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Background We have previously reported the anti-metastatic effects of 2-methoxy-1,4-naphthoquinone (MNQ) against MDA-MB-231 cell line. Purpose To investigate the molecular mechanism underlying the anti-metastatic effects of MNQ towards MDA-MB-231 cell line via the comparative proteomic approach. Study design/methods Differentially expressed proteins in MNQ-treated MDA-MB-231 cells were identified by using two-dimensional gel electrophoresis coupled with tandem mass spectrometry. Proteins and signalling pathways associated with the identified MNQ-altered proteins were studied by using Western blotting. Results Significant modulation of MDA-MB-231 cell proteome was observed upon treatment with MNQ in which the expressions of 19 proteins were found to be downregulated whereas another eight were upregulated (>1.5 fold, p < 0.05). The altered proteins were mainly related to cytoskeletal functions and regulations, mRNA processing, protein modifications and oxidative stress response. Notably, two of the downregulated proteins, protein S100-A4 (S100A4) and laminin-binding protein (RPSA) are known to play key roles in driving metastasis and were verified using Western blotting. Further investigation using Western blotting also revealed that MNQ decreased the activations of pro-metastatic ERK1/2 and NF-κB signalling pathways. Moreover, MNQ was shown to stimulate the expression of the metastatic suppressor, E-cadherin. Conclusion This study reports a proposed mechanism by which MNQ exerts its anti-metastatic effects against MDA-MB-231 cell line. The findings from this study offer new insights on the potential of MNQ to be developed as a novel anti-metastatic agent. [ABSTRACT FROM AUTHOR]

This study focuses on the design and evaluation of redox-responsive nanoparticles (NPs) by synthesizing disulfide-containing N -phthaloyl chitosan–SS–methoxy poly(ethylene glycol) (NPC-SS-mPEG) and incorporating the anti-cancer drug doxorubicin into the NPs. The structural features of NPC-SS-mPEG were investigated using FTIR, NMR, XRD, and TGA/DTA analysis. DLS and TEM analysis confirmed the particle size and morphology of the NPs. The stability of the NPs was measured with the presence and absence of glutathione (GSH) in buffers pH 5 and 7.4. Furthermore, the release of DOX from the NPs was studied in GSH (10 mM) containing/absent medium at pH 5 and pH 7.4 which mimics the intracellular environment with redox potential. The results indicated a significantly increased release of DOX in the GSH containing medium pH 5 (82.9 ± 2.1 %) and pH 7.4 (67.37 ± 0.88 %) compared to the GSH free pH 7.4 (29.99 ± 1.01 %) and pH 5 medium (56.56 ± 1.7 %) at 60 h. The cytotoxicity study in the MDA-MB-231 breast cancer cell line by MTT assay indicated higher toxicity of redox-responsive NPs to cancer cells than free DOX. In concurrence with the cytotoxicity assay, in-vitro fluorescence staining assays (AO/EB, Hoechst, ROS generation) also confirmed that NPs loaded with DOX induce higher toxicity to cancer cells than free DOX. Taken together, the overall results confirmed the superiority of the redox response-mediated release of DOX in effectively controlling cancer progression. [Display omitted] • Disulfide linked redox responsive Chitosan–SS–mPEG carrier was synthesized. • A redox-responsive nanocarrier loaded with doxorubicin was formulated. • Nanoparticles could destabilize and release drugs through a redox response mechanism. • The cell culture studies have confirmed the anti-cancer activity of the redox-responsive nanoparticles. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract A new combination of sulforaphane (a natural compound obtained from Brassicaceae vegetables) and the cytostatic drug doxorubicin was entrapped in nanometer-sized liposomes. In vitro experiments were performed to investigate the cytotoxicity of these structures on the human breast cancer cell line MDA-MB-231. Confocal microscopy studies revealed enhanced cellular endocytotic internalization, followed by the release of the examined combination from the lysosomes. The in vitro interaction analysis using the Chou-Talalay approach showed high synergistic activity of the examined combination. This synergistic activity enables a considerable reduction in cytostatic dosage and an increase in cancer treatment efficiency. [ABSTRACT FROM AUTHOR]

The main intention of this study was the investigation of impact of natural biologically active ligands of nuclear retinoid/retinoid X receptors (all- trans and 9- cis retinoic acid) on proteomic pattern in human estrogen receptor negative breast cancer cell line MDA-MB-231. For this purpose, proteomic strategies based on bottom-up method were applied. The total cell proteins were extracted utilizing a commercially Radio-Immunoprecipitation Assay (RIPA) buffer and separated on 2D sodium dodecyl sulfate polyacrylamide gel electrophoresis (2D SDS-PAGE). The proteins were subsequently digested in-gel by trypsin and their characterization was achieved by MALDI-TOF/TOF. By employing PDQuest™ software, we identified more than 50 proteins affected by retinoic acid isomers. For more information, 9 proteins which are associated with tumor process were selected. We determined that derivatives of retinoic acid led to significantly reduced level of proteins belonging to metabolic pathway (e. g. glyceraldehyde-3-phosphate dehydrogenase or pyruvate kinase 2) or to other cellular processes as apoptosis, regulation of transcription process or epithelial–mesenchymal transition (e.g. annexins, nucleoside diphosphate kinase B, vimentin). On the other hand all-trans retinoic acid treatment indicates up-regulated effect for heterogeneous nuclear ribonucleoprotein A2/B1. [ABSTRACT FROM AUTHOR]

Ethopharmacological relevance Uncaria tomentosa (Willd.) DC. (Rubiaceae) (Ut), also known as cat's claw, is a woody liana widely spread throughout the Amazon rainforest of Central and South America, containing many chemical constituents such as oxindole alkaloids, which are responsible for various biological activities. Since ancient times, the indigenous people of Peru have used it as a bark infusion for the treatment of a wide range of health problems gastric ulcers, arthritis and rheumatism. Recently, Ut is distributed worldwide and used as an immunomodulatory and anti-inflammatory herbal remedy. Additionally, U. tomentosa also has antitumural activity. However, little is known about the action of U. tomentosa on the purinergic system mechanisms, which is involved in tumor progression. Aim of the study Considering the pharmacological properties of U. tomentosa , we sought to evaluate the hydroalcoholic extract U tomentosa is able to influence the purinergic system in breast cancer cells, MDA-MB-231. Through the activity and expression of ectonucleotidases (NTPDase – CD39; Ecto-5′-nucleotidase – CD73) and purinergic repceptores (P2X7 and A1). Materials and methods A hydroalcoholic extract was prepared in two concentrations, 250 and 500 μg/mL. (Ut250; Ut500). The effect of these concentrations on the activity and expression of ectonucleotidases, as well as on the density of purinergic receptors were investigated in MDA-MB-231 breast cancer cells. Cells were treated with the hydroalcoholic extract of Uncaria tomentosa and/or doxorubicin (Doxo 1 μM; Ut250+Doxo; Ut500+Doxo) for 24 h. Results Although the results were not significant for the hydrolysis of the ATP, they presented an increase in the ADP hydrolysis in the Ut500+Doxo group when compared to the control group. Additionally, the activity of 5′-nucleotidase was inhibited in all groups when compared with the untreated group of cells. Inhibition of the enzyme was more evident in groups with U. tomentosa per se. The expression of CD39 was increased in the Ut250 and Ut250+Doxo groups when compared to the control group. No changes were found in the CD73 expression. Furthermore, a reduction in the density of the P2X7 receptor in all treated groups was detected. On the other hand, the density of the A1 receptor increased in all groups compared to the control group, with the exception of the Ut500+Doxo group. Conclusion Therefore, we conclude that hydroalcoholic extract of U. tomentosa may be responsible for the reduction of adenosine levels in the extracellular medium, which accelerates tumor progression. Interestingly, the dysregulation of A1 and P2X7 receptors in the MDA-MB-231 cells exacerbate the proliferation of this cells and U. tomentosa treatment may be stimulate the antitumor activity of adenosine A1 receptor and control the P2X7 effects. Our study demonstrates the significant participation of purinergic pathway in the regulation of MDA-MB-231 progression; additionally, U. tomentosa treatment alone or combined with chemotherapy may favor the action of doxorubicin. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancers (TNBCs) are aggressive cancers that do not benefit from hormonal therapy or therapies that target HER2 receptors. Insulin-like growth factor 1 receptor (IGF-1R), which has been shown to be overexpressed in breast cancer, activates numerous downstream kinases that associate with cell proliferation and survival. This study compared the effects caused by dual treatments targeting IGF-1R, PI3K, mTORC, or MEK with those by single treatments in a TNBC cell line, MDA-MB-231. We used small-molecule kinase inhibitors, namely, NVP-AEW541, NVP-BKM120, KU0063794, and PD0325901 to target IGF-1R, PI3K, mTORC, and MEK, respectively. Combination treatments of PD0325901 with NVP-AEW541, NVP-BKM120 or KU0063794 and NVP-AEW541 with KU0063794 demonstrated a significant synergistic growth inhibition. These dual treatments increased apoptosis and/or cell cycle arrest at G0/G1 phase and enhanced the inhibition of phosphorylation of Akt or downstream molecules of mTORC1, as compared to the single treatments. Our study suggests that targeting multiple kinases in IGF-1R signaling may be a promising therapeutic approach. [ABSTRACT FROM AUTHOR]

In this study, five known meroterpenoids sargaol (1), flabellinone (2), stypodiol (3), atomarianone A (4), atomarianone B (5), and a known steroid fucosterol (6) were isolated from brown alga Stypopodium schimperi. Their structures were elucidated by 1D- and 2D NMR and mass spectroscopic analyses. Isolated compounds were tested against human healthy fibroblast cells (CCD-1079Sk), and two different types of human breast cancer cell lines (MDA-MB-231 and MCF-7). They were also investigated by molecular docking studies on estrogen receptor alpha (ERα), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptors 1 and 2 (VEGFR1 and VEGFR2), cyclin-dependent kinases 2, 4 and 6 (CDK2/4/6) proteins. Molecular dynamics simulations were carried out to determine their ligand-protein stability and binding affinity. The four isolates (1 - 3 , 6) showed strong cytotoxic activity in vitro against both cancer cell lines, particularly the aggressive MDA-MB-231 cell line, which was verified by in silico screening. Fucosterol was found to be the most selective compound against cancer cell lines, particularly the aggressive MDA-MB-231 cell line with a selectivity index (SI>16). The ADME prediction was also carried out and all the isolate compounds showed drug likeness. As a result, stypodiol and fucosterol were found to be the most potent compounds against both cancer cell lines by in vitro and in silico studies. [Display omitted] • Five meroterpenoids and one steroid were isolated from Stypopodium schimperi for the first time. • Their structures were elucidated by NMR and HRMS. • Isolated compounds were tested against two different cancer cells and an healthy cell lines as in vitro. Stypodiol and Fucosterol were found as potent inhibitors of ERα and HER2, respectively. [ABSTRACT FROM AUTHOR]

• GUPA was synthesized as single crystal characterized by XRD analysis. • Quantum chemical studies were performed for GUPA through DFT/6–311++G(d,p). • TD-DFT was performed and validated through experimental UV–Visible spectrum. • GUPA was investigated through molecular docking against protein p53. • Cytotoxic effect of GUPA was assessed in MDA-MB-231 cell line. A novel organic crystal bis(guanidininium) n-carboxylatephenylalanine (GUPA) was synthesized and X-ray diffraction outcomes exposed P 2 1 , triclinic space group with cell dimensions a = 6.6492(3) Å, b = 16.2440(7) Å, c = 7.8985(3) Å, β = 0.127(2) °, V = 853.11(6) Å3, Z = 2 and possess good agreement with experimental data. Intermolecular interactions were revealed through hirshfeld and major contribution from O-H interaction confirms the presence of intermolecular hydrogen bonds. Through B3LYP algorithm with set 6–311++ G (d, p), chemical reactivity forms and molecular structure of GUPA was investigated, confirming a good stability and hard electrophilic nature. While first order hyperpolarizability value (35.37 × 10−31 esu) was indicative of good nonlinear optical material and hyperconjugate interactions and charge delocalization was further confirmed by natural bond orbitals. To further investigate the electronic properties theoretical (TD-DFT) and experimental absorption wavelengths were compared and excitation energies, oscillator strength and type of electronic transition with contributions have also been studied. The topological properties were evaluated using ELF/LOL maps and RDG with NCI were used to establish the type of interaction present in the GUPA molecular system. The anti-breast cancer effect of GUPA was computationally studied through molecular docking against p53 gene and was further investigated through in vitro MDA-MB-231 cell line studies and GUPA showed better inhibition of cancer cells and their expression. [Display omitted] [ABSTRACT FROM AUTHOR]

Green synthesis of silver nanoparticles using plant extracts as reducing agents is an environmental friendly and cost-effective approach. This study aims to provide a detailed overview on the antioxidant, antimetastatic and apoptotic potential of leaf derived (L-AgNPs) and callus derived (C-AgNPs) silver nanoparticles of Hyptis suaveolens. The IC50 value of L-AgNPs was found to be 74.22 µg/ml and for C-AgNPs it was 74.66 µg/ml. Antimetastatic potential of both L-AgNPs and C-AgNPs were tested on MDA-MB-231 cell line. Both IC50 concentrations of L-AgNPs (74.22 µg/ml) and maximum concentration of 100 µg/ml was used for all the tests conducted. Similar procedure was adopted for C-AgNPs as well. The maximum adhesion inhibition was 75.64% while cellular invasion reduction was 72.66% and wound recovery was 49.61% with respect to L-AgNPs. C-AgNPs also showed similar type of results as L-AgNPs when compared to control. The antioxidant potential of L-AgNPs and C-AgNPs was tested by using DPPH radical scavenging activity, FRAP activity and reducing power. The L-AgNPs and C-AgNPs showed highest antioxidant potential when compared to control. [Display omitted] • Green synthesis of AgNPs and its characterization. • L-AgNPs and C-AgNPs exhibited maximum antioxidant potential. • L-AgNPs and C-AgNPs significantly reduced cellular adhesion and invasion. • L-AgNPs and C-AgNPs inhibited the cell migration. • L-AgNPs and C-AgNPs increased TUNEL positive cells. [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]

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] • 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]

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]

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]

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]

Abstract A phytochemical study on the stem bark of Metasequoia glyptostroboides led to the isolation of sixty-one diterpenoids and sesquiterpenoids, including seventeen previously undescribed compounds, metaglyptins A-Q. Their structures were elucidated by extensive analysis of spectroscopic data (IR, UV, HRESIMS, and 1H, 13C and 2D NMR). The absolute configurations of metaglyptins I, J, and O were determined by the ECD data and single-crystal X-ray diffraction analysis. The undescribed compounds were evaluated for their cytotoxicity against HeLa, AGS, and MDA-MB-231 cancer cell lines. The results revealed that metaglyptin A exhibited moderate cytotoxicity against MDA-MB-231 cell line with IC 50 value of 20.02 μ M. Graphical abstract Seventeen previously undescribed diterpenoids and sesquiterpenoids, as well as forty-four known compounds, were isolated and structurally characterized from the stem bark of Metasequoia glyptostroboides. The isolated undescribed compounds were evaluated for their cytotoxic activity. Image 1 Highlights • Seventeen undescribed terpenoids were isolated from Metasequoia glyptostroboides. • Forty-four known diterpenoids and sesquiterpenoids were isolated. • Metaglyptin A exhibited moderate cytotoxicity against MDA-MB-231 cell line. [ABSTRACT FROM AUTHOR]

[Display omitted] • The overexpression of sugar receptors in cancer cells can be used as a target for nanomedicines ; • Sucrose esters can be used to insert sugar moieties on the surface of nanovesicles without surface chemistry reactions; • 3D printed microfluidics has been used to efficiently manufacture sucrose decorated liposomes loaded with berberine; • Sucrose decorated liposomes showed increased uptake and antiproliferative effect on breast cancer cells compared to normal liposomes. Developing targeted drug delivery systems is an urgent need to decrease the side effects and increase the drug's efficiency. Most cancer cells show an increased sugar consumption compared to healthy cells due to the deregulation of sugar transporters. Consequently, liposomes, as a biocompatible nanocarrier, could be surface decorated by sugars to enhance drug targeting into cancer cells. Our work outlines a new strategy to easily manufacture sucrose decorated liposomes using sucrose stearate, a biocompatible and biodegradable non-ionic surfactant, with a scalable microfluidic approach. Sucrose decorated liposomes were loaded with berberine hydrochloride, a well-known phytochemical compound to investigate its effects on triple-negative breast cancer cells (MDA-MB-231). Using the microfluidic manufacturing system, we prepared berberine-loaded liposomes using a mixture of phosphatidylcholine and cholesterol with and without sucrose stearate with a size up to 140 nm and narrow polydispersity. Stability was confirmed for 90 days, and the in vitro release profile was evaluated. The formulations showed acceptable in vitro biocompatibility and significantly higher anti-proliferative effect on MDA-MB-231 cell line. These results have been confirmed by an increased uptake evaluated by flow cytometry and confocal microscopy. Taken together, our findings represent an innovative, easy, and scalable approach to obtain sugar decorated liposomal formulations without any surface-chemistry reactions. They can be potentially used as an anticancer targeted drug delivery system. [ABSTRACT FROM AUTHOR]

Breast cancer represents the most incident cancer in women. Surgery, chemotherapy, radiation therapy, and hormone therapy remain the main treatment for this type of cancer. However, increasing resistance to anti-cancer drugs through poor response for some types of breast cancer to treatments highlights the need to develop new therapeutic agents to fight the disease. In this study, we evaluated the anti-tumor potential of the Chartergellus-CP1 peptide isolated from the wasp venom of Chartergellus communis in human breast cancer cell lines MCF-7 (HR+) and MDA-MB-231 (triple-negative). Cells viability, morphology, cell cycle dynamics, reactive oxygen species (ROS) production, and apoptosis were assessed for both cell lines after exposure to Chartergellus-CP1 during 24 and 48 h. The results showed that Chartergellus-CP1 led to a significant increase of cells in the S phase in addition to a high generation of ROS (being more evident in the MCF-7 cell line) associated with apoptotic cell death. This work demonstrates, for the first time, the cytotoxic effects of Chatergellus-CP1 on human breast cancer cell lines including cell cycle profile, oxidative stress generation, and cell death mechanisms. [Display omitted] • Chartergellus-CP1 peptide from Chatergellus communis wasp venom was cytotoxic to MCF-7 and MDA-MB-231 breast cancer cells.. • Chartergellus-CP1 induced impairments on cell cycle dynamic, promotes ROS generation and causes apoptosis in both cell lines. • MCF-7 cell line was more sensitive to Chartergellus-CP1 peptide than the MDA-MB-231 cell line. [ABSTRACT FROM AUTHOR]

• Four mononuclear and dinuclear carboxamide Pd complexes isolated. • Molecular structures confirmed using single crystal X-ray analyses. • Interactions of the Pd complexes with CT-DNA) investigated. • BSA interactions studies established static quenching mechanism. • Cytotoxic effects of the complexes examined in three cancer cell lines. Reactions of ligands [ N 2, N 3-bis(pyridin-2-yl)pyrazine-2,3-dicarboxamide] (L1), [ N 2, N 3-bis(6-methylpyridin-2-yl)pyrazine-2,3-dicarboxamide] (L2), [ N 2, N 3-bis(4-methylpyridin-2-yl)pyrazine-2,3-dicarboxamide] (L3) and [ N 2, N 3-bis(quinoline-8-yl)pyrazine-2,3-dicarboxamide] (L4) with [PdCl 2 (NCMe) 2 ] afforded the respective palladium(II) complexes: [Pd 2 (L1) 2 Cl 2 ] (Pd1) , [Pd 2 (L2) 2 Cl 2 ] (Pd2) , [Pd 2 (L3) 2 Cl 2 ] (Pd3) and [Pd(L4) Cl] (Pd4). Molecular structures of complexes Pd1 and Pd3 are dinuclear containing two bridging bidentate ligand units. The interactions of the palladium complexes (Pd1 - Pd4) with calf thymus DNA (CT-DNA) were monitored using UV–Vis and fluorescence spectroscopy and revealed intercalative binding modes, with intrinsic binding constants (K b) in the order of 106 M−1. Bovine serum albumin (BSA) interaction was evaluated using fluorescence techniques and displayed a static quenching mechanism. The cytotoxic effects of the complexes Pd1-Pd4 were examined against human breast cancer cell lines MCF-7 and MDA-MB-231, and human transformed lung cell line MRC5-SV2 (a model of lung cancer) and its parental normal lung fibroblast cell line MRC5. While the complexes Pd1 and Pd4 showed significant to moderate cytotoxicity against MCF-7 (IC 50 of 11.2 µM and 61.5 µM, respectively), complexes Pd2 and Pd3 were inactive. All the complexes were inactive against the MDA-MB-231 cell line, and Pd2-Pd4 were inactive against the MRC5-SV2 cell line. Compounds Pd1 exhibited lower cytotoxicity against the normal cell line MRC5. [Display omitted] [ABSTRACT FROM AUTHOR]

Phosphonate analogues of α-amino acids are increasingly valued for their significant potential in medicinal chemistry. Fluorine is a "magic" element that plays a huge role in modulating the properties of organic compounds. In this work, we combined the two pharmacophores in the synthesis of three series of new α-aminophosphonates. These compounds were obtained by diastereoselective hydrophosphonylation of imines prepared by an environmentally friendly mechanochemical approach. Results of computational SwissADME analysis suggested favorable drug-like properties of the α-aminophosphonates and indicated their potential for interaction with diverse biological targets including proteases, showing promising pharmacokinetic profiles compared to 5-fluoro-2′-deoxyuridine (FdU) used as a standard anticancer drug. Screening against ten cancer cell lines from seven types of cancer showed that five of the twenty compounds tested (1c , 2a , 2h , 3e , and 3f) exhibited superior activity against the HeLa cell line and lower cytotoxicity against normal MRC-5 cells than FdU. Compound 3e showed notable inhibitory effect on the MDA-MB-231 cell line, while 3a , 3h , and 3g demonstrated significant cytotoxic activity against U-87 MG and U-251 MG lines. Molecular docking highlighted the strong binding of compound 2a to the urokinase-type plasminogen activator (uPA) protein, with a binding affinity of −6.41 kcal/mol, suggesting the anti-metastatic potential of the compound. These findings enable to position the newly synthesized α-aminophosphonates as promising scaffolds for developing targeted anticancer therapies for metastatic cancers characterized by elevated uPA expression. [Display omitted] • New class of fluorinated α-aminophosphonates was synthesized diastereoselectively. • The cytotoxicity of these compounds was tested against seven types of cancer. • The mean values of IC 50 ranged from 8.71 μM for HeLa to 89.54 μM for MDA-MB-231. • Compound 2a strongly binds to the structure of urokinase-type plasminogen activator protein. • The synthesized compounds provide scaffold for development of new anticancer drugs. [ABSTRACT FROM AUTHOR]

• A new set of quinolin-4-ylcarbonylhydrazine derivatives having 2-arylamido-3-arylacryloyl moiety has been synthesized. • The newly synthesized derivatives were evaluated for their cytotoxic activity against MDA-MB-231 cancer cells. • Flow cytometric measurements were carried out for the most potent molecule. • Active compound was tested for β-tubulin assembly inhibition. • Mitochondrial membrane potential was assessed for the most active compound. A new set of quinolin-4-ylcarbonylhydrazine derivatives 7a-i and 9a,b bearing 3-arylacryloyl moiety has been synthesized and investigated for their potential anticancer activity. The synthetic protocol involves the following step: the target quinoline derivatives 7a-i and 9a,b appended to the acryloyl moiety were synthesized from quinolin-4-carbohydrazide intermediate with respective ethyl 2-arylamido-3-arylacrylate compounds. The cytotoxic activity study was evaluated using the functional MTT method. The most of target compounds displayed potent cytotoxic activity against MDA-MB-231 cell line. Among them, compounds 7d and 7 h were found to be promising antiproliferative agents with IC 50 values of 4.04 and 1.78 μM, respectively, relative to the effective anticancer drug, Dox (IC 50 = 5.33 μM). Compound 7 h exhibited cytotoxic activity by causing cell cycle to block at G2/M phase in addition to pro-apoptotic effect, as shown by flow cytometric measurement. In addition, the inhibitory action against β-tubulin polymerization was investigated. Finally, compound 7 h diminished the level of mitochondrial potential by almost 2.8-fold compared to control, indicating that the cellular death proceeds through the provoke of the intrinsic mitochondrial pathway of apoptosis. [ABSTRACT FROM AUTHOR]

• Synthesis, structural studies & application of Schiff base 1 and its Zn(II)-complex 2. • Complex 2 shows better effect in vitro cytotoxicity as compared to 1 Against MDA-MB-231 cell line. • Chromone-appended 1 acts as an exceptionally selective colorimetric receptor for Cu2+. • Complex 2 serves as ultrasensitive fluorescent probe for Ag+ and Fe3+ distinctly. • Interaction with Ag+ forms [2·Ag(NO3)]n and Fe3+ forms [2·{Fe(NO3)2H2O)}2] complex. • Comprehensive DFT studies have been carried out to validate the mechanism and binding. Present article delineates the design and synthesis of a chromone-appended Schiff base (1) and its complexes with Zn(II) (2) and Cu(II) (3), which have been characterized by various spectro-analytical techniques i.e., elemental analysis, FTIR, 1H & 13C NMR, ESI-MS, UV−vis and fluorescence. Structures of 1 and 3 have also been elucidated using single crystal X-ray diffraction analysis. Compounds 2 showed significant effect in vitro cytotoxicity as compared to 1 Against MDA−MB-231 cell line. Interestingly, 1 serves as a chromogenic sensor for Cu2+ with exceptional selectivity whereas, 2 serves as an ultrasensitive fluorescent probe for Ag+ and Fe3+ in mixed aqueous−ethanol. The presence of Ag+ causes ratiometric change in the fluorescence spectral feature of 2 whereas Fe3+ induces ' turn-off ' fluorescence in 2. Probe−analyte binding stoichiometry suggested by Job's plot analysis, ESI−MS and DFT studies, has been found to be 1:1 for 1 with Cu2+ and 2 with Ag+ whereas, 1:2 between 2 and Fe3+. Based on diverse analyses and binding constants, it is observed that 2 offers higher selectivity toward Ag+ over Fe3+. Limit of detection (LoD) of 1 for Cu2+ and 2 for Ag+ and Fe3+ have been found to be 2.33 nM, 22.4 µ M and 2.05 µ M, respectively. Complexes 2 +Ag+ and 2 +Fe3+ characterized by ESI−MS whereas DFT studies have been carried out to investigate the deeper bonding insights and provide support in our experimental investigations. Further, detection of Ag+ and Fe3+ has been practically accomplished in real water samples using probe 2. [Display omitted] Present research entails synthesis, characterization and structural validation along with anticancer activities, UV−vis and fluorescent detection studies of chromone−based probes 1 and 2 toward colorimetric recognition of Cu2+ and ultrafast fluorescent detection of Ag+ and Fe3+ with excellent reusability and LoDs. Both 1 and 2 exhibits anti-cancer properties Against MDA−MB-231 cell line. Detailed DFT studies to support the experimental results and practical application in real water samples have also been accomplished. [ABSTRACT FROM AUTHOR]

Chemical investigation of the Tinospora sinensis led to the isolation of a new cadinane sesquiterpene (1) and twelve known sesquiterpenes (2 − 13). The structures of these compounds were deduced using a suite of comprehensive spectroscopic techniques including NMR, MS etc. , and the absolute configuration of 1 was established through a combination of TDDFT calculations and chemical methods. Compound 1 demonstrated mild cytotoxicity against MDA-MB-231 cell line, with an inhibition rate of 46.8% and 54.2% at 50 μmol/L and 100 μmol/L, respectively. Compounds 1 , 5 − 13 were reported to exist in the Menispermaceae family for the first time. Furthermore, the chemotaxonomic significance of the isolates is also discussed. • Thirteen sesquiterpenes were isolated from the Tinospora sinensis. • A new cadinane sesquiterpene was isolated from the Tinospora sinensis. • Compounds 1 , 5–13 were isolated from Menispermaceae for the first time. • The chemotaxonomic significance of the isolates is discussed. [ABSTRACT FROM AUTHOR]

Metastatic cancer remains a formidable challenge in anticancer therapy. Despite efforts to develop effective antimetastasis drugs over the past half-century, currently approved treatments fall short of expectations. This report highlights the promising antiproliferative activity of a ruthenium-based therapeutic agent, namely dichlorido(p -cymene)[2-amino-4-(pyridin-3-yl)-4 H -benzo[ h ]-chromene-3-carbonitrile]ruthenium(II) (complex 1) against metastatic cell lines. Complex 1 shows significant efficacy in metastatic LoVo and Du-145 cell lines at nanomolar concentrations, being markedly more active than clinically used anticancer cisplatin. Studies on the MDA-MB-231 cell line, which displays invasive characteristics, demonstrated that 1 significantly reduces cell invasion. This efficacy was confirmed by its impact on matrix metalloproteinase production in MDA-MB-231 cells. Given that cell migration drives cancer invasion and metastasis, complex 1 's effect on MDA-MB-231 cell migration was evaluated via wound healing assay and vimentin network analysis. Results indicated a strong reduction in migration. A re-adhesion assay further demonstrated that 1 significantly lowers the re-adhesion ability of MDA-MB-231 cells compared to cisplatin. To better simulate the human body environment, a 3D spheroid invasion assay was used. This method showed that 1 effectively inhibits tumor spheroids from infiltrating the surrounding extracellular matrix. This study underscores the potential of (arene)ruthenium(II) complexes with naphthopyran ligands as potent antimetastatic agents for chemotherapy. • (Arene)Ru(II) complex with naphthopyran (1) exhibits antimetastatic efficacy. • 1 reduces invasion and migration activity of tumor cells displaying invasive traits. • 1 prevents metastatic 3D spheroids from infiltrating the adjacent extracellular matrix. • (Arene)Ru(II) complexes with naphthopyran represent promising antimetastatic agents for chemotherapy. [ABSTRACT FROM AUTHOR]

Progressive incidence and a pessimistic survival rate of breast cancer in women worldwide remains one of the most concerning topics. Progressing research indicates a potentially high effectiveness of use cold atmospheric plasma (CAP) systems. The undoubted advantage seems its simplicity in combination with other anti-cancer modalities. Following observed trend of studies, one inventory CAP system was applied to directly treat human breast cancer cell lines and culturing in two different Plasma Activated Media (PAM) for combined utilization. Proposed CAP treatments on MCF-10 A, MCF-7, and MDA-MB-231 cell lines were studied in terms of impact on cell viability by MTT assay. Disturbances in cell motility following direct and combined CAP application were assessed by scratch test. Finally, the induction of apoptosis and necrosis was verified with annexin V and propidium iodide staining. Reactive species generated during CAP treatment were determined based on optical emission spectrometry analysis along with colorimetric methods to qualitatively assess the NO 2 −, NO 3 −, H 2 O 2 , and total ROS with free radicals concentration. The most effective approach for CAP utilization was combined treatment, leading to significant disruption in cell viability, motility and mostly apoptosis induction in breast cancer cell lines. Determined CAP dose allows for mild outcome, showing insignificant harm for the non-cancerous MCF-10 A cell line, while the highly aggressive MDA-MB-231 cell line shows the highest sensitivity on proposed CAP treatment. Direct CAP treatment seems to drive the cells into the sensitive state in which the effectiveness of PAM is boosted. Observed anti-cancer response of CAP treatment was mostly triggered by RNS (mostly NO 2 − ions) and ROS along with free radicals (such as H 2 O 2 , OH•, O 2 -•, 1O 2 , HO 2 •). The combined application of one CAP source represent a promising alternative in the development of new and effective modalities for breast cancer treatment. [Display omitted] • Innovative CAP system used for direct and combined treatment of human breast cancer cells. • CAP significantly reduces viability and motility of breast cancer cells and induces their apoptosis. • Direct CAP treatment sensitizes breast cancer cells on the PAM usage. • Anti-cancer activity of CAP was triggered by reactive oxygen and nitrogen species. [ABSTRACT FROM AUTHOR]

The literature reports that thiazole and isatin nuclei present a range of biological activities, with an emphasis on anticancer activity. Therefore, our proposal was to make a series of compounds using the molecular hybridization strategy, which has been used by our research group, producing hybrid molecules containing the thiazole and isatin nuclei. After structural planning and synthesis, the compounds were characterized and evaluated in vitro against breast cancer cell lines (T-47D, MCF-7 and MDA-MB-231) and against normal cells (PBMC). The activity profile on membrane proteins involved in chemoresistance and tumorigenic signaling proteins was also evaluated. Among the compounds tested, the compounds 4c and 4a stood out with IC 50 values of 1.23 and 1.39 μM, respectively, against the MDA-MB-231 cell line. Both compounds exhibited IC 50 values of 0.45 μM for the MCF-7 cell line. Compounds 4a and 4c significantly decreased P-gp mRNA expression levels in MCF-7, 4 and 2 folds respectively. Regarding the impact on tumorigenic signaling proteins, compound 4a inhibited Akt2 in MDA-MB-231 and compound 4c inhibited the mRNA expression of VIM in MCF-7. [Display omitted] • Facile synthesis of thiazole and isatin derivatives. • 28 new thiazolyl-isatin were synthesized. • In vitro evaluation against breast cancer cell lines. • 4a and 4c exhibited IC 50 less than 1.4 μM in both tested cells. • Analysis on tumorigenic signaling proteins (Akt2 and VIM). [ABSTRACT FROM AUTHOR]

Caffeic acid phenethyl ester, derived from natural propolis, has been reported to have anti-cancer properties. Voltage-gated sodium channels are upregulated in many cancers where they promote metastatic cell behaviours, including invasiveness. We found that micromolar concentrations of caffeic acid phenethyl ester blocked voltage-gated sodium channel activity in several invasive cell lines from different cancers, including breast (MDA-MB-231 and MDA-MB-468), colon (SW620) and non-small cell lung cancer (H460). In the MDA-MB-231 cell line, which was adopted as a ‘model’, long-term (48 h) treatment with 18 μM caffeic acid phenethyl ester reduced the peak current density by 91% and shifted steady-state inactivation to more hyperpolarized potentials and slowed recovery from inactivation. The effects of long-term treatment were also dose-dependent, 1 μM caffeic acid phenethyl ester reducing current density by only 65%. The effects of caffeic acid phenethyl ester on metastatic cell behaviours were tested on the MDA-MB-231 cell line at a working concentration (1 μM) that did not affect proliferative activity. Lateral motility and Matrigel invasion were reduced by up to 14% and 51%, respectively. Co-treatment of caffeic acid phenethyl ester with tetrodotoxin suggested that the voltage-gated sodium channel inhibition played a significant intermediary role in these effects. We conclude, first, that caffeic acid phenethyl ester does possess anti-metastatic properties. Second, the voltage-gated sodium channels, commonly expressed in strongly metastatic cancers, are a novel target for caffeic acid phenethyl ester. Third, more generally, ion channel inhibition can be a significant mode of action of nutraceutical compounds. [ABSTRACT FROM AUTHOR]

Osteopontin (OPN) is a phosphoglycoprotein, with a wide range of physiological and pathological roles. High expression of OPN promotes aggressive behavior, causes poor prognosis in tumor cells, and reduces the survival of patients. Since overexpression of OPN gives rise to radioresistance, the effects of the gene knock out using the CRISPR/Cas9 system in combination with radiation are emphasized. We used the CRISPR/Cas9 technique to knock out the OPN gene in the MDA-MB-231 cell line. After transfection, the cells were irradiated. The changes of the OPN mRNA levels, the apoptosis, and the differences in cell viability were assessed. A significant reduction in the OPN expression was observed alone or along with irradiation. The knocked out gene alone increased apoptosis rate. The cell viability decreased to after knocking out of the OPN gene. The gene knocking-out combined with irradiation led to more decline of cell viability. Our results demonstrated that after knocking out the OPN gene, the MDA-MB-231 cells showed a significant radiosensitivity. Therefore, the OPN knock out in combination with conventional radiotherapy, may become an efficient therapeutic target in the future. [ABSTRACT FROM AUTHOR]

Black chickpea is a good source of bioactive compounds, particularly isoflavones. Sprouting improves nutraceutical value in chickpea seeds. This study aimed to explore the role of sprouting of black chickpea seeds on the synthesis of isoflavones and evaluate the impact of the soluble isoflavone on cellular antioxidant activity (CAA) and antiproliferative activity in breast cancer cells. Isoflavones were identified and quantified by HPLC-UV-MS. The CAA and antiproliferative activity were determined in HepG2 cells and MDA-MB-231 cancer cells, correspondingly. In sprouted black chickpea, six isoflavones (formononetin, biochanin-A, and its glycosides) were identified and the total isoflavones content increased (0.31 to 35.72 µgBA/mg of extract). The CAA was increased five times from 137.2 to 788.2 µMEQ/100 g of sample. The bioactive compounds in sprouted chickpea decreased the proliferation of MDA-MB-231 cell line. Also caused morphological changes such as cell shrinkage, rounding and nuclear fragmentation. The results herein suggest that bioactive compounds, as isoflavones, in sprouted black chickpea showed a potential antioxidant and antiproliferative activity. Therefore, it may be considered as a value-added product or ingredient for produce functional foods. [ABSTRACT FROM AUTHOR]

Mesoporous materials have attracted extensive consideration in the field of drug delivery. The targeted release of anti-neoplastic agents depends on the carrier used to transport such drugs in the body. In this study, mesoporous bioactive glass nanoparticles (MBGN) of an average size of 120 ± 10 nm were used to load and release silibinin, which is a natural flavonolignan used as anticancer agent and tumor suppressor. Mesoporous bioactive glass nanoparticles were characterized in terms of morphology and release potential after being loaded with silibinin. The loading and release amounts of silibinin were quantified using UV-VIS spectrophotometer at λ max = 280 nm in PBS buffer solution (pH 7.4). It was found that MBGN have a maximum loading efficiency of 61% against optimal silibinin concentration (i.e. 40 μg/ml silibinin in PBS buffer solution (pH 7.4)). The drug was released in a sustained manner from loaded mesoporous bioactive glass nanoparticles and a release of 18 μg/ml silibinin was measured during the first 24 h post-drug loading. Further, the chemotherapeutic effect of silibinin was tested on metastatic MDA-MB-231 breast cells and the non-metastatic breast cell line MCF-10A at two different concentrations (9.0 μg/ml and 18 μg/ml). As our results show, silibinin exhibits a chemotherapeutic potential towards MDA-MB-231 cell line, which is a much lower concentration compared to values reported in literature. According to our knowledge, this is the first study elucidating the use of MBGN as a carrier for silibinin, as well as testing its lethal effect in contact with breast neoplastic cells. Taken collectively, the results of the present study suggest that silibinin-loaded MBGN can be applied as an effective drug delivery system to cause a chemo preventive response which has the potential to be beneficial for the treatment of breast cancer. Image 1 [ABSTRACT FROM AUTHOR]

Brain metastases manifest the advanced stage of breast cancer disease with poor prognosis for patient survival. Recent reports demonstrate that some therapeutic agents can activate the expression of several breast cancer-associated genes, whose products are involved in the onset and development of brain metastases. In this study, we discovered a functional link between KISS1 and E-cadherin that could be observed in both primary brain metastatic lesions and paired cell lines, such as parental CN34TGL and MDA-MB-231 and their respective brain metastatic subclones CN34Brm2Ctgl and MDA-MB-231Br. Remarkably, expression of KISS1 and E-cadherin genes consistently showed an inverse correlation in all of the above cell/tissue types. While E-cadherin expression was strongly upregulated in metastatic clones isolated from blood and brain, the levels of this protein in parental MDA-MB-231 cell line was low. Furthermore, E-cadherin upregulation can be artificially induced in MDA-MB-231Br and CN34Brm2Ctgl cell populations by knocking down KISS1 expression directly or through overexpressing the miR345 mimic. In the aggregate, our data suggest that the tumor microenvironment, which controls breast cancer spreading via miR345-regulated KISS1 expression, might modulate metastatic spreading by a mechanism(s) involving upregulation of E-cadherin production. • KISS1 and E-cadherin expression levels exhibit an inverse correlation in the primary patient samples. • KISS1 inhibition induces E-cadherin. • MiR345 induces E-cadherin expression via KISS1 suppression on the mRNA level. • Downregulation of KISS1 induces cancer cell resistance to ionizing radiation and chemotherapy (temozolomide). [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are cell-released vesicles that mediate intercellular communication by transferring bioactive cargo. Protein and RNA sorting into EVs has been extensively assessed, while selective enrichment of glycans in EVs remains less explored. In this study, a mass spectrometry-based approach, glycan node analysis (GNA), was applied to broadly assess the sorting of glycan features into EVs. Two metastatic variants (lung and bone) generated in mouse modes from the MDA-MB-231 human breast cancer cell line were assessed, as these EVs are known to contain distinct organotropic biomolecules. EVs were isolated from conditioned cell culture medium by tangential flow filtration and authenticated by standard techniques. GNA analysis revealed selective enrichment of several glycan features in EVs compared to the originating cells, particularly those associated with binding to the extracellular matrix, which was also observed in EVs from the parental MDA-MB-231 cell line (human pleural metastases). The bone-tropic variant displayed enrichment of distinct EV glycan features compared to the lung-tropic one. Additionally, the metastatic variants generated in mouse models displayed reduced EV glycan sorting compared to the parental metastatic cell line. This study represents the first comprehensive assessment of differences in glycan features between EVs and originating cells and provides evidence that the diversity of EV glycan sorting is reduced upon generation of variant cell lines in mouse models. Future research is likely to uncover novel mechanisms of EV glycan sorting, shed light on glycan features for EV authentication or biomarker purposes, and assess functional roles of the EV glycocode in (patho)physiology. • Glycan sorting into extracellular vesicles (EVs) is largely unexplored. • Previous technical challenges prevent comprehensive EV-glycan studies. • Efficient EV isolation and unique mass spectrometry methods were used. • First study to comprehensively assess glycans in EV sorting. • Extracellular matrix-binding glycans are enriched in EVs versus originating cells. [ABSTRACT FROM AUTHOR]

Tumor microenvironment has a high concentration of inorganic phosphate (Pi), which is actually a marker for tumor progression. Regarding Pi another class of transporter has been recently studied, an H+-dependent Pi transporter, that is stimulated at acidic pH in Caco2BBE human intestinal cells. In this study, we characterized the H+-dependent Pi transport in breast cancer cell (MDA-MB-231) and around the cancer tissue. MDA-MB-231 cell line presented higher levels of H+-dependent Pi transport as compared to other breast cell lines, such as MCF-10A, MCF-7 and T47-D. The Pi transport was linear as a function of time and exhibited a Michaelis-Menten kinetic of K m = 1.387 ± 0.1674 mM Pi and V max = 198.6 ± 10.23 Pi × h−1 × mg protein−1 hence reflecting a low affinity Pi transport. H+-dependent Pi uptake was higher at acidic pH. FCCP, Bafilomycin A1 and SCH28080, which deregulate the intracellular levels of protons, inhibited the H+-dependent Pi transport. No effect on pHi was observed in the absence of inorganic phosphate. PAA, an H+-dependent Pi transport inhibitor, reduced the Pi transport activity, cell proliferation, adhesion, and migration. Arsenate, a structural analog of Pi, inhibited the Pi transport. At high Pi conditions, the H+-dependent Pi transport was five-fold higher than the Na+-dependent Pi transport, thus reflecting a low affinity Pi transport. The occurrence of an H+-dependent Pi transporter in tumor cells may endow them with an alternative path for Pi uptake in situations in which Na+-dependent Pi transport is saturated within the tumor microenvironment, thus regulating the energetically expensive tumor processes. • MDA-MB-231 presented higher H+-dependent Pi transport than MCF-10A. • PAA, an inorganic phosphate analogue, inhibited H+-dependent Pi transport. • High extracellular Pi concentration stimulated H+-dependent Pi transport. [ABSTRACT FROM AUTHOR]

Abstract Treatment of breast cancer by delivering important tumor suppressor plasmids is a promising approach in the field of clinical medicine. We transfected p21 and p53 tumor suppressor plasmids, into different breast cancer cell lines using inorganic nanoparticles (NPs) of carbonate apatite to evaluate the effect of gene expression on reducing breast cancer cell growth. In triple negative MDA-MB-231 breast cancer cell line, the cytotoxicity assay upon combined delivery of p21 and p53 plasmid loaded NPs showed significant decrease in cell growth compared to distinct p21 or p53 treatments. Also, in MCF-7 and 4T1 cell lines, significant reduction in cellular growth was observed following p21 or p53 plasmid transfection. The Western blot data showed that NP loaded p21 and p53 transgene delivery in MDA-MB-231 cell line resulted in a noteworthy decrease in phosphorylated form of MAPK protein of MAPK/ERK pathway. The in vivo studies in syngeneic breast cancer mouse model demonstrated that the rate of growth and final tumor volume were reduced to a greater extent in mice that received intravenous injection of p21 + NP and p53 + NP therapeutics. Highlights • Transfection with p21 and p53 plasmids significantly reduced breast cancer cell growth. • Decreased expression of P-MAPK protein was observed in the transfected cells. • Tumor volume was significantly decreased in breast cancer mouse model treated with the tumor suppressors. [ABSTRACT FROM AUTHOR]

Four new limonoids, 7,12-dihydroxyvilasinone (1), vilasindione (2), 4-dehydroxynimbandiol (3) and azadiramide B (4), were isolated from extracts of Bacillus subtilis -fermented neem seeds. Their planar structures and relative configurations were elucidated by spectroscopic methods including UV, IR, MS and NMR, and the absolute stereochemistry was determined by comparing their experimental and calculated CD spectra. 4 is a rare salannin-class limonoid alkaloid. In cytotoxic assays, 3 showed inhibitory activity against MDA-MB-231, A375 and Hela cell lines with IC 50 values of 21.45 ± 5.41, 17.67 ± 3.96 and 28.13 ± 9.12 μM, respectively, while 4 selectively inhibited growth of MDA-MB-231 cell line with an IC 50 value of 15.73 ± 6.07 μM. Unlabelled Image [ABSTRACT FROM AUTHOR]

Abstract Background The expression of p38 MAPK is high in breast cancer while its subunit p38γ had been rarely reported. We aimed to explain the effect of p38γ in breast cancer from the perspective of metabolomics. Methods In this study, we detected the expression of p38γ in 28 breast carcinoma and para-tumor samples. Following MDA-MB-231 cell transfection with p38γ siRNAs and pc-DNA-3.1, cell viability, apoptosis, metastasis were determined through CCK-8, the cytometry analysis, transwell assay and wound healing assay. Finally, gas chromatograph-mass spectrometer (GC–MS) was used for analysis the differential metabolites. Results The expression of p38γ was significantly up-regulated in breast cancer tissues. The transfection of si-p38γs could inhibit MDA-MB-231 cell propagation, metastasis, and induced cell apoptosis while overexpressed p38γ could promote the cell propagation, metastasis, and inhibit cell apoptosis. A total of 238 metabolites were identified and 72 of them differentially expressed in three groups (all P < 0.05, FDR < 0.05). Then the metabolites were enriched in the metabolism pathway, 85 pathways were included and 27 were significant (all P < 0.05, FDR < 0.05). Conclusions p38γ was up-regulated in breast cancer, which exerts a great influence on the cell growth, cell mobility, invasiveness, and apoptosis of MDA-MB-231 cells and also affected the metabolism. [ABSTRACT FROM AUTHOR]

In the spectrum of breast neoplasms, approximately 15 to 20% of all diagnosed cases are triple-negative breast carcinoma. TNBC grows and spreads faster than other invasive breast cancers and has a worse prognosis. The existing therapies and chemotherapeutic drugs have several limitations, so the development of safe and affordable treatment options is currently in demand. Hence, this research focuses on scientifically evaluating the therapeutic anticancer effect of ethyl acetate extract of MSG and its combined efficacy with doxorubicin against TNBC. MSG has shown an IC 50 value of 48.40 ± 1.68 µg/ml on the MDA-MB-231 cell line, and the combination of MSG with Dox demonstrated the synergistic effect. Apoptotic changes such as membrane blebbing chromatin condensation were observed in MSG alone and in combination with doxorubicin treatments. Apoptosis was confirmed with Annexin V-FITC/PI staining and increased apoptotic markers such as Cleaved caspase-3 Bax and decreased anti-apoptotic markers Bcl-2 by western blotting. The tumor burden significantly decreased in MSG and combination treatment groups while restoring their body weights. Meanwhile, the Dox-treated group indicated a decreased tumor burden combined with weight loss. The present investigation revealed that MSG and doxorubicin have a synergistic anticancer effect in TNBC. [ABSTRACT FROM AUTHOR]

• Synthesis of 1-(2-((aryl-1,3,4-thiadiazol-2-yl)amino)acetyl)indoline-2,3-diones. • The title compounds exhibit notable in-vitro anti-breast cancer activity. • Isatin thiadiazoles display excellent binding affinity with EGFR receptor. • Promising drug likeliness of isatin hybrids is ascertained in ADMET projections. Despite rapid advances in drug accessibility for diagnosis and treatment, breast cancer remains a common malignancy among women across the world due to the inadequacy of current therapeutic alternates and the emergence of drug-resistant cancerous cells. A series of 1-(2-((aryl-1,3,4-thiadiazol-2-yl)amino)acetyl)indoline-2,3-diones has been synthesized, characterized, and explored for their potency as anti-breast cancer leads. In-vitro cell viability screening via MTT assay displayed significant antiproliferative efficacy of isatin hybrids against MDA-MB-231 cell line, and the most potent compound 4c bearing chlorophenyl substituent, showed an IC 50 value of 57.79 µg/ml. The stability and reactivity aspects of synthesized hybrids have been deduced through Density Functional Theory. Molecular docking studies against epidermal growth factor receptor (EGFR) project the title compounds as potent EGFR inhibitors with an effective binding score. In-silico ADMET studies annunciate the synthesized hybrids as proficient and safer chemotherapeutic leads in drug discovery explorations for breast cancer treatment, especially against TNBC. Synthesis and anti-breast cancer evaluation of isatin-tagged thiadiazoles. [Display omitted] [ABSTRACT FROM AUTHOR]