gram-positive and Gram-negative bacteria and comparable to Ampicillin & Ciprofloxacin. Further, the biological activities were supported and studied by DFT studies and ADMET predictions. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) remains the leading cause of mortality in women, despite significant advancements in diagnosis. Thus, the identification of new compounds for its treatment is critical. Phytochemicals are known to exhibit anti-cancer properties. Here, we investigated the anti-proliferation potential of extracts from carrot, Calendula officinalis flower, and Aloe vera on breast cancer vs. epithelial cell lines. Various extraction methods were used, and the proliferative effect of the resulting extracts was assessed by proliferation assay on breast cancer and epithelial cell lines. Carrot, Aloe leaf, and Calendula flower extracts were extracted by hexane and methanol methods, and their semi-purified extracts were able to specifically inhibit the proliferation of breast cancer cell lines. The extract composition was investigated by colorimetric assays, UHPLC-HRMS, and MS/MS analysis. All the extracts contained monogalactosyl-monoacylglycerol (MGMG), while digalactosyl-monoacylglycerol (DGMG) and aloe-emodin were found in Aloe, and glycerophosphocholine (GPC) derivatives were identified in Calendula, except for the isomer 2 detected in carrot, suggesting that their observed different anti-proliferative properties may be associated with the different lipid compounds. Interestingly, Calendula extract was able to strongly inhibit the triple negative breast cancer MDA-MB-231 cell line proliferation (about 20% cell survival), supporting MGMG and GPC derivatives as potential drugs for this BC subtype treatment. [ABSTRACT FROM AUTHOR]

A total of 23 diterpenoids were isolated from the seeds of Euphorbia lathyris, and one new compound (1) and twenty-two known compounds (2-23) were characterized by using 1D- and 2D-NMR spectra and HRESIMS analysis. Cytotoxicity of the isolated compounds against BT-549 and MDA-MB-231 cancer cells lines were evaluated further. Compounds 3, 10, 14, and 22 were found to exhibit considerable cytotoxic activities against BT-549 cells, with IC50 values ranging from 4.7 to 10.1 µM. Compounds 1, 2, 14 and 22 were able to inhibit the MDA-MB-231 cell line growth with IC50 values of 5.7 to 21.3 µM, while other compounds showed no obvious inhibitory effects. [ABSTRACT FROM AUTHOR]

The development of dual-stimuli-responsive hydrogels attracts much research interest owing to its unique stimuli-responsive characteristics. In this study, a poly-N-isopropyl acrylamide-co-glycidyl methacrylate-based copolymer was synthesized by incorporating N-isopropyl acrylamide (NIPAm) and a glycidyl methacrylate (GMA) monomer. The synthesized copolymer, pNIPAm-co-GMA was further modified with L-lysine (Lys) functional units and further conjugated with fluorescent isothiocyanate (FITC) to produce a fluorescent copolymer pNIPAAm-co-GMA-Lys hydrogel (HG). The in vitro drug loading and dual pH- and temperature-stimuli-responsive drug release behavior of the pNIPAAm-co-GMA-Lys HG was investigated at different pH (pH 7.4, 6.2, and 4.0) and temperature (25 °C, 37 °C, and 45 °C) conditions, respectively, using curcumin (Cur) as a model anticancer drug. The Cur drug-loaded pNIPAAm-co-GMA-Lys/Cur HG showed a relatively slow drug release behavior at a physiological pH (pH 7.4) and low temperature (25 °C) condition, whereas enhanced drug release was achieved at acidic pH (pH 6.2 and 4.0) and higher temperature (37 °C and 45 °C) conditions. Furthermore, the in vitro biocompatibility and intracellular fluorescence imaging were examined using the MDA-MB-231 cell line. Therefore, we demonstrate that the synthesized pNIPAAm-co-GMA-Lys HG system with temperature- and pH-stimuli-responsive features could be promising for various applications in biomedical fields, including drug delivery, gene delivery, tissue engineering, diagnosis, antibacterial/antifouling material, and implantable devices. [ABSTRACT FROM AUTHOR]

Background: Long-non-coding RNA PVT1 (lncRNA PVT1) can be used as an oncogenic regulatory non-coding RNA (ncRNA) for many cancers. However, its function and mechanism in breast cancer (BRCA) are still not clearly elucidated. Objective: We attempt to explain the mechanism of PVT1's role in breast cancer from different perspectives. Methods: We analyzed the expression of PVT1 and its correlation with the breast cancer related clinical data in the The Cancer Genome Atlas (TCGA) database. We used PVT1 overexpression and knockdown lentivirus to infect breast cancer MDA-MB-231 cell line for cell function verification, in vitro using CCK-8 to measure proliferation, flow cytometry to measure apoptosis, transwell test to measure invasion and migration ability, detecting cell extracellular acidification rate (ECAR) to assess glycolysis metabolism and explore the biological functions of PVT1 in breast cancer cells. Transcriptome sequencing was used to analyze the changes of related genes in cells after overexpression of PVT1. In vivo we used a xenograft model to study the effect of PVT1 on breast cancer. Results: PVT1 was up-regulated in breast cancer tissues and was positively correlated with the clinical stage of breast cancer patients. Overexpression of PVT1 in vitro promoted cell proliferation, migration and invasion, and promoted tumor growth in vivo. Knockdown of PVT1 led to the opposite biological consequence. Further bioinformatics analysis showed that PVT1 changes the glycolysis metabolism of tumors through regulation of glycolysis-related genes. In addition, the expression of miR-145-5p is negatively correlated with PVT1. We consider the possibility of PVT1 promoting cell proliferation and metastasis by regulating the aerobic glucose metabolism in breast cancer cells through sponging the miR-145-5p. Conclusion: Our results reveal a potential pathway for competing endogenous RNA to regulate breast cancer glucose metabolism. PVT1 regulates glycolysis related genes expression by competitively binding to endogenous miR-145-5p in breast cancer cells to change the metabolic phenotype. This may Provide new ideas for precise molecular therapy targets for breast cancer. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) subtype is one of the most aggressive tumors with no definite receptor, hence has a limited number of effective chemotherapeutics. Doxorubicin (Dox) is the first-line drug for the TNBC treatment, acting as a DNA intercalator and topoisomerase II (Topo II) inhibitor; however, it has been observed to exhibit strong cardiotoxicity. Tanshinone IIA (Tan IIA) has a previously confirmed antitumor activity against breast cancer in addition to its well-known cardioprotective effect. In our study, molecular docking reveals the potential activity of Tan IIA as a DNA intercalator and Topo II inhibitor as a recommended possible mechanism of action compared to Dox as a reference drug. Moreover, we wanted to assess a new use for Tan IIA in the TNBC treatment in combination with Dox to broaden its therapeutic window and compensate for its cardiotoxic effects by the cardioprotective effects of Tan IIA. On performing the in vitro MTT assay to evaluate the cytotoxic effects of Dox, Tan IIA and their combinations at different concentrations of the MDA-MB-231 cell line revealed the potential activity of Tan IIA compared to Dox, in addition to the confirmed synergistic effects of Dox/Tan IIA combinations on TNBC cell lines. Furthermore, the analysis of the gene expression profiles of PI3K, mTOR, and AKT as anti-apoptotic genes were examined in the MDA-MB-231 cell line after the treatment with the IC50 of Dox, Tan IIA, and their combination, and compared to the control using PCR. These results confirmed the synergistic effect of the Dox/Tan IIA combination that exceeded that of Dox alone. [ABSTRACT FROM AUTHOR]

Glycosphingolipid expression differs between human breast cancer stem cells (CSC) and cancer non-stem cells (non-CSC). We performed studies of viability, type of cell death, cancer stem cell percent and glycosphingolipid expression on CSC and non-CSC after treatment of MDA-MB-231 and MDA-MB-453 triple-negative breast cancer cells with a newly developed thienopyridine anticancer compound (3-amino-N-(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide, 1). Compound 1 was cytotoxic for both breast cancer cell lines and the majority of cells died by treatment-induced apoptosis. The percent of cancer stem cells and number of formed mammospheres was significantly lower. Glycosphingolipids IV6Neu5Ac-nLc4Cer and GalNAc-GM1b (IV3Neu5Ac-Gg5Cer) not reported previously, were identified in both CSCs and non-CSCs. IV6Neu5Ac-nLc4Cer had increased expression in both CSCs and non-CSCs of both cell lines after the treatment with 1, while GM3 (II3Neu5Ac-LacCer) had increased expression only on both cell subpopulations in MDA-MB-231 cell line. GalNAc-GM1b, Gb4Cer (GalNAcβ1-3Galα1-4Galβ1-4Glcβ1-1Cer) and GM2 (II3Neu5Ac-GalNAcβ1-4Galβ1-4Glcβ1-1Cer) were increased only in CSCs of both cell lines while GD3 was decreased in CSC of MDA-MB-231 cell line. Due to its effect in reducing the percentage of cancer stem cells and number of mammospheres, and its influence upon several glycosphingolipid expressions, it can be concluded that compound 1 deserves attention as a potential new drug for triple-negative breast cancer therapy. [ABSTRACT FROM AUTHOR]

The combination of a porphyrin system and a platinum fragment in the same molecule should not only result in the additivity of the photodynamic activity of the porphyrin and the cytostatic activity of the platinum, but also in the enrichment of the porphyrin platinum conjugate in tumors, which platinum compounds alone do not show. New porphyrin platinum conjugates were obtained from the platinum complexes of a series of 1,2-diamines and hematoporphyrin or 13,17-bis(2-carboxyethyl)-3,8-bis[1-(ethyleneglycolmonoethylether)oxyethyl]-2,7,12,18-tetramethylporphin. The 1,2-diamines were synthesized starting from the corresponding stilbenes via 1,2-diazides. The new platinum porphyrin conjugates showed promising antitumor activity in tests with the mammary carcinoma cell line MDA-MB-231. [Copyright &y& Elsevier]

Since multifunctional nanomaterials have exhibited significant ability as carriers in biomedical applications, it is valuableto create such a drug delivery system for cancer treatment. In this context, a novel type of trifunctional nanocomposite (high magnetization (26.25 emu.g−1) and size about 24 nm)) with pH-responsive, luminescent and magnetic properties (NaCeF 4 :Yb/Er@SiO 2 @Fe 3 O 4 -NH 2 @poly(MAA-co-IA)), has been designed as a new platformfor efficient loading and the pH-responsive concurrent release of methotrexate (MTX) and doxorubicin (DOX). The luminescent and hollow NaCeF 4 :Yb/Er as a core is more suitable for deep-tissue diagnosis while Fe 3 O 4 in outer shell (instead of core) caused its magnetic property retain in comparison with other core shell drug nanocarriers. MTX and DOX were loaded into nanocarrier, the loading capacity being 35% and 99%, respectively) The structure and morphology of the prepared nanocarrier were characterized by XRD, FT‐IR, VSM, TEM, FE-SEM, PL, EDAX, DLS and Zeta potential analyses. The in vitro release studies at different pH values (7.4 and 5) exhibited the pH-responsive system. The biocompatibility of the drug free nanocarrier and the cytotoxicity of DOX, MTX, the mixture of drugs (MTX@DOX) and MTX@DOX-nanocarrier were investigated in different concentration (0.01 to 100 µg/mL) by MTT test on human breast epithelial adenocarcinoma (MDA-MB-231) cell line. The anti-cancer studies of the nanocarrier exhibited very low cytotoxicity and high cell viability (70%) against MDA-MB-231 cell line after 72 h. In vitro cytotoxicity tests of the MTX@DOX-nanocarrier against MDA-MB-231 cell line revealed low cell viability (11%) after 72 h. Cellular uptake depicted notably higher uptake percentage for DOX-NPs than free DOX within 3 h while DAPI staining results demonstrated the higher apoptotic effects of drugs-loaded nanocarrier than free form of the drugs. Based on the enticing results attained, the NaCeF 4 :Yb/Er@SiO 2 @Fe 3 O 4 -NH 2 @poly(MAA-co-IA) nanocomposite could be used as a pH-sensitive and non-toxic carrier for the targeted therapy of aggressive MDA-MB-231 breast cancer cells and is suitable for controlled drug release and monitoring drug delivery. [Display omitted] • Trifunctional drug carrier NaCeF 4 :Yb/Er@SiO 2 @Fe 3 O 4 -NH 2 @poly(MAA-co-IA)) was designed and synthesized. • The nanostructured carrier could serve as imaging contrast agents and drug delivery system for cancer imaging and therapy. • A promising drug delivery system with high drug loading capacity and pH-responsive feature. • Nanocomposite can also be used as effective thermal energy source for hyperthermia therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel, potent and effective EZH2 degraders were developed. • Compound P4 can effectively induce EZH2 protein degradation and inhibit breast cancer cell growth. • Compound P4 can significantly decrease the degree of H3K27me3 in MDA-MB-231 cell line, induce apoptosis and G 0 /G 1 phase arrest in Pfeiffer and MDA-MB-231 cell lines. • Compound P4 significantly inhibited the migratory and invasive capacity of MDA-MB-231 cells at micromolar concentrations in a dose-dependent manner. • Adequate metabolic stability in vitro. EZH2 (enhancer of zeste homolog 2) is one of the most important histone methyltransferases (HMTs), and overexpression of EZH2 can lead to proliferation, migration and angiogenesis of tumor cells. But most of EZH2 inhibitors are only effective against some hematologic malignancies and have poor efficacy against solid tumors. Here, we report the design, synthesis, and evaluation of highly potent proteolysis targeting chimeric (PROTACs) small molecules targeting EZH2. We developed a potent and effective EZH2 degrader P4 , which effectively induced EZH2 protein degradation and inhibited breast cancer cell growth. Further studies showed that P4 can significantly decrease the degree of H3K27me3 in MDA-MB-231 cell line, induce apoptosis and G 0 /G 1 phase arrest in Pfeiffer and MDA-MB-231 cell lines. Therefore, P4 is a potential anticancer molecule for breast cancer treatment. [ABSTRACT FROM AUTHOR]

IKKα has been shown to be responsible of multiple pro-tumorigenic functions and therapy resistance independent of canonical NF-κB, but its role in acquired chemotherapy resistance in breast cancer remains unclarified. In this study, we obtained pre-treatment biopsy and post-treatment mastectomy specimens from a retrospective cohort of triple-negative breast cancer (TNBC) patients treated with neoadjuvant chemotherapy(NAC) (n = 43). Immunohistochemical methods were used to detect the expression of IKKα before and after NAC, and the relationship between IKKα and the pathologic response to NAC was examined. In addition, we developed a new ADR-resistant MDA-MB-231 cell line(MDA-MB-231/ADR) and analyzed these cells for changes in IKKα expression, the role and mechanisms of the increased IKKα in promoting drug resistance were determined in vitro and in vivo. We demonstrated that the expression of IKKα in residual TNBC tissues after chemotherapy was significantly higher than that before chemotherapy, and was positively correlated with lower pathological reaction. IKKα expression was significantly higher in ADR-resistant TNBC cells than in ADR-sensitive cells, IKKα knockdown results in apoptotic cell death of chemoresistant cells upon drug treatment. Moreover, IKKα knockdown promotes chemotherapeutic drug-induced tumor cell death in an transplanted tumor mouse model. Functionally, we demonstrated that IKKα knockdown significantly upregulated the expression of cleaved caspase 3 and Bax and inhibited the expression of Bcl-2 upon ADR treatment. Our findings highlighted that IKKα exerts an important and previously unknown role in promoting chemoresistance in TNBC, combining IKKα inhibition with chemotherapy may be an effective strategy to improve treatment outcome in chemoresistant TNBC patients. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) in oncology is characterized by low invasiveness, minimal side effects, and little tissue scarring. Increasing the selectivity of PDT agents toward a cellular target is a new approach intended to improve this method. This study is devoted to the design and synthesis of a new conjugate based on meso-arylporphyrin with a low-molecular-weight tyrosine kinase inhibitor, Erlotinib. A nano-formulation based on Pluronic F127 micelles was obtained and characterized. The photophysical and photochemical properties and biological activity of the studied compounds and their nano-formulation were studied. A significant, 20–40-fold difference between the dark and photoinduced activity was achieved for the conjugate nanomicelles. After irradiation, the studied conjugate nanomicelles were 1.8 times more toxic toward the EGFR-overexpressing cell line MDA-MB-231 compared to the conditionally normal NKE cells. The IC50 was 0.073 ± 0.014 μM for the MDA-MB-231 cell line and 0.13 ± 0.018 μM for NKE cells after irradiation for the target conjugate nanomicelles. [ABSTRACT FROM AUTHOR]

Herein, we investigate the combinatorial therapeutic effects of naturally occurring flavonoids kaempferol (K) and fisetin (F) on triple-negative breast cancer (TNBC: MDA-MB-231 cell line). Dose-dependent MTT assay results show that K and F exhibited cytotoxicity in MDA-MB-231 cells at 62 and 75 μM (IC50), respectively, after 24 h. However, combined K + F led to 40% and more than 50% TNBC cell death observed at 10 and 20 μM, respectively, which revealed the synergistic association of both. The combination of K and F was determined to be more effective in inhibiting cell viability than either of the agents alone. The morphological changes associated with significant apoptotic cell death were observed under a fluorescent microscope, strongly supporting the synergistic association between K and F. We also proposed that combining the effects of both polyphenols, as opposed to their individual effects, would increase their in vitro efficacy. Furthermore, we assessed the cell death pathway by the combinational treatment via reactive oxygen species-induced DNA damage and the mitochondrially mediated apoptotic pathway. This study reveals the prominent synergistic role of phytochemicals, which helps in elevating the therapeutic efficacy of dietary nutrients and that anticancer effects may be a result of nutrients that act in concert. [ABSTRACT FROM AUTHOR]

In this study, effective transport of small interfering RNAs (siRNAs) via hyaluronic acid (HA) receptor was carried out with biodegradable HA and low‐molecular weight polyethyleneimine (PEI)‐based transport systems. Gold nanoparticles (AuNPs) capable of giving photothermal response, and their conjugates with PEI and HA, were also added to the structure. Thus, a combination of gene silencing, photothermal therapy and chemotherapy, has been accomplished. The synthesized transport systems ranged in size, between 25 and 690 nm. When the particles were applied at a concentration of 100 μg mL−1 (except AuPEI NPs) in vitro, cell viability was above 50%. Applying radiation after the conjugate/siRNA complex (especially those containing AuNP) treatment, increased the cytotoxic effect (decrease in cell viability of 37%, 54%, 13%, and 15% for AuNP, AuPEI NP, AuPEI‐HA, and AuPEI‐HA‐DOX, respectively) on the MDA‐MB‐231 cell line. CXCR4 gene silencing via the synthesized complexes, especially AuPEI‐HA‐DOX/siRNA was more efficient in MDA‐MB‐231 cells (25‐fold decrease in gene expression) than in CAPAN‐1 cells. All these results demonstrated that the synthesized PEI‐HA and AuPEI‐HA‐DOX conjugates can be used as siRNA carriers that are particularly effective, especially in the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Over the years, carbazoles have been largely studied for their numerous biological properties, including antibacterial, antimalarial, antioxidant, antidiabetic, neuroprotective, anticancer, and many more. Some of them have gained great interest for their anticancer activity in breast cancer due to their capability in inhibiting essential DNA-dependent enzymes, namely topoisomerases I and II. With this in mind, we studied the anticancer activity of a series of carbazole derivatives against two breast cancer cell lines, namely the triple negative MDA-MB-231 and MCF-7 cells. Compounds 3 and 4 were found to be the most active towards the MDA-MB-231 cell line without interfering with the normal counterpart. Using docking simulations, we assessed the ability of these carbazole derivatives to bind human topoisomerases I and II and actin. In vitro specific assays confirmed that the lead compounds selectively inhibited the human topoisomerase I and interfered with the normal organization of the actin system, triggering apoptosis as a final effect. Thus, compounds 3 and 4 are strong candidates for further drug development in multi-targeted therapy for the treatment of triple negative breast cancer, for which safe therapeutic regimens are not yet available. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis, lacking therapeutic targets. miRNAs play crucial roles in TNBC through regulating various mechanisms, including cellular growth and proliferation. This study aims to identify critical target genes of two novel miRNAs (miR‐3143 and miR‐3182) involved in the cell cycle of TNBC as possible therapeutic targets and investigates their regulatory and therapeutic roles through a systems biology approach and in vitro experiment. Datasets related to the TNBC cell line (MDA‐MB‐231) were screened and retrieved, and Gene regulatory networks were constructed. Significant regulatory motifs were detected and analyzed using the FANMOD and Cytoscape analyzer, and the clusters and seeds were identified using the MCODE. Functional enrichment analysis was also performed using DAVID and STRING. The most critical genes were determined using the analysis of GRN motifs and PPI clusters. The essential genes involved in the cell cycle were selected and verified using the bc‐GenExMiner v4.7. We overexpressed miR‐3143 and miR‐3182 in the MDA‐MB‐231 cell line using human umbilical cord mesenchymal stem cell (HUCMSC)‐miRNA loaded exosomes, and the expression of the critical target genes was investigated using RT‐qPCR. We identified eight critical genes as potential therapeutic targets. Their expression decreased by overexpression of miR‐3143 and miR‐3182 in RT‐qPCR. The identified critical genes have probably significant roles in the pathogenesis of TNBC through the cell cycle. We suggest that the overexpression of miR‐3143 and miR‐3182 could be a new therapeutic candidate in TNBC and is worth more investigation. [ABSTRACT FROM AUTHOR]

We studied the effect of CCDC3 on the viability of human breast cancer cell line MDA-MB-231. The levels of CCDC3 mRNA and the corresponding protein in MDA-MB-231, MCF-7, T-47D, and HCC1937 cell lines were measured by reverse transcription quantitative real-time PCR and Western blotting. Since MDA-MB-231 cells had higher expression of mRNA CCDC3 and CCDC3 protein, we used this cell line for transfection with small interfering RNA by lentivirus. Cell Counting Kit-8 and clone formation assay were used to detect the effects of CCDC3 knockdown on cell viability; flow cytometry was used to detect the effects of CCDC3 knockdown on cell apoptosis and cell cycle. In MDA-MB-231 cell line, the CCDC3 protein level was significantly down-regulated after CCDC3 knockdown in comparison with the control group (p<0.05). The cell viability and the number of clones in the CCDC3 knockdown group were significantly reduced (p<0.05), while the apoptosis rate significantly increased (p<0.05). Thus, after CCDC3 knockdown, cell viability is weakened in MDA-MB-231 cells, and cell apoptosis rate is increased. Therefore, CCDC3 gene is promising as a new candidate target for BC treatment. [ABSTRACT FROM AUTHOR]

Among natural chemopreventive agents, polyphenol curcumin and naphthoquinone juglone, which has broad-spectrum anticancer activity, are highly valued. Fatty acid-binding proteins (FABPs), which vary depending on the type of cancer, are small (14–15 kDa) proteins belonging to the lipid-binding protein superfamily. FABPs are located in many tissues and play an essential role in fatty acid metabolism, cell growth, and proliferation. It is suggested that they can be used as tumor markers. The objective of this work is to study the effects of curcumin and juglone on cell viability and to evaluate their anticancer and cytotoxic effects and changes in the FABP5 and FABP9 gene expression and protein levels in breast cancer cell lines MCF-7 and MDA-MB-231. Information on FABP5 and FABP9 gene expression in BRCA (breast invasive cancer) and normal cells was collected from the GEPIA2 and UALCAN databases. MTT analysis revealed that the IC50 (concentration of half maximal inhibitory effect) in MCF-7 cells was 22.4 and 16.3 μM for curcumin and juglone, respectively, and in MDA-MB-231 cells, 10.4 and 3.4 μM for curcumin and juglone, respectively. In both cell lines, FABP5 and FABP9 gene expression and protein levels were also analyzed. We found that treatment of MCF-7 cells with curcumin and juglone reduced cell viability, expression of the FABP5 and FABP9 genes, and the levels of the FABP5 and FABP9 proteins. In the MDA-MB-231 cell line, the FABP5 and FABP9 levels were increased at low doses of curcumin and juglone and decreased at higher doses. [ABSTRACT FROM AUTHOR]

Currently, the exploration of fungal organisms for novel metabolite production and its pharmacological applications is much appreciated in the biomedical field. In the present study, the fungal strains were isolated from soil of unexplored Yellapura regions. The potent isolate NP5 was selected based on preliminary screening and identified as Penicillium brasilianum NP5 through morphological, microscopic, and molecular characterizations. Synthesis of silver nanoparticles from P. brasilianum was confirmed by the color change of the reaction mixture and UV-visible surface plasmon resonance (SPR) spectra of 420 nm. Fourier transform infrared (FTIR) analysis revealed the functional groups involved in synthesis. Atomic force microscopy (AFM) and transmission electron microscope (TEM) analysis showed aggregation of the NPs, with sizes ranged from 10 to 60 nm, an average particle size of 25.32 nm, and a polydispersity index (PDI) of 0.40. The crystalline nature and silver as the major element in NP5-AgNPs was confirmed by X-ray diffraction (XRD) and energy dispersive X-ray (EDX) analysis. The negative value −15.3 mV in Zeta potential exhibited good stability, and thermostability was recorded by thermogravimetric analysis (TGA). NP5-AgNPs showed good antimicrobial activity on selected human pathogens in a concentration-dependent manner. The MTT assay showed concentration-dependent anticancer activity with an IC50 of 41.93 µg/mL on the MDA-MB-231 cell line. Further, apoptotic study was carried out by flow cytometry to observe the rate of apoptosis. The calculated sun protection factor (SPF) value confirms good photoprotection capacity. From the results obtained, NP5-AgNPs can be used in the pharmaceutical field after successful in vitro clinical studies. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) represents an aggressive subtype of breast cancer (BC) with a typically poorer prognosis than other subtypes of BC and limited therapeutic options. Therefore, new drugs would be particularly welcome to help treat TNBC. Preussin, isolated from the marine sponge-associated fungus, Aspergillus candidus, has shown the potential to reduce cell viability and proliferation as well as to induce cell death and cell cycle arrest in 2D cell culture models. However, studies that better mimic the tumors in vivo, such as 3D cell cultures, are needed. Here, we studied the effects of preussin in the MDA-MB-231 cell line, comparing 2D and 3D cell cultures, using ultrastructural analysis and the MTT, BrdU, annexin V-PI, comet (alkaline and FPG modified versions), and wound healing assays. Preussin was found to decrease cell viability, both in 2D and 3D cell cultures, in a dose-dependent manner, impair cell proliferation, and induce cell death, therefore excluding the hypothesis of genotoxic properties. The cellular impacts were reflected by ultrastructural alterations in both cell culture models. Preussin also significantly inhibited the migration of MDA-MB-231 cells. The new data expanded the knowledge on preussin actions while supporting other studies, highlighting its potential as a molecule or scaffold for the development of new anticancer drugs against TNBC. [ABSTRACT FROM AUTHOR]

Alterations in centrosome proteins may result in centrosome abnormalities such as disorganized spindles and centrosome amplification, leading to aneuploidy and genomic instability. Centrosomes exhibit unique epigenetic properties in which structural or positional information is propagated through somatic lineage by non-genetic pathways. Excessive centrosome amplification in breast cancer is accompanied by efficient clustering and loss of E-cadherin, indicating an important adaptive mechanism of cancer. This study sought to elucidate the effect of epigenetic alterations on centrosome amplification, epithelial-mesenchymal transition (EMT) and apoptosis in triple negative human breast adenocarcinoma derived MDA-MB-231 cell line. The results obtained here show that siRNA mediated silencing of DNMT1 and specific inhibition of HDAC1 & HDAC2 by Tricostatin A (TSA) synergistically inhibit cell proliferation through modulation of centrosome proteins γ-tubulin, TUBGCP2 and pericentrin. In addition, induction of apoptosis was observed by downregulation of Bcl2, upregulation of Bax and activation of PARP cleavage. Inhibition of EMT was confirmed through upregulation of E-cadherin and downregulation of N-cadherin and vimentin. Similarly, downregulation of Myc, RAS and CDK2, which plays important roles in proliferation and survival, was observed. Nuclear protein analysis revealed downregulation in the nuclear translocation of E2F1, which regulates centrosome amplification and metastasis in breast cancer. In conclusion, this study confirmed the role of epigenetic regulators in centrosome amplification and suggests that inhibition of DNA methylation and histone deacetylation-mediated chromatin remodelling synergistically disrupt EMT through modulation of centrosome amplification and Myc/RAS axis to potentiate apoptosis and attenuate cell proliferation in triple negative breast cancer cells. [ABSTRACT FROM AUTHOR]

The cancer treatment by laser-conjugated nanomaterial has become a new developing trend due of their unique physicochemical performance. The previous few studies reported the preparation of undoped CuS nanoprisms. The current research was concerned with the Mn doping effect on the CuS nanoprisms and its activity in tumor toxicity of M.D. Anderson-Metastatic Breast 231 (MDA-MB-231) cell line with laser treatment. To prepare a novel CuS and Mn-doped CuS nanoprisms with high surface area by two-phase colloidal method, copper nitrate and sulfur powder were used as sources of copper and sulfur respectively. The prepared nanoprisms were investigated as antibacterial and photothermal agents in MDA-MB-231 cancer treatment using near-infrared (NIR) laser. The Mn-CuS nanoprisms were modified with glutathione (GSH) to decrease the cytotoxicity and increase the biocompatibility. The characterization of synthesized nanoprisms involved the structural, compositional, surface charges, optical, and morphological property analyses. X-ray diffraction (XRD) showed the peaks of hexagonal covellite copper sulfide nanoparticles and additional diffraction peaks at Mn-CuS which are assigned to orthorhombic chalcocite CuS. The transmission electron microscopy (TEM) images showed that the CuS and Mn-CuS nanoparticles have nanoprism morphology. The antibacterial activity test revealed that the activity enhances by doping and the prepared Mn-CuS nanostructures were more effective against the Staphylococcus aureus and Escherichia coli bacteria. The results of photothermal treatment indicated that the cancer cells were effectively killed and the GSH@Mn-CuS nanoprisms are able to be used as an efficient theranostic agent for tumor photothermal therapy in the future. [ABSTRACT FROM AUTHOR]

Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein that belongs to the serine protease inhibitor (serpin) family. An increase in PEDF activity has been shown to be a potent inhibitor of tumour progression and proliferation, suggesting a possible therapeutic target. There is still a great deal to learn about how PEDF controls metabolic pathways in breast cancer and its metastatic form. Given this, the primary purpose of this study was to use a metabolomics approach to gain a better understanding of the mechanisms driving the reprogramming of metabolic events involved in breast cancer pertaining to PEDF under various glycaemic loads. We employed gas chromatography–quadrupole mass spectrometry (GC-Q-MS) to investigate metabolic changes in the triple-negative breast cancer (TNBC) cell line MDA-MB-231 treated with PEDF under glycaemic loading. Multivariate and univariate analyses were carried out as indicative tools via MetaboAnalyst (V.5.0) and R packages to identify the significantly altered metabolites in the MDA-MB-231 cell line after PEDF exposure under glycaemic loading. A total of 61 metabolites were found, of which nine were selected to be distinctively expressed in MDA-MB-231 cells under glycaemic conditions and exhibited differential responses to PEDF (p < 0.05, VIP > 1). Abnormalities in amino acid metabolism pathways were observed. In particular, glutamic acid, glutamine, and phenylalanine showed different levels of expression across different treatment groups. The lactate and glucose-6-phosphate production significantly increased in high-glucose vs. normal conditions while it decreased when the cells were exposed to PEDF, confirming the positive influence on the Warburg effect. The TCA cycle intermediates, including malate and citric acid, showed different patterns of expression. This is an important finding in understanding the link of PEDF with metabolic perturbation in TNBC cells in response to glycaemic conditions. Our findings suggest that PEDF significantly influenced the Warburg effect (as evidenced by the significantly lower levels of lactate), one of the well-known metabolic reprogramming pathways in cancer cells that may be responsive to metabolic-targeted therapeutic strategies. Moreover, our results demonstrated that GC-MS-based metabolomics is an effective tool for identifying metabolic changes in breast cancer cells after glycaemic stress or in response to PEDF treatment. [ABSTRACT FROM AUTHOR]

Even though Olea europaea L. is one of the most important and well-studied crops in the world, embryonic parts of the plants remain largely understudied. In this study, comprehensive phytochemical profiling of olive vegetative buds of two Croatian cultivars, Lastovka and Oblica, was performed with an analysis of essential oils and methanol extracts as well as biological activities (antioxidant, antimicrobial, and cytotoxic activities). A total of 113 different volatiles were identified in essential oils with hydrocarbons accounting for up to 60.30% and (Z)-3-heptadecene being the most abundant compound. Oleacein, oleuropein, and 3-hydroxytyrosol had the highest concentrations of all phenolics in the bud extracts. Other major compounds belong to the chemical classes of sugars, fatty acids, and triterpenoid acids. Antioxidant, antimicrobial, and cytotoxic activities were determined for both cultivars. Apart from antioxidant activity, essential oils had a weak overall biological effect. The extract from cultivar Lastovka showed much better antioxidant activity than both isolates with both methods (with an oxygen radical absorbance capacity value of 1835.42 μM TE/g and DPPH IC50 of 0.274 mg/mL), as well as antimicrobial activity with the best results against Listeria monocytogenes. The human breast adenocarcinoma MDA-MB-231 cell line showed the best response for cultivar Lastovka bud extract (IC50 = 150 μg/mL) among three human cancer cell lines tested. These results demonstrate great chemical and biological potential that is hidden in olive buds and the need to increase research in the area of embryonic parts of plants. [ABSTRACT FROM AUTHOR]

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

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

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

[Display omitted] • Pyrimidine-based morpholine or piperidine conjugates were designed and synthesized. • Several derivatives were endowed with potent antiproliferative activities against MCF-7 and MDA-MB-231 cell lines. • 3c , 6a elicited ARO inhibition while 4c , 4d exhibited EGFR inhibition. • They showed multiformed potential inhibition of CD-1K, PI3K, Hsp90, ERK/AKT signaling pathways. Committed to our growing effort addressed toward the development of potent anti-breast cancer candidates, new 4-hydrazinylpyrimidine-5-carbonitriles featuring a morpholinyl or piperidinyl moiety at the position-2 and derivatized with various functionalities at the hydrazinyl group were designed through structure optimization, and their antiproliferative potency against two human breast cancer (BC) cell lines, relative to the reference drug 5-FU, was evaluated. Compounds showing remarkable cytotoxic activity versus the hormone dependent MCF-7 cell line (IC 50 = 1.62 ± 0.06 µM– 9.88 ± 0.38 µM) and the non-hormone dependent MDA-MB-231 cell line (IC 50 = 3.26 ± 0.14 µM–12.93 ± 0.55 µM) were further tested by multiple assays for clarification of their potential activity. Promising derivatives revealing low damage to healthy cells were subject to enzymatic inhibitory assessment against ARO and EGFR and their activities compared to letrozole and erlotinib respectively. Compounds 3c , 6a as well as compounds 4c , 4d proved to be good inhibitors of the ARO and EGFR enzymes respectively. Active compounds were also evaluated for their underlying mode of action by further investigation for CDK, Hsp90, PI3K inhibition and compared to normal MCF-10A cells and assessed for their enhancement of the caspase 9 levels. Additionally, cell cycle analysis and apoptotic induction were performed. They demonstrated remarkable activities in the previous assays and emanated as leads as anti-breast cancer candidates. Eventually, molecular docking analysis revealed that hit compounds 3c, 4c, 4d, and 6a could bind favorably to the proposed in silico models of various protein–ligand interactions. Therefore, our promising top candidates, by demonstrating appreciable anti-breast cancer activities, present valuable prospects for optimization, potency enhancement and future application. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is an aggressive type of tumor that tends to recur in women. It is characterized by the absence of hormonal receptors, making it challenging to diagnosis and treatment. In this study, we investigated the anti-tumor effects of a pro-oxidant naphthoquinone derivative called bromo-naphthoquinone (BrNQ) isolated and combined with the antioxidant tannic acid (TA) in order to improve treatment. We used tumor cell lines MDA-MB-231 and HCC-70, as well as normal breast cells, HB4a, as control. Initially, viability assays conducted within 72 hours showed that the combination of compounds had a synergistic and notable cytotoxic effect on the tumor cells. The increased cytotoxicity appeared to be linked to changes in the cellular redox status, as indicated by a significant rise in reactive oxygen species (ROS) and though alterations in the level of thiol. The treatment also induced apoptosis, inhibited proliferation, and reduced migration, particularly in the MDA-MB-231 cell line. Furthermore, relevant changes were detected in the expression of Bcl-2, BAX, FAS, and BIRC-5, while no significant alteration in the expression of NOXs was observed. In conclusion, our findings suggested that the combination of BrNQ and TA though the ability to change redox status in tumor cells could act as a potential adjuvant treatment modality for improve prognosis in TNBC. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel benzenesulfonamides 6a-r were designed and synthesized. • The synthesized compounds were tested for their VEGFR2/FGFR1 inhibitory activities. • Compound 6l showed as the most potent VEGFR-2/FGFR1 inhibitor and anticancer activity by a mean GI% of 60.38%. • Compound 6l induced cell cycle arrest at G1 phase, apoptosis and necrosis, and anti-migratory effect in T-47D cells. • Molecular docking studies were also performed for 6a-r on VEGFR-2/FGFR1 binding sites. In the current study, a new series of benzenesulfonamides 6a-r was designed and synthesized as dual VEGFR-2 and FGFR1 kinase inhibitors with anti-cancer activity. The 4-trifluoromethyl benzenesulfonamide 6l exhibited the highest dual VEGFR-2/FGFR1 inhibitory activity with IC 50 values of 0.025 and 0.026 µM, respectively. It showed a higher activity than sorafenib and staurosporine by 1.8- and 1.3-fold, respectively. Furthermore, compound 6l was further tested on EGFR and PDGFR-β kinases showing IC 50 values of 0.106 and 0.077 µM, respectively. The target compounds were tested for their anticancer activity against NCI-60 panel of cancer cell lines at 10 µM concentration, where compound 6l displayed the highest mean growth inhibition percent % (GI%) of 60.38%. Compounds 6a , 6b , 6e , 6f , 6h-l , and 6n-r revealed promising GI% on breast cancer cell lines (MCF-7, T-47D, and MDA-MB-231), and were subjected to IC 50 determination on these cell lines. The tested compounds showed a higher activity on T-47D and MCF-7 cell lines over MDA-MB-231 cell line compared to the used reference standard; sorafenib. Compounds 6e , 6h-j , 6l and 6o revealed IC 50 values ≤ 20 µM against T-47D cell line, furthermore, they were found to be non-cytotoxic on Vero normal cell line. Furthermore, the effect of the most active compounds 6i , and 6l in T-47D cells on cell cycle analysis progression, cell apoptosis, and apoptosis markers was investigated. Both compounds arrested cell cycle progression at G1 phase, furthermore, they enhanced early and late apoptosis, as well as necrosis. The capability of compounds 6i , and 6l to induce apoptosis was further confirmed by their ability to raise BAX/BCl-2 ratio and caspase-3 level in the treated cells. Cell migration assay revealed that both compounds 6i and 6l have anti-migratory effects compared to control T-47D cells after 24, and 48 h. Molecular docking studies for compounds 6a-r on VEGFR-2 and FGFR1 binding sites showed that they exhibit an analogous binding mode in both target kinases which agrees with that of type II kinase inhibitors. [ABSTRACT FROM AUTHOR]

Although a number of biosensing technologies have been reported for the detection of cancer-derived exosomes used as early diagnosis markers for cancers, it is necessary to identify them with various biomarkers to distinguish the stages and types of cancers owing to the extreme heterogeneity of cancer. Here, we developed a new multiplexed assay platform for the detection of exosomes using magnetic encoded microparticles (MEMPs), which can recognize multiple proteins expressed on exosomes, and a deep learning-based decoding algorithm. This platform, in which the accuracy of the decoding algorithm was evaluated to be 93 %, was applied to detect exosomes from four types of cancer cell lines and plasma from patients with cancer using three cancer biomarkers: PD-L1 (Programmed Death-Ligand 1), EpCAM (Epithelial cell adhesion molecule), and EGFR (Epidermal growth factor receptor). The limit of detections (LODs) of this platform when applied to the detection of exosomes from MDA-MB-231 cell line were calculated as 4.03 × 106 mL−1 for PD-L1, 1.00 ×107 mL−1 for EpCAM, and 7.17×106 mL−1 for EGFR, respectively. In a clinical study, four types of samples from patients with cancer (n = 92) showed higher signals than those of healthy controls (n = 18). Based on these results, we confirmed that this platform can distinguish patients with cancer from healthy individuals. [Display omitted] • Development of a multiplex detection platform using magnetic particle encoding and a deep learning-based decoding algorithm. • Proposal of a novel detection method through microparticle rotation. • Detection of exosomes from various cancer cell lines using multiple biomarkers. • Confirmation of the potential for cancer diagnosis through exosome detection in cancer patient plasma. [ABSTRACT FROM AUTHOR]

• G4 motif regulating the expression profile of the ORAI1 transporter. • Structural analysis revealed a parallel G4 structure with high thermal stability. • Stable G4 formation alters Store Operated Calcium Entry in TNBC. ORAI1 is an intrinsic component of store-operated calcium entry (SOCE) that strictly regulates Ca2+ influx in most non-excitable cells. ORAI1 is overexpressed in a wide variety of cancers, and its signal transduction has been associated with chemotherapy resistance. There is extensive proteomic interaction of ORAI1 with other channels and effectors, resulting in various altered phenotypes. However, the transcription regulation of ORAI1 is not well understood. We have found a putative G-quadruplex (G4) motif, ORAI1-Pu , in the upstream promoter region of the gene, having regulatory functions. High-resolution 3-D NMR structure elucidation suggests that ORAI1-Pu is a stable parallel-stranded G4, having a long 8-nt loop imparting dynamics without affecting the structural stability. The protruded loop further houses an E-box motif that provides a docking site for transcription factors like Zeb1. The G4 structure was also endogenously observed using Chromatin Immunoprecipitation (ChIP) with anti-G4 antibody (BG4) in the MDA-MB-231 cell line overexpressing ORAI1. Ligand-mediated stabilization suggested that the stabilized G4 represses transcription in cancer cell line MDA-MB-231. Downregulation of transcription further led to decreased Ca2+ entry by the SOCE pathway, as observed by live-cell Fura-2 Ca2+ imaging. ORAI1 expression is downregulated in the presence of a stable G4 structure at the predicted ORAI1-Pu motif, which is formed at a regulatory docking site for transcription factors and RNA polymerase II. The G4 structure might act as a dynamic switch, as it is a transient structure and is regulated by various factors within a cell. Ligand-mediated stabilization of ORAI1-Pu via TMPyP4/ BRACO-19 indicated gain-of-function in ORAI1 expression. In MDA-MB-231, we observed greater fold endogenous binding of Zeb1 at the ORAI-Pu motif, compared to BG4, which binds to stable G4 structures. In MDA-MB-231, the ORAI1-Pu locus might be in a partially unfolded state or unfolded state, leading to over-expression of ORAI1. However, further studies can reveal the physiological dynamics of the structure and its functional effects on ORAI expression. Overexpression of ORAI1 increases its transport to the plasma membrane and increases SOCE on interaction with activated STIM at physiological conditions where there is loss of Ca2+ in the endoplasmic reticulum (ER) calcium store. A spike in intracellular Ca2+cascades its effect on deregulated cellular activity and enhances various hallmarks of cancer, epithelial-mesenchymal transition (EMT), drug resistance, and immune evasion. Etc. [Display omitted] [ABSTRACT FROM AUTHOR]

European mistletoe extract (Iscador Qu) has been studied for decades, but it has not ceased to arouse scientific interest. The purpose was to investigate the impact of Iscador Qu on the antiproliferative potential of 11 standard chemotherapeutic agents on two breast cancer cell lines: MCF-7 low-metastatic and MDA-MB-231 high-metastatic and control cell lines (MCF-10A). MTT-dye reduction assay, FACS analysis, and PI staining were utilized. The most promising combinations acting against the MDA-MB-231 cell line were observed upon the simultaneous application of Iscador Qu (80 µg/mL) and Docetaxel, with 4-fold reduction in IC50. An antagonistic effect was found under treatment with Cisplatin and Iscador Qu (1.5-fold increase in IC50). The response of the low-metastatic breast cancer cell line MCF-7 to the tested combinations was different compared to the high-metastatic one. The most pronounced cytotoxic effect was found for the combination of Oxaliplatin and Iscador Qu (20 µg/mL) (5.2-fold IC50 reduction). An antagonistic effect for MCF-7 line was also observed when combinations with Olaparib and Tamoxifen were applied. This in vitro study offers new combinations between Iscador Qu and standard chemotherapeutic agents that hold great promise in establishing breast cancer therapeutic protocols compared to traditional monotherapies.

Abstract A new series of 2-amino-1,4-naphthoquinone-benzamides 5a-n was designed based on previously reported potent cytotoxic agents. These compounds were synthesized from the reaction of 1,4-naphthoquinone, 4-aminobenzoic acid, and appropriate amine derivatives in good yields. Cytotoxic activities of the target compounds 5a-n were evaluated against three cancer cell lines MDA-MB-231, SUIT-2, and HT-29 by MTT assay and the obtained in vitro data. All newly synthesized compounds were more potent than positive control cisplatin against MDA-MB-231 cell line and less potent than this control against SUIT-2 cell line. Moreover, most of the synthesized compounds were more potent than cisplatin against HT-29 cell line. Among the synthesized compounds, compound 5e was the most potent cytotoxic agent against all the three evaluated cell lines. Moreover, cell cycle analysis showed that derivatives 5f and 5l dose-dependently increase the percentage of sub-G1 cells. Induction of apoptosis as an important mechanism of anti-cancer drugs was confirmed morphologically in the most potent new compounds 5e, 5f, 5g, and 5l by Hoechst 33,258 staining.

Triple-negative breast cancer (TNBC) is a subtype of breast tumor with the highest breast cancer stem cells (BCSCs) content and resistance to conventional treatment. Due to the immunosuppressive tumor microenvironment and immunogenicity of breast cancer cells, the use of immune cells, especially natural killer cells (NK) in the treatment of solid tumors, including breast cancer, has been unsatisfactory. Therefore, identifying novel therapies is requisite for breast cancer treatment. Furthermore, the combination of cancer therapies is an effective strategy to improve therapeutic effectiveness. In this study, we inhibited telomerase (hTERT) with BIBR1532, in stimulating NK cell cytotoxicity against breast cancer cells. The MDA-MB-231 cell line was cured with IC50 level of BIBR1532 for 24 h. Afterward, cells were washed with PBS and were co-cultured with peripheral blood NK cell for 5h. Finally, we assessed the impact of telomerase inhibition on the cytotoxicity of NK cells and apoptosis of breast cancer. Also, the expression of hTERT and apoptotic-related genes were evaluated. The data revealed that inhibition of telomerase increases NK cell cytotoxicity against breast cancer. Furthermore, telomerase inhibition and NK cell synergistically enhanced cell death in breast cancer cells by suppressing hTERT, upregulation of bax, and bad expression. In conclusion, telomerase suppression makes breast cancer cells more sensitive to NK cell therapy. Consequently, the combination of telomerase inhibition and NK cells can be useful in the treatment of breast cancer cells. • Telomerase inhibition increased NK cell cytotoxicity against breast cancer cells. • Telomerase inhibition and using NK cells upregulated apoptotic genes in the breast cancer cells. • BIBR1532 inhibited telomerase and sensitized breast cancer cells to NK cell therapy. [ABSTRACT FROM AUTHOR]

Background: The transcription factor twist-related protein 1 (TWIST1) plays a major role in the prognosis of breast cancer. Our present study aimed to identify the network of TWIST1 with related oncogenes and their associated miRNAs. Method: This in silico study included the differential expression analysis of genes and miRNA associated with breast carcinoma. The breast cancer patients' data were retrieved from the Gene Expression Omnibus database and the differential expression analysis was done using GEO2R. Transfac analysis was performed to determine the binding sites of TWIST1. We predicted the target genes of MicroRNA-96 (miR-96) using miRBase. An integrated network was generated among TWIST1 and target genes of miR-96 through Gene MANIA. Survival analysis was carried out for TWIST1 using UALCAN. Experimental methods, including gene expression analysis, were performed in the MDA-MB-231 cell line for validating in silico findings. Results: miR-96, the second differentially expressed miRNA among the top 250 miRNAs, was found to have eight binding sites for TWIST1. TWIST1 was observed to be significantly correlated with patient prognosis. ACTN4, BCL2, and FRMD4A were upregulated and CAMTA1, DAB2IP, and E- Cadherin were downregulated in the expression studies carried out in the MDA-MB-231 breast cancer cell line. Conclusion: A network between TWIST1 and target genes of miR-96 was analyzed. Hence, targeting the genes linked with miR-96 could work toward an efficient therapeutic option for breast cancer metastasis. [ABSTRACT FROM AUTHOR]

Cancer is one of the most common pathologies in the world, which for centuries has led to a decline in the standard of living and even death of many people. In short, cancer is a disease that occurs when mutations in genes that limit and regulate cell proliferation, survival, and movement are reflected in somatic cells. In recent years, there have been many new and promising developments in the world of science for cancer treatment. However, due to the side effects of some treatments, the cost of others, and the fact that some drugs are still in the trial phase, it has not yet reached the expected level of treatment and success. This has encouraged the scientific community to investigate natural agents due to their lower cost and limited side effects. Juglans regia L., popularly known as walnut, is a plant containing many natural compounds that have been used both as a foodstuff and for various medicinal purposes from past to present. As a result of the literature review, it is known that walnut has many medicinal and biological properties, especially antiinflammatory, antifungal and antiallergic properties. In this study, the outer shells of J. regia were used and the components of these shells were extracted with three different solvents: methanol, ethanol, and hexane. These extracts were used in cytotoxic activity and antioxidant activity assays. The antioxidant activity of the extract was determined using a DPPH assay. Cytotoxic activity was determined by MTT assay using a breast cancer cell line (MDA-MB-231). J. regia extracts were found to have significant cytotoxic activity on the MDA-MB-231 cell line. It has been observed that the outer bark of J. regia showed more potent anticancer effects than antioxidant activity. According to the results obtained from the study, the antioxidant and cytotoxic effect of the outer bark of J. regia is thought to contribute significantly to the identification of new active substances for cancer treatment. Therefore, further studies are needed to fully determine the effects of the outer bark of J. regia. [ABSTRACT FROM AUTHOR]

Euparin (1) as a natural product was derivatized by maleic anhydride (2), semicarbazide (3), phenylacetic acid (4 and 5), and thiosemicarbazide (6) and their activities were evaluated in silico by molecular docking studies to investigate the binding affinities and interaction modes between the samples and N-myristoyltransferase enzyme. Among the tested samples (1–6), compounds 1–3 showed significant hydrophobic and hydrogen bonding interactions with the important residues at the active site of the receptor. Therefore, the biological properties of compounds 1–3 were investigated in this work. The antifungal activity of compounds 1–3 was tested against Candida albicans. Amongst them, euparin 1 with minimum inhibitory concentration (MIC) of 7.81 µg/mL and minimum fungicidal concentration (MFC) of 15.62 µg/mL exhibited the highest antifungal activity. Furthermore, antibacterial activities were studied against two Gram-positive (Staphylococcus aureus and Bacillus subtilis), and two Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria, the highest zone of growth on B. subtilis for compound 3 was 13.5 ± 0.7 mm, while for compound 2, the zone of growth inhibition against B. subtilis and S. aureus was 10.0 ± 1.4 and 9.5 ± 0.70 mm, respectively. Finally, the anticancer effects of 1– 3 were examined using MTT assay against MDA-MB-231 and A-549 cell lines. Compound 2 displayed cytotoxicity on MDA-MB-231 cell line with IC50 of 166 µg/mL. [ABSTRACT FROM AUTHOR]