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Breast cancer has been recorded as a frequent malignant cancer. The side effects of current chemotherapy drugs are still a severe problem. Hence, naturally occurring phytochemicals can be a possible solution to overcome this issue. Therefore, naturally occurring hyperforin was used to assess its anticancer effect against triple-negative breast cancer cells (MDA-MB-231) and its effectiveness against taxol (clinically used drug). Both compounds' anticancer activity and mechanism of action were evaluated by analysing various approaches such as ELISA, flow cytometry and PCR microarray. Our results showed a lower IC50 of hyperforin (7.18 µg/mL) compared to taxol (7.91 µg/mL, P < 0.05) and hyperforin has almost similar anticancer effects as taxol against MDA-MB-231 cells. PCR microarray results showed that hyperforin induced the expression of caspases activator leading to a caspases-dependent cell death pathway whereas taxol uses TNF-mediated cell death. The results suggest that hyperforin may act as a good cell death-inducing agent. ABBREVIATIONS: TNBC: Triple negative breast cancer; DNA: Deoxyribonucleic acid; RNA: Ribonucleic acid; ROS: Reactive oxygen species; 5-FU: Fluorouracil; TRAIL: TNF-related apoptosis-inducing ligand; AKT: Protein kinase B; COX-2: Cyclooxygenase-2; PCR: Polymerase chain reaction; Bax: Bcl-2-associated X protein; BCL-2: B-cell lymphoma 2; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; mRNA: Messenger ribonucleic acid; MCL1: Myeloid-cell leukemia 1; LDH: Lactate dehydrogenase; ELISA: Enzyme-linked immunosorbent assay; MMP: Mitochondrial membrane potential; MCP-1: Monocyte chemoattractant protein-1; ATCC: American Type Culture Collection; RPMI: Roswell Park Memorial Institute; XIAP: X-linked inhibitor of apoptosis protein; FBS: Fetal bovine serum; MCL-1: Myeloid-cell leukemia 1; DMEM: Dulbecco's Modified Eagle Medium; DMSO: Dimethyl sulfoxide; CASP3: Caspase 3; RPMI: Roswell Park Memorial Institute; DMEM: Dulbecco's Modified Eagle Medium; FBS: Fetal bovine serum; h: Hour; TNF-α: Tumour necrosis factor alpha; P53: Tumor protein P53; min: Minutes; cps: Count presecond; OD: Optical density; rpm: Revolutions per minute; PI: Propidium iodide; SD: Standard deviation; DDR: Death Domoin Receptor; TRADD: Tumor necrosis factor receptor type 1-associated DEATH domain; HRK: Harakiri, BCL2 Interacting Protein; RIPK2: Receptor-interacting serine/threonine-protein kinase 2; BIK: BCL2 interacting killer; DCF: 2', 7' –dichlorofluorescein; DCF-DA: Dichlorofluorescin Diacetate; FADD: Fas Associated Via Death Domain; TNFRSF: Tumor necrosis factor receptor superfamily; FITC: Fluorescein isothiocyanate; DMSO: Dimethyl sulfoxide; CFLAR: CASP8 And FADD Like Apoptosis Regulator; BID: BH3-interacting domain death agonist; BIRC: Baculoviral IAP repeat-containing protein; CIDEA: Cell death activator CIDE-A; CIDEB: Cell Death Inducing DFFA Like Effector B; BrdU: Bromodeoxyuridine; RFU: Relative fluorescence unit; NF-kB: Nuclear Factor kappa-light-chain-enhancer of activated B cells; %: Percentage; µL: microliter; µM: Micromolar; °C: degree Celcius; ng/mL: Nanograms per millimeter; mg/mL: Milligrams per milliliter; µg/mL: Micrograms per milliliter; ΔΨm: Mitochondrial membrane potential; TNFα: Tumour necrosis factor α; Bcl-xL: B-cell lymphoma-extra large; MDR1: Multidrug Resistance Mutation; AIB1: Amplified in breast cancer 1; LTBR: Lymphotoxin Beta Receptor Highlights Utilization of hyperforin as anticancer agent against triple negative breast cancer. Hyperforin exhibited a lower IC50 compared to taxol in inhibiting growth of MDA-MB-231 cells. Hyperforin shows similar potential anticancer activity as taxol. Hyperforin uses mitochondrial death pathway to induce cell death in MDA-MB-231 cells. [ABSTRACT FROM AUTHOR]

In our effort to develop novel and powerful agents with anti-proliferative activity, two new series of 1H-benzo[f]chromene derivatives, 4a-h and 6a-h, were synthesised using heterocyclocondensation methodologies under microwave irradiation condition. The structures of the target compounds were established on the basis of their spectral data, IR, 1H NMR, 13 C NMR, 13 C NMR-DEPT/APT, and MS data. The new compounds have been examined for their anti-proliferative activity against three cancer cell lines, MCF-7, HCT-116, and HepG-2. Vinblastine and Doxorubicin have been used as positive controls in the viability assay. The obtained results confirmed that most of the tested molecules revealed strong and selective cytotoxic activity against the three cancer cell lines. Moreover, these molecules exhibited weak cytotoxicity on the HFL-1 line, which suggested that they might be ideal anticancer candidates. The SAR study of the new benzochromene compounds verified that the substituents on the phenyl ring of 1H-benzo[f]chromene nucleus, accompanied with the presence of bromine atom or methoxy group at the 8-position, increases the ability of these molecules against the different cell lines. Due to their high anti-proliferative activity, compounds 4c and 6e were selected to be examined their proficiency to inhibit the invasiveness of the highly sensitive and invasive breast cancer cell line, MDA-MB-231. The anti-invasion behaviour of these molecules against the highly sensitive, non-oestrogen, and progesterone MDA-MB-231 cell line gave rise to their decreasing metastatic effect compared to the reference drug. Furthermore, this report explores the apoptotic mechanistic pathway of the cytotoxicity of the target compounds and reveals that most of these compounds enhance the Caspase 3/7 activity that could be considered as potential anticancer agents. [ABSTRACT FROM AUTHOR]

Chest X-rays are used to assess diagnostic conditions for patients with breast cancer. The aim of this research was to study the radiation dose from chest X-ray on the response of breast cancer cells. In this research, the proliferation and cell numbers of the MDA-MB-231 cell line were studied at 1, 24, 48, 72 and 96 h after 0.42–0.82 mGy of chest X-ray irradiation. The results showed that the cell morphology of breast cancer cells did not change after irradiation. In contrast, it was found that the radiation dose from chest X-ray inhibited cell growth and the cell viability of MDA-MB-231. It can be seen that the changes at the cellular level occur within cancer cells from low-dose radiation. [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]

A new series of 4-aryl-2-(naphthalen-1-yl)thiazole (7a-b), 4-aryl/pyridyl-2-(2-substituted quinolin-4-yl)thiazole (13a-o) and 4-(pyridin-4-yl)-2-(quinolin-4-yl)thiazole (15) have been synthesized. The newly synthesized compounds were evaluated for anticancer activity against breast cell lines MDA-MB-231 and MCF-7. Among the derivatives compounds 7a, 7 b and 13e showed good activity against the MCF-7 cell line, compounds 13 m, 13o and 15 showed good activity against MDA-MB-231 cell line. The new analogs were also screened to evaluate their in vitro antimicrobial potential against Escherichia coli (NCIM 2574), Proteus mirabilis (NCIM 2388), Bacillus subtilis (NCIM 2063), Staphylococcus albus (NCIM 2178), Aspergillus niger (ATCC 504), and Candida albicans (NCIM 3100). Amongst the naphthalenyl-thiazole and quinolinyl-thiazole derivatives, ten compounds 7a, 7 b, 13a, 13 b, 13c, 13d, 13e, 13f, 13 h and 15 showed good activity against P. mirabilis. The structure-activity relationship study revealed that naphthalene, quinoline, and 2-phenyl quinoline tethered thiazole showed good activity against P. mirabilis. These compounds could assist in the development of lead compounds for the treatment of cancer and microbial infections. [ABSTRACT FROM AUTHOR]

Nisin is an antibacterial peptide with anticancer properties, but the main drawback is its rapid enzymatic degradation and limited permeation across the cell membrane. This research aims to overcome these drawbacks by developing nisin-loaded nanoparticles (NPN) with improved cytotoxic effects. PLGA nanoparticles are one of the most effective biodegradable and biocompatible drug delivery carriers. In the present study, nisin-loaded nanoparticles showed enhanced anticancer effects. NPN was prepared by a double emulsion solvent evaporation method and characterized for different parameters. The cytotoxic investigation of NPN was carried out on various cell lines, including A549, SW-620, HT-29, PC-3, MDA-MB-231, MCF-7, MiaPaca-2, and fR2 by sulforhodamine B (SRB) assay. Mechanistic investigation of cellular cytotoxicity was performed by using bright-field microscopy, DAPI staining, intracellular reactive oxygen species (ROS), changes in mitochondrial membrane potential (ΔΨm), Western blotting and cellular uptake study. A comparative cytotoxicity study of nisin and NPN was performed on normal breast epithelial cells (fR2). NPN showed spherical shape, 289.09 ± 3.63 nm particle size, and 63.37 ± 3.12% entrapment efficiency. NPN was more cytotoxic to the MDA-MB-231 cell line, showing higher nuclear fragmentation, ROS generation, depletion of ΔΨm, and enhanced intracellular uptake with apoptosis signs compared with nisin and with no cytotoxicity on normal cells. The findings suggest that nisin delivery via PLGA nanoparticles can be used to treat cancer without significant effects on healthy cells. [ABSTRACT FROM AUTHOR]

Benzimidazolium salts (1a and 1b) and respective palladium complexes (2a and 2b) were prepared and characterized with 1H and 13C NMR, IR, elemental analysis as well as HRMS (for 2a). All target compounds were screened as potential anticancer agents against human cell lines for assessing their cytotoxicity. Heterocyclic organic compounds (1a and 1b) showed more cytotoxic activity than their complexes (2a and 2b) in the tested two cell lines. Particularly, a benzimidazolium salt including a 4-methylbenzyl group had a high cytotoxic potency towards MDA-MB-231 and DLD-1 cell lines with IC50 values comparable to a well-known anticancer drug cisplatin, which is generally used in clinical studies. Furthermore, a compound namely 1-(2-hydroxyethyl)-3-(2,3,4,5,6-pentamethylbenzyl)-1H-benzo[d]imidazol-3-ium bromide was found to be more cytotoxic activity in MDA-MB-231 cell line compared to cisplatin with following IC50 value of 7.59 ± 0.68 μM. [ABSTRACT FROM AUTHOR]

A series of novel acridine-thiazole bridged coumarin derivatives 3a–3i were designed, synthesized and subjected for their in-vitro antiproliferative activity on human breast cancer (MDA-MB-231), lung cancer (A-549) and colon cancer (HT29) cell lines. In case of human breast (MDA-MB-231) cell line, among the nine screened compounds, 3d, 3c, 3g, and 3a exhibited moderate to good antiproliferative activity with IC50 values in the range 14.06–8.03 µM concentration. The compound 3d exhibited higher activity with IC50 value 8.03 µg/mL, compared to 3c with IC50 value of 12.03 µg/mL. Whereas, compounds 3g, 3b, 3h, 3a, and 3i also exhibited significant cytotoxicity with IC50 values in the range 05.18–18.17 µM concentration. Further, the compound 3g exhibited distinct activity with IC50 value 05.18 µg/mL, followed by compound 3b with IC50value of 09.09 µg/mL for A-549 cancer cell line. However, for HT29 cell line all of the compounds showed significantly lesser activity when compared with standard drug Cisplatin. In addition, the synthesized compounds were screened for their anti-TB activity and its cytotoxicity, the compound 3g exhibited excellent antitubercular activity with MIC of 0.78 µg/mL, while the compound 3b exhibiting MIC of 1.56 µg/mL with the highest safety percentage survival of 72% and 78%. [ABSTRACT FROM AUTHOR]

A differential diet with royal jelly (RJ) during early larval development in honeybees shapes the phenotype, which is probably mediated by epigenetic regulation of gene expression. Evidence indicates that small molecules in RJ can modulate gene expression in mammalian cells, such as the fatty acid 10-hydroxy-2-decenoic acid (10-HDA), previously associated with the inhibition of histone deacetylase enzymes (HDACs). Therefore, we combined computational (molecular docking simulations) and experimental approaches for the screening of potential HDAC inhibitors (HDACi) among 32 RJ-derived fatty acids. Biochemical assays and gene expression analyses (Reverse Transcriptase – quantitative Polymerase Chain Reaction) were performed to evaluate the functional effects of the major RJ fatty acids, 10-HDA and 10-HDAA (10-hydroxy-decanoic acid), in two human cancer cell lines (HCT116 and MDA-MB-231). The molecular docking simulations indicate that these fatty acids might interact with class I HDACs, specifically with the catalytic domain of human HDAC2, likewise well-known HDAC inhibitors (HDACi) such as SAHA (suberoylanilide hydroxamic acid) and TSA (Trichostatin A). In addition, the combined treatment with 10-HDA and 10-HDAA inhibits the activity of human nuclear HDACs and leads to a slight increase in the expression of HDAC-coding genes in cancer cells. Our findings indicate that royal jelly fatty acids collectively contribute to HDAC inhibition and that 10-HDA and 10-HDAA are weak HDACi that facilitate the acetylation of lysine residues of chromatin, triggering an increase in gene expression levels in cancer cells. [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) and sirtuins (SIRTs) are important epigenetic regulators of cancer pathways. There is a limited understanding of how transcriptional regulation of their genes is affected by chemotherapeutic agents, and how such transcriptional changes affect tumour sensitivity to drug treatment. We investigated the concerted transcriptional response of HDAC and SIRT genes to 15 approved antitumor agents in the NCI-60 cancer cell line panel. Antitumor agents with diverse mechanisms of action induced upregulation or downregulation of multiple HDAC and SIRT genes. HDAC5 was upregulated by dasatinib and erlotinib in the majority of the cell lines. Tumour cell line sensitivity to kinase inhibitors was associated with upregulation of HDAC5, HDAC1, and several SIRT genes. We confirmed changes in HDAC and SIRT expression in independent datasets. We also experimentally validated the upregulation of HDAC5 mRNA and protein expression by dasatinib in the highly sensitive IGROV1 cell line. HDAC5 was not upregulated in the UACC-257 cell line resistant to dasatinib. The effects of cancer drug treatment on expression of HDAC and SIRT genes may influence chemosensitivity and may need to be considered during chemotherapy. [ABSTRACT FROM AUTHOR]

Context: Tabersonine has been investigated for its role in modulating inflammation-associated pathways in various diseases. However, its regulatory effects on triple-negative breast cancer (TNBC) have not yet been fully elucidated. Objective: This study uncovers the anticancer properties of tabersonine in TNBC cells, elucidating its role in enhancing chemosensitivity to cisplatin (CDDP). Materials and methods: After tabersonine (10 μM) and/or CDDP (10 μM) treatment for 48 h in BT549 and MDA-MB-231 cells, cell proliferation was evaluated using the cell counting kit-8 and colony formation assays. Quantitative proteomics, online prediction tools and molecular docking analyses were used to identify potential downstream targets of tabersonine. Transwell and wound-healing assays and Western blot analysis were used to assess epithelial–mesenchymal transition (EMT) phenotypes. Results: Tabersonine demonstrated inhibitory effects on TNBC cells, with IC50 values at 48 h being 18.1 μM for BT549 and 27.0 μM for MDA-MB-231. The combined treatment of CDDP and tabersonine synergistically suppressed cell proliferation in BT549 and MDA-MB-231 cells. Enrichment analysis revealed that the proteins differentially regulated by tabersonine were involved in EMT-related signalling pathways. This combination treatment also effectively restricted EMT-related phenotypes. Through the integration of online target prediction and proteomic analysis, Aurora kinase A (AURKA) was identified as a potential downstream target of tabersonine. AURKA expression was reduced in TNBC cells post-treatment with tabersonine. Discussion and conclusions: Tabersonine significantly enhances the chemosensitivity of CDDP in TNBC cells, underscoring its potential as a promising therapeutic agent for TNBC treatment. [ABSTRACT FROM AUTHOR]

Oestrogen related receptor α participated in the regulation of oxidative metabolism and mitochondrial biogenesis, and was overexpressed in many cancers including triple-negative breast cancer. A set of new ERRα inverse agonists based on p-nitrobenzenesulfonamide template were discovered and compound 11 with high potent activity (IC50 = 0.80 &#191'M) could significantly inhibit the transcription of ERRα-regulated target genes. By regulating the downstream signalling pathway, compound 11 could suppress the migration and invasion of the ER-negative MDA-MB-231 cell line. Furthermore, compound 11 demonstrated a significant growth suppression of breast cancer xenograft tumours in vivo (inhibition rate 23.58%). The docking results showed that compound 11 could form hydrogen bonds with Glu331 and Arg372 in addition to its hydrophobic interaction with ligand-binding domain. Our data implied that compound 11 represented a novel and effective ERRα inverse agonist, which had broad application prospects in the treatment of triple-negative breast cancer. [ABSTRACT FROM AUTHOR]

A series of sulfonamide benzoquinazolinones 5–18 was synthesized and evaluated for cytotoxic activity against MDA-MB-231 cell line. The compounds showed IC50 ranging from 0.26 to 161.49 µM. The promising compounds were evaluated for their inhibitory profile against epidermal growth factor (EGFR) and HER2 enzymes. Compound 10 showed more potent activity on both EGFR and HER2 than erlotinib (IC50 3.90 and 5.40 µM versus 6.21 and 9.42 µM). The pro-apoptotic activity of 10 was evaluated against caspase-3, Bax, B-cell lymphoma protein 2 (Bcl-2) expression levels, and cell cycle analysis. Compound 10 increased the level of caspase-3 by 10 folds, Bax level by 9 folds, decreased the level of the Bcl-2 by 0.14 and arrested the cell cycle in the G2/M phase. The radio-sensitizing activity of 10 was measured using a single dose of 8 Gy gamma radiation (IC50 decreased from 0.31 to 0.22 µM). Molecular docking was performed on EGFR and HER2 receptors. [ABSTRACT FROM AUTHOR]

Three aryl-tetralin-type lignans, including 2 previously undescribed compounds, were isolated from the root of Sanguisorba officinalis. The structures of the new compounds were elucidated by 1D- and 2D-NMR spectroscopic analyses and mass spectrometry. Experimental and calculated ECD were used to determine the absolute configurations. The isolated compounds were evaluated for cytotoxicity against two cell lines (MV4-11 and MDA-MB-231) and compound 1 exhibited moderate growth inhibition against MDA-MB-231 cell line with IC50 value of 15.76 μM. [ABSTRACT FROM AUTHOR]

We investigated the cytotoxic and apoptotic effects of a methanol extract of Centaurea nerimaniae, a plant endemic in Turkey, on HeLa and MDA-MB-231 cells. Eight concentrations of C. nerimaniae extract were applied to cells, and cytotoxic effects were measured using the xCELLigence system. The TUNEL assay was used to assess apoptotic cell death and immunohistochemistry was used to determine active caspase-3 using the effective cytotoxic doses of the extract. Doses of 1.42 mg/ml C. nerimaniae inhibited the growth of HeLa cells and 3.67 mg/ml C. nerimaniae inhibited the growth of MDA-MB-231 cells in a dose- and time-dependent manner. The apoptotic indexes for HeLa and MDA-MB-231 cells were increased significantly compared to control groups. Immunohistochemistry showed that the number of caspase-3 immunostained cells increased in the extract treatment groups for both HeLa and MDA-MB-231 cells. In the MDA-MB-231 cell line, caspase-3 immunostaining was observed in nuclei and/or cytoplasm in the extract treated group. Caspase-3 activation was greater in HeLa cells than in MDA-MB-231 cells. We found that the extract of C. nerimaniae had a strong antiproliferative effect and induced apoptosis via caspase-3; MDA-MB-231 cancer cells were more resistant than HeLa cells. [ABSTRACT FROM AUTHOR]

According to the cancer stem cell (CSC) theory, a small subset of cells with stem cell-like characteristics is responsible for tumor initiation, progression, and recurrence. CD44+/CD24- phenotype is assumed to be one of the main characteristics of the breast CSCs. We developed an MDA-MB-231 cell line overexpressing cell surface HER2 antigen for the evaluation of targeting efficiency of anti-HER2 nanobody (Nb)-conjugated polyamidoamine (PAMAM) polyplexes. Apoptosis-inducing tBid gene under control of CXCR1 promoter was delivered by this nanoparticle. Cellular uptake study showed higher uptake of Nb-targeted PAMAM carriers compared to non-targeted nanoparticles after 6 h of incubation. Gene expression analysis showed a significant rise in the expression of tBid in both MDA-MB-231/HER2+ and MDA-MB-231 compared to the two other cell lines. The same effect was observed after transfection with Nb-conjugated polyplexes within MDA-MB-231/HER2+ cell line compared to non-conjugated PAMAM polyplexes. We confirmed the killing efficiency of the gene construct in both MDA-MB-231/HER2+ and MDA-MB-231 cell lines by caspase 3 activity assay. These findings suggest that imposing pre-entry and post-entry restrictions on tBid killer gene might be a promising approach to specifically target the breast CSCs. [ABSTRACT FROM AUTHOR]

Herein, we report the synthesis of fluorescent 1,4-dihydropyridine-linked bis-triazoles (2a-2n) through Hantzsch synthesis by the condensation of o/m-chloro-substituted benzaldehyde, ethyl 3-oxo-4(prop-2-yn-1-yloxy)butanoate, and ammonium acetate in the presence of Ba(NO3)2 as a catalyst followed by the click reaction of resultant Hantzsch product (1) with various aromatic as well as aliphatic azides. All the synthesized compounds were well characterized by 1H-NMR, 13C-NMR, FTIR, and HRMS spectral techniques. Antibreast cancer evaluation of all the synthesized derivatives revealed that the compounds 2f (IC50 = 7 ± 0.02 µM) and 2g (IC50 = 5 ± 0.03 µM) showed better anticancer activity (lower IC50) than the standard drug tamoxifen (IC50 = 11.2 ± 0.01 µM) against breast carcinoma (MDA-MB-231) cell line. The synthesized compounds were also screened against normal human embryonic kidney (HEK-293) cell line and found to be nontoxic. The fluorescent nature and cytotoxicity assay of these newly synthesized hybrids recommend their utility in tumor cell imaging. [ABSTRACT FROM AUTHOR]

Murraya koenigii leaves are widely used as a spice and also have several biological activities. The major active constituents are carbazole alkaloids. Quantitation by HPLC or HPTLC requires pure marker compounds, whereas nuclear magnetic resonance spectroscopy can be used as a quantitative technique without the requirement of a pure marker compound. An alkaloid-rich fraction was prepared from the leaves and a validated qNMR method was developed for the quantitation of nine carbazole alkaloids, namely mahanimbine, girinimbine, koenimbine, koenine, kurrayam, mukonicine, isomahanimbine, euchristine B and bismahanine. One of the major compounds, koenimbine, was isolated and quantified by HPTLC to compare the results. The results obtained by qNMR were compared with the reported yields of these compounds. [ABSTRACT FROM AUTHOR]

Pseudobombax marginatum, popularly known as "embiratanha," is widely used by traditional communities as anti-inflammatory and analgesic agent. This study aimed to determine the phytochemical profile as well as cytotoxicity, acute oral toxicity, genotoxicity, and mutagenicity attributed to exposure to aqueous (AqEx) and ethanolic (EtEx) extracts of embiratanha bark. Phytochemical screening was conducted using thin-layer chromatography (TLC). Cell viability was analyzed using MTT assay with human mammary gland adenocarcinoma (MDA-MB-231) and macrophage (J774A.1) cell lines, exposed to concentrations of 12.5, 25, 50, or 100 µg/ml of either extract. For acute oral toxicity, comet assay and micronucleus (MN) tests, a single dose of 2,000 mg/kg of either extract was administered orally to Wistar rats. TLC analysis identified classes of metabolites in the extracts, including cinnamic acid derivatives, flavonoids, hydrolyzable tannins, condensed tannins, coumarins, and terpenes/steroids. In the cytotoxicity assay, the varying concentrations of extracts derived from embiratanha induced no significant alterations in the viability of MDA-MB-231 cells. The lowest concentration of EtEx significantly increased macrophage J774A.1 viability. However, the higher concentrations of AqEx markedly lowered macrophage J774A.1 viability. Animals exhibited no toxicity in the parameters analyzed in acute oral toxicity, comet assay, and MN tests. Further, EtEx promoted a significant reduction in DNA damage index and DNA damage frequency utilizing the comet assay, while the group treated with AqEx exhibited no marked differences. Thus, data demonstrated that AqEx or EtEx of embiratanha may be considered safe at a dose of 2,000 mg/kg orgally under our experimental conditions tested. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial function may be impaired in a number of diseases including metabolic syndrome, cardiovascular disease and endocrine disorders. Therefore it is important to be able to measure mitochondrial function in human cells. Purpose: The aim of the present study was to evaluate a method to measure mitochondrial function in human derived cells, which also would reflect regulation by thyroid hormones. Methods: The MDA-MB-231 cell line (a human breast cancer cell line) was incubated with bioactive iodothyronines (T4, 3′-3, 5-T3, 3, 5-T2) 50nmol/l for 3 h. Mitochondrial membrane potentials (MMP) were measured by a flow cytometer after staining with Tetramethylrhodamine methyl ester (TMRM). Also, the effect of TRIAC (a stimulator of thyroid hormone nuclear receptors) and L-Carnitine (an inhibitor of thyroid hormone passage into the nucleus) was examined. Findings: It was possible to measure mitochondrial membrane potential (MMP) in human derived cells and to examine thyroid hormone effects using flow cytometry. Bioactive iodothyronines increased mitochondrial membrane potential. TRIAC had no effect and L-Carnitine only inhibited T4 stimulation of membrane potential. Conclusion: Flow cytometry may be a valuable method for examining and testing mitochondrial function in human cells. Our findings demonstrate increase of mitochondrial membrane potential and an extra nuclear short time effect of 3, 5-T2 on mitochondrial activity. [ABSTRACT FROM AUTHOR]

Some novel chemically modified frameworks of ursolic acid have been designed and synthesized. The key step was the cycloaddition of azidopropyl-3β-hydroxy-urs-12-en-28-oate with the appropriate C28 propargyl esters of ursolic, corosolic, asiatic, oleanolic, and betulinic acid under Click reaction conditions, and the products were obtained in 74–84% yields. In view of their intriguing structural diversity, they have been subjected to detailed 1D and 2D NMR studies and their structures are thoroughly assigned. The synthesized compounds were screened for their anticancer potential against two human breast cancer cell lines (MCF-7 & MDA-MB-231) using sulforhodamine B cell proliferation assay. The GI50data revealed that the synthesized compounds exhibit highly potent activities against the two tested cell lines. Interestingly, the synthesized compounds showed selectivity and higher activity against MDA-MB-231 cell line than MCF-7. Among the tested compounds, compound17is the most potent one with GI50value of 1.4 ± 0.1 μM and showed 2.9 times more activity than the standard doxorubicin against MDA-MB-231. In addition,17arrests cells in mitotic phase of cell cycle, resulting in a change in cell phenotype. In view of the selective and highly promising activity against breast cancer cell lines, these compounds can serve as promising leads for further development. [ABSTRACT FROM PUBLISHER]

Two new cycloartane glycosides, cycloatriosides A and B (1–2), and a new oleanolic acid glycoside, thaliatrioside A (3), along with 7 known triterpenoids (4–10) were isolated from Thalictrum atriplex. The structures of the new compounds were established as 3-O-β-D-galactopyranosyl (20S, 24 R)-3β,16β,25,29-tetrahydroxy-20,24-epoxycycloartane-29-O-β-D-glucopyranoside (1), 3-O-β-D-glucopyranosyl-(1→2)-α-arabinopyranosyl-3β,22ξ,30-trihydroxycycloart-24-en-21-oic acid α-L-arabinopyranosyl-(1→6)-β-D-glucopyranoside (2) and 3-O-[α-L-rhamnopyranosyl-(1→3)-β-D-xylopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl]-oleanolic acid 28-O-β-D-glucopyranosyl ester (3) on the basis of extensive NMR and HR-ESI-MS analyses, along with acid hydrolysis. Their cytotoxic activities against human lung cancer cells A549 and human breast cancer cells MDA-MB-231 were evaluated using MTT method. Compound 9 showed cytotoxicity against MDA-MB-231 cell line with the IC50 value of 72.53 ± 1.08 μM. [ABSTRACT FROM AUTHOR]

Treatment of patients with triple-negative breast cancer (TNBC) is challenging due to the absence of well- defined molecular targets and the heterogeneity of such disease. In our endeavor to develop potent isatin-based anti-proliferative agents, we utilized the hybrid-pharmacophore approach to synthesize three series of novel isatin-based hybrids5a–h,10a–hand13a–c, with the prime goal of developing potent anti-proliferative agents toward TNBC MDA-MB-231 cell line. In particular, compounds5eand10gwere the most active hybrids against MDA-MB-231 cells (IC50 = 12.35 ± 0.12 and 12.00 ± 0.13 μM), with 2.37- and 2.44-fold increased activity than 5-fluorouracil (5-FU) (IC50 = 29.38 ± 1.24 μM). Compounds5eand10ginduced the intrinsic apoptotic mitochondrial pathway in MDA-MB-231; evidenced by the reduced expression of the anti-apoptotic protein Bcl-2, the enhanced expression of the pro-apoptotic protein Bax and the up-regulated active caspase-9 and caspase-3 levels. Furthermore,10gshowed significant increase in the percent of annexin V-FITC positive apoptotic cells from 3.88 to 31.21% (8.4 folds compared to control). [ABSTRACT FROM PUBLISHER]

Context: The use of graphene oxide (GO) in biomedicine and cancer therapy has increased significantly owing to its unique physical and chemical properties. As a consequence, the toxicity of GO in the environment and in humans has garnered more and more attention. Objective: In this paper, we studied the potential cytotoxicity of GO nanosheets via examining the effect of GO on the viability, cellular colony formation and proliferation of a human breast cancer MDA-MB-231 cell line, which was an ideal model used to study breast diseasein vitro. Methods and results: The results suggested that higher concentrations of GO (≥100 μg/mL) exhibited time- and dose-dependent cytotoxicity against MDA-MB-231 cells, suppressed the colony-forming capacity and cellular proliferation. Moreover, higher concentrations of GO increased the proportion of G0/G1 phase cells and induced the LDH release, as well as the generation of intracellular ROS which was also remarkably increased and may directly related with cytotoxicity. Conclusion: Together, the above results suggested that GO can induce cytotoxicity against human breast cancer MDA-MB-231 cells probably due to the cellular ROS generation, which providing useful toxicity and mechanism information that can help to better inform safety assessments of GO. [ABSTRACT FROM PUBLISHER]

Four ball-type phthalocyanines (H22c, MgPc, CoPc, and ZnPc) containing 4-tert-butylcatechol substituents at alpha-positions were synthesized from 3,3'-(4-tert-butyl-1,2-phenylene)bis(oxy)diphthalonitrile. The structures were elucidated by elemental analysis and ultraviolet-visible, Fourier-transform infrared, proton nuclear magnetic resonance, and Maldi-Tof mass spectroscopies. The photophysicochemical properties of H2Pc, MgPc, and ZnPc were investigated in dimethylsulphoxide. The fluorescence quantum yields (FF), triplet state quantum yields (ΦT), and singlet oxygen quantum yields (ΦΔ) with respect to H2Pc, MgPc and ZnPc were experimentally obtained. Furthermore, the degradation quantum yield (Φd) was evaluated for all complexes. Finally, the magnetic circular dichroism spectra of the four Pcs were obtained. Among these ball-type phthalocyanines, MgPc had the highest triplet lifetime and ZnPc had the highest singlet oxygen quantum yield. Moreover, the in vitro antiproliferative effect of ball-type phthalocyanines (H2Pc, MgPc, CoPc, and ZnPc) was evaluated on MCF-7 cell line originated from luminal A breast cancer and MDA-MB-231 cell line originated from triple negative breast cancer. For this purpose, cell viability MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used. For all compounds, 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, 12.8, 25.6, 51.2, 102.4 µM concentrations were applied to both cell lines. There was a significant decrease in cell viability for MCF-7 and MDA-MB-231 cells (p<0.05). [ABSTRACT FROM AUTHOR]

Cytokine-Induced Killer (CIK) cells share several functional and phenotypical properties of both T and natural killer (NK) cells. They represent an attractive approach for cell-based immunotherapy, as they do not require antigen-specific priming for tumor cell recognition, and can be rapidly expanded in vitro. Their relevant expression of FcγRIIIa (CD16a) can be exploited in combination with clinical-grade monoclonal antibodies (mAbs) to redirect their lytic activity in an antigen-specific manner. Here, we report the efficacy of this combined approach against triple negative breast cancer (TNBC), an aggressive tumor that still requires therapeutic options. Different primitive and metastatic TNBC cancer mouse models were established in NSG mice, either by implanting patient-derived TNBC samples or injecting MDA-MB-231 cells orthotopically or intravenously. The combined treatment consisted in the repeated intratumoral or intravenous injection of CIK cells and cetuximab. Tumor growth and metastasis were monitored by bioluminescence or immunohistochemistry, and survival was recorded. CIK cells plus cetuximab significantly restrained primitive tumor growth in mice, either in patient-derived tumor xenografts or MDA-MB-231 cell line models. Moreover, this approach almost completely abolished metastasis spreading and dramatically improved survival. The antigen-specific mAb favored tumor and metastasis tissue infiltration by CIK cells, and led to an enrichment of the CD16a+ subset. Data highlight the potentiality of this novel immunotherapy strategy where a nonspecific cytotoxic cell population can be converted into tumor-specific effectors with clinical-grade antibodies, thus providing not only a therapeutic option for TNBC but also a valid alternative to more complex approaches based on chimeric antigen receptor-engineered cells. ACT, Adoptive Cell Transfer; ADCC, Antibody-Dependent Cell-mediated Cytotoxicity; ADP, Adenosine diphosphate; BLI, Bioluminescence Imaging; CAR, Chimeric Antigen Receptor; CIK, Cytokine Induced Killer cells; CTX, Cetuximab; DMEM, Dulbecco's Modified Eagle Medium; EGFR, Human Epidermal Growth Factor 1; ER, Estrogen; FBS, Fetal Bovine Serum; FFPE, Formalin-Fixed Paraffin-Embedded; GMP, Good Manufacturing Practices; GVHD, Graft Versus Host Disease; HER2, Human Epidermal Growth Factor 2; HRP, Horseradish Peroxidase; IFN-γ, Interferon-γ; IHC, Immunohistochemistry; IL-2, Interleukin-2; ISO, Irrelevant antibody; i.t., intratumoral; i.v., intravenous, mAbs, Monoclonal Antibodies; mIHC, Multiplex Fluorescence Immunohistochemistry; MHC, Major Histocompatibility Complex; NK, Natural Killer; NKG2D, Natural-Killer group 2 member D; NSG, NOD/SCID common γ chain knockout; PARP, Poly ADP-ribose polymerase; PBMCs, Peripheral Blood Mononuclear Cells; PBS, Phosphate-buffered saline; PDX, Patient-derived xenograft; PR, Progesterone; rhIFN-γ, Recombinant Human Interferon-γ; RPMI, Roswell Park Memorial Institute; STR, Short tandem Repeat; TCR, T Cell Receptor; TNBC, Triple Negative Breast Cancer; TSA, Tyramide Signal Amplification [ABSTRACT FROM AUTHOR]

The surface-functionalised gelatin nanoparticles (GNPs) containing cisplatin were developed and characterised for breast cancer targeting using fibroblast growth factor-2 (FGF2) receptors which are overexpressed on breast cancer cells. The GNPs were prepared using two-step desolvation method and then the surface of GNPs was functionalised with activated heparin. They were characterised for surface morphology, particle size and size distribution, surface charge, entrapment efficiency and in vitro drug release. The results revealed that the mean diameter of GNPs was 173 ± 2.2 nm with smooth surface, which was increased to 189 ± 3.4 nm after coupling with heparin (H-GNPs). The targeting effect of H-GNPs and GNPs was investigated by in vitro cell uptake study on human breast cancer MDA-MB-231 cell line, which exhibited greater uptake of H-GNPs as compared to GNPs. Therefore, it is suggested that H-GNPs can be used as an effective carrier for solid tumour targeting. [ABSTRACT FROM AUTHOR]

Chemical composition, antioxidant, anticancer, and antimacrobial activities of essential oil obtained from leaves of Rumex nervosus has been evaluated here for the first time. GC/MS analysis reveals the presence of Palmitoleic Acid (28.35%) and Palmitic acid, (25. 37%) as their methyl ester as major components. The essential oil showed significant DPPH radical scavenging activity (94.907 ± 0.1089% and 94.003 ± 0.0749%) at concentration (100 and 80) μg/mL respectively. The oil showed promising activity against staph aureus, while showed weak activity against (Hela and 3T3) cell lines. The crude extract / fractions of R. nervosus (leaves) showed significant antioxidant activity at dose (100 and 80) μg/mL. Futhermore the crude showed significant activity against (MCF-7 and MDA-MB-231) cell lines with IC50 (20.5138 ± 0.933 and 25.1728 ± 0.9176) μg/mL respectively, and chloroform fraction showed good activity against (MCF-7 and MDA-MB-231) cell lines with IC50 (31.154 ± 0.965 and 42.269 ± 2.1045) μg/mL. [ABSTRACT FROM AUTHOR]

To investigate the role of estrogen and estrogen receptor (ER) during benzo[a]pyrene (BaP) carcinogenesis, BaP–DNA adduct formation, and DNA synthesis were examined in ER-positive, MCF-7, and ER-negative, MDA-MB-231, human breast cancer cell lines. In MCF-7, the ER-positive human breast cancer cell line, treated with BaP, the formation of BaP–DNA adducts and DNA synthesis were inhibited in a concentration-responsive manner, but there was no change in MDA-MB-231, the ER-negative cell line. In the [ 3 H]BaP–DNA binding assay, an increase of BaP–DNA adduct formation was observed with 17β-estradiol (E 2 )-induced ERα. Treatments of [ 3 H]BaP in conjunction with the E 2 induced a 2.1-fold increase in BaP–DNA adduct over BaP alone in the ER-positive MCF-7 cell line. In addition, the antiestrogen tamoxifen (TAM) blocked this effect by 82%, while E 2 produced no change in the ER-negative MDA-MB-231 cell line. These observations suggest that the increased formation of BaP–DNA adducts may be mediated through the ERα expressed by E 2 . [ABSTRACT FROM AUTHOR]

This study was set to study the anti-proliferative effects of secoxyloganin in MDA-MB-231 breast cancer cells. The MTT cell viability assay results demonstrated that secoxyloganin significantly (p < 0.05) inhibited the growth of the MDA-MB-231 cells with an IC50 of 6.5 μM which was significantly (p < 0.05) lower than the IC50 of 38 μM against the normal fR2 cells. Unveiling of molecular mechanism revealed that secoxyloganin disrupted the DNA integrity of MDA-MB-231 cells and triggered apoptosis. Annexin V/PI staining revealed that the percentage of apoptotic MDA-MB-231 cells increased from 3.7% in control to 40.2% at 24 μM of secoxyloganin. This was accompanied by an enhancement of Bax, and suppression of Bcl-2. The effects of secoxyloganin on the distribution of cells in various cell cycle phases was also assessed. The results showed the proportion of cells in the G0/G1 phase increased from 32.76% in control to 77.50% at 24 μM of secoxyloganin suggesting G0/G1 cell cycle arrest. This was also associated with suppression of cyclin D2 expression. Taken together, these findings demonstrate the anticancer properties of secoxyloganin through cell cycle arrest and apoptosis. [ABSTRACT FROM AUTHOR]

Triple-negative breast Cancer (TNBC) is an aggressive subtype lacking estrogen, progesterone, and HER2 receptors. Known for limited targeted therapies, it poses challenges and requires personalized treatment strategies. Differential analysis revealed a significant decrease in keratin 81 (KRT81) expression in non-TNBC samples and an increase in TNBC samples, lower KRT81 expression correlated with better TNBC patient outcomes. It emerged as an independent predictive factor for TNBC, with associations found between its expression and clinically relevant features. We further developed a nomogram for survival probability assessment based on Cox regression results, demonstrating its accuracy through calibration curves. Gene annotation analysis indicated that KRT81 is involved in immune-related pathways and tumor cell adhesion. KRT81 is associated with immune cell infiltration of Follicular helper T cells (Tfh) and CD8 + T cells, suggesting its potential impact on the immunological microenvironment. The study delved into KRT81's predictive value for immunotherapy responses, high expression of KRT81 was associated with greater potential for immune evasion. Single-cell RNA sequencing analysis pinpointed KRT81 expression within a specific malignant subtype which was a risk factor for TNBC. Furthermore, KRT81 promoted TNBC cell proliferation, migration, invasion, and adhesion was confirmed by gene knockout or overexpression assay. Co-culture experiments further indicated KRT81's potential role in inhibiting CD8 + T cells, and correlation analysis implied KRT81 was highly correlated with immune checkpoint CD276, providing insights into its involvement in the immune microenvironment via CD276. In conclusion, this comprehensive study positions KRT81 as a promising prognostic marker for predicting tumor progression and immunotherapy responses in TNBC. [ABSTRACT FROM AUTHOR]

In eukaryotes, the ribosomal small subunit (40S) is composed of 18S rRNA and 33 ribosomal proteins. 18S rRNA has a special secondary structure and is an indispensable part of the translation process. Herein, a special sequence located in mammalian 18S rRNA named Poly(G)7box, which is composed of seven guanines, was found. Poly(G)7 can form a special and stable secondary structure by binding to the translation elongation factor subunit eEF1D and the ribosomal protein RPL32. Poly(G)7box was transfected into cells, and the translation efficiency of cells was inhibited. We believe that Poly(G)7box is an important translation-related functional element located on mammalian 18S rRNA, meanwhile the Poly(G)7 located on mRNA 5' and 3' box does not affect mRNA translation. [ABSTRACT FROM AUTHOR]

sh-oligopeptide-1 is a cosmetic that is considered to be the bioequivalent of the Epidermal Growth Factor (EGF). The systematic search and selection of the information available on sh-oligopeptide-1, and field research on laboratories manufacturing cosmetics and the legal regulation of their products. Specialised search in Medline and Google Scholar (March 2023). A total of 22 references were obtained and 12 articles were selected for analysis, 7 of which were included in Medline. 9 articles correspond to clinical trials that use sh-oligopeptide-1 as equivalent to a functional recombinant human EGF (hr-EGF). The manufacturers are investigated and they are requested to provide scientific information. Using an inactive ingredient, clinical trials are published with favourable results in order to treat diabetics and cancer patients. These trials do not follow medical standards. Active EGF is not a cosmetic, rather it is a potent unauthorised drug. Likewise, sh-oligopeptide-1 is not a functional EGF, and it is not authorised for medical treatments. Topical hr-EGF is not authorised as a medication in any concentration, except for clinical trials. However, sh-EGF (sh-oligopeptide-1) is authorised as a cosmetic in several different concentrations for generalised use, with unknown long-term risks. Clinical studies on sh-oligopeptide-1 have no scientific basis, as the preclinical bioactivity of this molecule has not been proven. [ABSTRACT FROM AUTHOR]

The Mannich reaction is commonly used to introduce N atoms into compound molecules and is thus widely applied in drug synthesis. The Mannich reaction accounts for a certain proportion of structural modifications of natural products. The introduction of Mannich bases can significantly improve the activity, hydrophilicity, and medicinal properties of compounds; therefore, the Mannich reaction is widely used for the structural modification of natural products. In this paper, the application of the Mannich reaction to the structural modification of natural products is reviewed, providing a method for the structural modification of natural products. [ABSTRACT FROM AUTHOR]

Boronic acids/esters have recently emerged in the field of medicinal and pharmaceutical research due to their exceptional oxophilicity, low toxicity, and unique structure. They are known as potent enzyme inhibitors, cancer therapy capture agents, and can mimic certain types of antibodies to fight infections. They have been designed and developed into drugs, and this approach has emerged in the last 20 years. Five boronic acid drugs have been approved by the FDA and Health Canada, two of which are used to treat cancer, specifically multiple myeloma. The purpose of this review is to investigate boronic acid/ester derivatives as potential pharmaceutical agents as well as the mechanism of action. It will concentrate on six types of cancer: multiple myeloma, prostate cancer, breast cancer, lung cancer, cervical cancer, and colon cancer. Some newly developed boron-containing compounds have already demonstrated highly promising activities, but further investigation is required before final conclusions can be drawn. [ABSTRACT FROM AUTHOR]

In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide isomerase (PDI, EC 5.3.4.1) inhibitors. The inhibitory activity on PDI was determined against recombinant human PDIA1 and PDIA3 proteins using an insulin reduction assay. These compounds in low micromolar to low nanomolar concentrations showed the effective in vitro inhibitory properties of PDIA1 with weaker effects on PDIA3. Complexes of 15N- and 15N,13C- uniformly labelled recombinant human PDIA1a with two PDIA1 inhibitors were produced and investigated by a protein nuclear magnetic resonance (NMR) spectroscopy. It was found that both C53 and C56 of the PDIA1 enzyme were involved in covalent binding. Finally, in a range of pharmacological studies, we demonstrated that investigated compounds displayed anti-cancer and anti-thrombotic activity. These findings demonstrate that sulphonamides of Az-COOH derivatives are promising candidates for the development of novel anti-cancer and anti-thrombotic agents. [ABSTRACT FROM AUTHOR]

A series of 1H-benzo[f]chromene moieties (4a–z) were synthesised under Ultrasonic irradiation and confirmed with spectral analyses. Derivative 4i solely possessed an X-ray single crystal. The anti-proliferative efficacy of the desired molecules has been explored against three cancer cells: MCF-7, HCT-116, and HepG-2 with the cytotoxically active derivatives screened against MCF-7/ADR and normal cells HFL-1 and WI-38. Furthermore, compounds 4b–d, 4k, 4n, 4q, and 4w, which possessed good potency against MCF-7/ADR, were tested as permeability glycoprotein (P-glycoprotein [P-gp]) expression inhibitors. The attained data confirmed that 4b–d, 4q, and 4w exhibited strong expression inhibition against the P-gp alongside its cytotoxic effect on MCF-7/ADR. The western blot results and Rho123 accumulation assays showed that compounds 4b–d, 4q, and 4w effectively inhibited the P-gp expression and efflux function. Meanwhile, 4b–d, 4q, and 4w induced apoptosis and accumulation of the treated MCF-7/ADR cells in the G1 phase and 4k and 4n in the S phase of the cell cycle. [ABSTRACT FROM AUTHOR]

Propolis is a resinous substance from beehive produced by the combination of plants and bee secretions. For a long time, this substance has gotten high attention in traditional and modern medicine. The aim of this review was to discuss the recent advances in the chemical composition and biological activities of propolis. The search for recent publications was based on several databases, such as PubMed, Google Scholar, Science-Direct, and Web of Sciences using relevant keywords. Literature data showed that several new compounds have recently been identified in propolis. The most important biological properties of propolis were discussed in this review, namely antibacterial, antiparasitic, antiviral, antioxidant, antileishmanial, anti-inflammatory, antidiabetic, immunomodulatory, and anticancer. In terms of safety, the data showed low toxicity of propolis even at high doses. Overall, propolis can be considered a promising source of bioactive compounds for drug development. [ABSTRACT FROM AUTHOR]

PI3K/Akt/mTOR pathway activation causes relapse and resistance after radiotherapy in breast cancer (BC). We aimed to radiosensitize BC cell lines to irradiation (IR) by PKI-402, a dual PI3K/mTOR inhibitor. We performed cytotoxicity, clonogenicity, hanging drop, apoptosis and double-strand break detection, and phosphorylation of 16 essential proteins involved in the PI3K/mTOR pathway. Our findings showed that PKI-402 has cytotoxic efficiency in all cell lines. Clonogenic assay results showed that PKI-402 plus IR inhibited the colony formation ability of MCF-7 and breast cancer stem cell lines. Results showed that PKI-402 plus IR causes more apoptotic cell death than IR alone in the MCF-7 cells but did not cause significant changes in the MDA-MB-231. γ-H2AX levels were increased in MDA-MB-231 in PKI-402 plus IR groups, whereas we did not observe any apoptotic and γ-H2AX induction in BCSCs and MCF-10A cells in all treatment groups. Some pivotal phosphorylated proteins of the PI3K/AKT pathway decreased, several proteins increased and others did not change. In conclusion, if the combined use of PKI-402 with radiation is supported by in vivo studies, it can contribute to the treatment options and the course of the disease. [ABSTRACT FROM AUTHOR]

Current conventional therapy for colorectal cancer includes surgery, radiation and chemotherapy, all of which produce side effects. Herbal medicine can control the side effects of conventional treatments. We investigated the synergistic effect of a mixture of Zingiber officinale Roscoe (Ginger) and Ganoderma lucidum extracts on colorectal cancer cell apoptosis in vitro. We prepared ethanolic extracts of ginger (GEE) and G. lucidum (GLEE). Cytotoxicity was evaluated using MTT assay and the half-maximal inhibitory concentration (IC50) of each extract was calculated. The effect of these extracts on apoptosis in cancer cells was assessed using flow cytometry; Bax, Bcl2 and caspase-3 gene expression was evaluated using real-time PCR. GEE and GLEE decreased CT-26 cell viability significantly in a dose-dependent manner; however, the combined application of GEE + GLEE was most effective. Bax:Bcl-2 gene expression ratio, caspase-3 gene expression and the number of apoptotic cells were increased significantly in CT-26 cells treated at the IC50 level of each compound, especially in the GEE + GLEE treatment group. Combined ginger and Ganoderma lucidum extracts exhibited synergistic antiproliferative and apoptotic effects on colorectal cancer cells. [ABSTRACT FROM AUTHOR]

Heterocyclic compounds are an essential part of drug design and discovery. The pharmaceutical industry uses and investigates nitrogen-containing heterocycles because they are crucial in discovering and developing novel therapeutic compounds. Due to their diverse pharmacological potentials, benzimidazole derivatives have been widely useful in medicinal chemistry over the past few decades. Similarly, indole derivatives also possess a wide range of biological potential. It is observed that compounds incorporating two or more structural moieties in a single hybrid structure are always known to have a wide range of pharmacological activities. Thus, the pharmacological properties of benzimidazole scaffolds can be improved by incorporating indole moieties. The present review demonstrates the recent development in pharmacology and structure-activity relationships of indole-benzimidazole hybrid derivatives. It may help researchers and computational chemists to find the lead structures associated with indole-benzimidazole in drug discovery and design. [ABSTRACT FROM AUTHOR]