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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]

Novel coumarin derivatives were synthesised and tested for their cytotoxicity against human cancer cells (PC-3 and MDA-MB-231). Compounds 5, 4b, and 4a possessed potent cytotoxic activity against PC-3 cells with IC50 3.56, 8.99, and 10.22 µM, respectively. Compound 4c displayed cytotoxicity more than erlotinib in the MDA-MB-231 cells with IC50 8.5 µM. Moreover, compound 5 exhibited potent inhibitory activity on EFGR with IC50 0.1812 µM, as well as PI3Kβ inhibitory activity that was twofold higher than LY294002, suggesting that this compound has a dual EGFR and PI3Kβ inhibiting activity. Docking aligns with the in vitro results and sheds light on the molecular mechanisms underlying dual targeting. Furthermore, compound 5 decreased AKT and m-TOR expression in PC-3 cells, showing that it specifically targets these cells via the EGFR/PI3K/Akt/m-TOR signalling pathway. Simultaneously, compound 5 caused cell cycle arrest at S phase and induced activation of both intrinsic and extrinsic apoptotic pathways. [ABSTRACT FROM AUTHOR]

Targeting Heat shock protein 90 (HSP90) C-terminus is an important strategy to develop HSP90 inhibitors without inducing heat shock response. The development of C-terminal inhibitors, however, is hampered by a lack of understanding regarding the interaction between the HSP90 C-terminus and the present inhibitors. We collected seven classical and structurally diverse HSP90 C-terminal inhibitors and constructed a ligand-based pharmacophore model. The subsequent virtual screening and structural optimisation led to the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors. 9 and 27 exhibited strong antitumour activity in vitro by inhibiting proliferation and inducing apoptosis in multiple cancer cell lines. These compounds disrupted the interaction between HSP90 C-terminus and peptidylprolyl isomerase D, exerting a stronger inhibitory effect than novobiocin. 27 significantly induced the degradation of HSP90 clients without triggering heat shock response. In an in vivo study using 4T1 mice breast cancer models, 9 showed a potent antitumour effect without obvious toxicity. [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]

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]

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]

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]

Edible flowers are attracting special therapeutic attention and their administration is on the rise. Edible flowers play pivotal modulatory roles on oxidative stress and related interconnected apoptotic/inflammatory pathways toward the treatment of cancer. In this review, we highlighted the phytochemical content and therapeutic applications of edible flowers, as well as their modulatory potential on the oxidative stress pathways and apoptotic/inflammatory mediators, resulting in anticancer effects. Edible flowers are promising sources of phytochemicals (e.g., phenolic compounds, carotenoids, terpenoids) with several therapeutic effects. They possess anti-inflammatory, anti-diabetic, anti-microbial, anti-depressant, anxiolytic, anti-obesity, cardioprotective, and neuroprotective effects. Edible flowers potentially modulate oxidative stress by targeting erythroid nuclear transcription factor-2/extracellular signal-regulated kinase/mitogen-activated protein kinase (Nrf2/ERK/MAPK), reactive oxygen species (ROS), nitric oxide (NO), malondialdehyde (MDA) and antioxidant response elements (AREs). As the interconnected pathways to oxidative stress, inflammatory mediators, including tumor necrosis factor (TNF)-α, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interleukins (ILs) as well as apoptotic pathways such as Bcl-2-associated X protein (Bax), Bcl-2, caspase and cytochrome C are critical targets of edible flowers in combating cancer. In this regard, edible flowers could play promising anticancer effects by targeting oxidative stress and downstream dysregulated pathways. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer in women ın the world. Many anticancer drugs are currently used clinically have been isolated from plant species or are based on such substances. Linalool is aromatic compounds from the monoterpene group. It is the main constituents of essential oils and show antiproliferative, antioxidant, and antiseptic properties. The aim of this study was to investigate the antiproliferativeand apoptotic, effects of linalool in MCF-7 and MDA-MB-231 human breast cancer cells. MCF-7 and MDA-MB-231 human breast cancer cells were treated with different concentrations of linalool (100, 200, 400, 600, 800, 1000 µM) at 24 h and 48 h. MTT assay for cell proliferation and Annexin V assay for apoptosis was done. The morphology of breast cancer cells was investigated by lıght mıcroscope and scanning electron microscope (SEM). The study show that linalool significantly induced apoptosis in all groups as dose and time-dependent (p <.05). Linalool has apoptotic and antiproliferative properties in a concentration and time-dependent manner in breast cancer cells. The cytotoxic effects of linalool on MCF-7 and MDA-MB-231 human breast cancer cells was found to be associated with apoptotic cell death. Linalool was more effective on MCF-7 human breast cancer cells in smaller amounts. [ABSTRACT FROM AUTHOR]

Puffballs are a class of fungi widely distributed worldwide and associated with various bioactivities. This research mainly showed the antitumor bioactivity of extracts from Calvatia lilacina (CL), which is a common variety of puffballs. NMR and high-performance liquid chromatography methods are used to characterize the extracts. Results showed that CL extracts obtained with petroleum ether, ethyl acetate, ethanol, and water elicited obvious inhibitory effects on the proliferation of A549, Caco-2, and MDA-MB-231. Among these extracts, petroleum ether extract demonstrated the highest performance. This extract was then separated into seven sub-fractions (SFs). Three of these SFs (3#, 6#, and 7#) induces a decrease in the viability of MDA-MB-231 cells in which 7# SF exhibited the highest cytotoxicity, where the major component was found to be ergosta-7,22-dien-3-one. Further tests revealed that 7# SF from petroleum ether extract could trigger severe cell death in human breast cancer cells (MDA-MB-231) by activating the apoptotic pathway dependent on mitochondrial reactive oxygen species and caspase activation. All these results in combination indicate that the mechanism of extract-potentiated apoptosis associates closely with ROS-dependent mitochondrial dysfunction events which further induces mitochondria-mediated intrinsic cytochrome C-caspase-related pathway of apoptosis. Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.1936576 [ABSTRACT FROM AUTHOR]

This systematic review was performed with a focus on the effects of quercetin (QT) on the human breast cancer cell lines MCF-7 and MDA-MB-231. PubMed, Scopus, Science Direct, and Google Scholar databases were searched up to May 2020 using relevant keywords. All articles written in English evaluating the effects of QT on the human breast cancer cell lines MCF-7 and/or MDA-MB-231 were eligible for the review. Totally, 31 articles were included in this review. Out of them, 23 studies investigated the effects of QT on MCF-7 cells and indicated that QT induces apoptosis in the cells. Of 15 studies that examined the effects of QT on MDA-MB-231 cells, 14 reports showed successful apoptosis. It is concluded that QT might be beneficial in the eliminating of breast cancer cells. However, further clinical trials are warranted to further verify these outcomes. [ABSTRACT FROM AUTHOR]

Pterostilbene is a natural nonflavonoid polyphenolic compound. It shows a remarkable range of biological activities, including antiproliferative, antiinflammatory, and antioxidant activity. However, the mechanism of action of PT in breast cancer cells containing mutant p53 protein has not been fully elucidated. Therefore, the present study was aimed at investigating the influence of PT on signaling pathways involved in the apoptosis of mutant p53-breast cancer cell lines. Immunocytochemistry and Western Immunoblotting techniques were used in this study. The present data showed that the viabilities and the proliferations of MDA-MB-231 and T-47D decreased significantly (P < 0.001) after treatment with different concentrations of PT. In addition, the morphological characteristics of both cell lines were changed after treatment with PT. Decreased protein expression of mutant p53 (R280 K, L194F) in MDA-MB-231 and T-47D breast cancer cell lines has also been achieved. In addition, overexpression of pro-apoptotic (Bax) protein, caspase-3 activity and histone release were increased after treatment of both cell lines with different PT concentrations. Furthermore, the protein expressions of cyclin D1, mTOR, and oncogenic β-catenin were significantly downregulated after treatment of both cell lines with PT. In conclusion, downregulations of protein expression of mutant p53, cyclin D1, mTOR, and β-catenin were increased after both cell lines had been treated with pterostilbene. PT could point to a promising use against the development and the progression of breast cancer as a natural therapeutic agent. [ABSTRACT FROM AUTHOR]

The present study is aimed to formulate baicalein-loaded mixed micelles to enhance the solubility and oral bioavailability. Baicalein encapsulated D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and pluronic F127 (F127) combined micelles were prepared and investigated for anticancer effect. The optimized formulation contains 25.04 ± 0.24 nm mean particle size of micelles with a zeta potential value of −4.01 ± 0.5 mV. The calculated entrapment efficiency percentage of baicalein within the micellar structure was 83.43 ± 0.13% and the in vitro release of baicalein from micelles displayed a sustained release profile at pH 7.4. The incorporation of baicalein within micelles core was also confirmed by FTIR analysis of formulation, which hardly represents the characteristic peak of baicalein, indicating successful entrapment of the drug. In vitro cell culture experiments revealed baicalein-loaded micelles significantly enhanced cellular uptake and cytotoxicity against MDAMB-231 cell lines in comparison to free baicalein. Additionally, as compared to free baicalein, baicalein micelles demonstrated greater apoptosis-inducing potential while the results of the cell cycle study exhibited arrest of cells at the G0/G1 phase of the cell cycle. Results of ROS (reactive oxygen species) and MMP (mitochondrial membrane potential) assay revealed the ROS-dependent mitochondrial-mediated apoptosis pathway utilized by developed formulation to inhibit cell proliferation. Thus, the developed nano micelles can serve as a potent carrier system for baicalein against breast cancer. [ABSTRACT FROM AUTHOR]

Solanum chacoense (wild potato) is intensively used in breeding, its biochemical profile and putative human health-related traits being transferred into potato cultivars aimed for consumption. The goal of this study was to evaluate the biochemical profile and the anti-tumor potential of methanolic extracts obtained from S. chacoense leaves and tubers against three breast cancer cell lines in comparison to healthy endothelial cells (HUVEC). The biochemical profile of the extracts was determined by HPLC-PDA/-ESI+-MS and ITEX/GC-MS, the selective cytotoxicity by MTT assay whereas RT-qPCR was used to evaluate the expression of proliferation- and apoptosis-related genes. Both extracts proved to be rich in phenolic acids and volatile compounds, the leaf extract also containing glycoalkaloids. Both extracts proved to be cytotoxic for breast cancer cell lines, with IC50 values varying between 132.9 and 390.7 µg/ml. Both extracts had selective cytotoxicity against MCF7 cell line in comparison to HUVECs (selectivity coefficients >2.3). The treatment with the extracts induced overexpression of the pro-apoptotic gene BAX¸ down-regulation of the anti-apoptotic gene BCL-2 and the pro-proliferation genes NFkB, CCND1, and STAT3. Thus S. chacoense extracts proved to be rich in compounds with anticancer proprieties and are capable of inducing selective cytotoxicity on MCF7 cell line. [ABSTRACT FROM AUTHOR]

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field. [ABSTRACT FROM AUTHOR]

As a continuation for our previous work, a novel set of N-alkylindole-isatin conjugates (7, 8a–c, 9 and 10a–e) is here designed and synthesised with the prime aim to develop more efficient isatin-based antitumor candidates. Utilising the SAR outputs from the previous study, our design here is based on appending four alkyl groups with different length (ethyl and n-propyl), bulkiness (iso-propyl) and unsaturation (allyl) on N-1 of indole motif, with subsequent conjugation with different N-unsubstituted isatin moieties to furnish the target conjugates. As planned, the adopted strategy achieved a substantial improvement in the growth inhibitory profile for the target conjugates in comparison to the reported lead VI. The best results were obtained with N-propylindole –5-methylisatin hybrid 8a which displayed broad spectrum anti-proliferative action with efficient sub-panel GI50 (MG-MID) range from 1.33 to 4.23 µM, and promising full-panel GI50 (MG-MID) equals 3.10 µM, at the NCI five-dose assay. Also, hybrid 8a was able to provoke cell cycle disturbance and apoptosis in breast T-47D cells as evidenced by the DNA flow cytometry and Annexin V-FITC/PI assays. Furthermore, hybrid 8a exhibited good inhibitory action against cell cycle regulator CDK2 protein kinase and the anti-apoptotic Bcl-2 protein (IC50= 0.85 ± 0.03 and 0.46 ± 0.02 µM, respectively). Interestingly, molecular docking for hybrid 8a in CDK2 and Bcl-2 active sites unveiled that N-propyl group is involved in significant hydrophobic interactions. Taken together, the results suggested conjugate 8a as a promising lead for further development and optimisation as an efficient antitumor drug. [ABSTRACT FROM AUTHOR]

In the current medical era, spirooxindole motif stands out as a privileged heterospirocyclic scaffold that represents the core for a wide range of bioactive naturally isolated products (such as Strychnofoline and spirotryprostatins A and B) and synthetic compounds. Interestingly, no much attention has been paid to develop spirooxindole derivatives with dual antioxidant and anticancer activities. In this context, a series of spirooxindoles 6a-p was examined for their anticancer effect towards HepG2 hepatocellular carcinoma and PC-3 prostate cancer cell lines. Spirooxindole 6a was found to be an efficient anti-proliferative agent towards both HepG2 and PC-3 cells (IC50 = 6.9 and 11.8 µM, respectively). Afterwards, spirooxindole 6a was assessed for its apoptosis induction potential in HepG2 cells, where its pro-apoptotic impact was approved via the significant elevation in the Bax/Bcl-2 ratio and the expression levels of caspase-3, [ABSTRACT FROM AUTHOR]

In this study, a new series of N-(di or trimethoxyaryl)-5-arylisoxazole-3-carboxamide derivatives were synthesized and evaluated against human breast cancer cell lines including MCF-7, MDA-MB-231, and T-47D. Among the synthesized compounds, 5-(m-tolyl)-N-(3,4,5-trimethoxyphenyl)isoxazole-3-carboxamide (8f) showed significant cytotoxicity against all three cell lines comparing with etoposide as the reference drug. Also, Annexin V-FITC/propidium iodide and acridine orange/ethidium bromide staining assay were performed to validate apoptotic activity of compound 8f. The results confirmed induction of apoptosis at early stage. [ABSTRACT FROM AUTHOR]

Certain cancer types, including breast cancer, are accompanied with stiffening of the surrounding extracellular matrix (ECM). Previous studies suggest that this stiffened matrix influences cancer cell progression, such as proliferation and invasion, both biochemically and mechanically. However, the contribution of ECM stiffness to cellular response to diverse stresses, which most cancer cells are exposed to, has not been elucidated. In this study, we demonstrate that expression of the Shwachman-Bodian-Diamond syndrome protein (SDBS) in a stiff matrix protects cells from apoptosis induced by environmental stress, including anticancer drugs. Cells cultured on stiff matrices were less apoptotic process induced by serum depletion than those cultured on the soft matrix. Interestingly, knockdown (KD) of SDBS among the apoptosis-related genes significantly increased apoptosis induced by serum depletion in cells cultured in a stiff matrix. Apoptosis of SDBS KD cells in a stiff matrix was significantly inhibited by the caspase 8 inhibitor, indicating that activation of the caspase 8 pathway by SDBS KD is critical for cancer cell apoptosis in stiff matrices. Additionally, we also found that downregulation of SDBS also effectively increased cell death induced by anticancer drugs, including paclitaxel, cisplatin, and eribulin. Taken together, our findings suggest that inhibition of SDBS enhances effective chemotherapy of malignant breast cancer cells in stiff ECM environments. [ABSTRACT FROM AUTHOR]

Lactobacillus and Bifidobacterium strains, their isolated constituents and substances that they secrete exert various anti-cancer actions, resulting from their anti-proliferative, pro-apoptotic and anti-oxidant properties. They can express and secrete anti-oxidant enzymes, bind reactive oxygen species, release small molecular weight anti-oxidants and chelate transition metals, preventing detrimental actions of many carcinogens. Lactobacillus and Bifidobacterium can interact with proteins regulating the cell cycle inhibiting proliferation of cancer cells, which often are intrinsically resistant to apoptosis. Lactobacilli and bifidobacteria can break this resistance through activation of pro-caspases and downregulation of the anti-apoptotic Bcl-2 and upregulation of pro-apoptotic Bax proteins. Anti-cancer effects of these bacteria can be also associated with their multi-pathways action in the microbiota. However, exact mechanism of their anti-cancer action is poorly known and needs further studies, which are justified by the important role of these bacteria in cancer biology as well as their potential preventive and therapeutic use. [ABSTRACT FROM AUTHOR]

In this study, we explored whether co-nanoencapsulated Curcumin (Cur) and Chrysin (Chr), natural herbal compounds with antitumor activities, regulate miR-132 and miR-502c and their downstream targets, leading to the synergistic growth inhibition in MDA-MB-231 breast cancer cells. For this purpose, Cur and Chr were co-encapsulated into PLGA-PEG nanoparticles (NPs) and characterized through DLS, FTIR and FE-SEM. MTT assay and cell cycle arrest analysis revealed that CurChr-loaded NPs had a considerable synergistic cytotoxicity against MDA-MB-231 cells with more cell accumulation in G2/M phase compared to the other groups. In addition, highest percentage of cell apoptosis was acquired in cells treated with CurChr-loaded NPs according to apoptosis analysis. Real-time PCR findings revealed that co-encapsulated form of Cur and Chr than free combination could further upregulate miR-132 and miR-502c expression (P < 0.001). Also, the strong reduction was detected in the protein levels of HN1 and P65 at the cells co-nanodelivered with Cur and Chr. These findings demonstrated that the co-nanodelivery of Cur and Chr through targeting miR-132 and miR-205c might be a novel strategy for the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer among women. Need for novel preventive and curative approaches with more safety than the present one seems inevitable. This review is devoted to potentially favorable role of probiotics in prevention and treatment of breast cancer as well as their alleviating role regarding chemotherapy-induced side effects. Literature was searched for human, animal, and in vitro studies about the role of probiotics in breast cancer. In vitro studies showed that probiotic intervention induces cancer cells apoptosis and inhibits their proliferation. In animal models, treatment with probiotics inhibited tumor growth and reduced tumor size; also, the immunomodulatory, antiangiogenesis and antimetastatic activities of probiotics were illustrated. Human studies showed that intake of Lactobacillus casei shirota reduced the breast cancer incidence and consumption of fermented milk products and yogurt was inversely associated with breast cancer incidence; however, no study regarding the curative role of probiotics in breast cancer is available. Studies on the effect of probiotics on chemotherapy-induced side effects in breast cancer were contradictory but showed potential for more investigation. Probiotics seem to have a potential role in both prevention and treatment of breast cancer. However, more clinical studies are needed to elucidate their efficacy and safety. [ABSTRACT FROM AUTHOR]

Context: Dicranopteris linearis (Burm.f.) Underw. (Gleicheniaceae) has been scientifically proven to exert various pharmacological activities. Nevertheless, its anti-proliferative potential has not been extensively investigated. Objective: To investigate the anti-proliferative potential of D. linearis leaves and determine possible mechanistic pathways. Materials and methods: MTT assay was used to determine the cytotoxic effects of D. linearis methanol (MEDL) and petroleum ether (PEEDL) extracts at concentrations of 100, 50, 25, 12.5, 6.25 and 3.125 µg/mL against a panel of cancer cell lines (breast [MCF-7 and MDA-MB-231], cervical [HeLa], colon [HT-29], hepatocellular [HepG2] and lung [A549]), as compared to negative (untreated) and positive [5-fluorouracil (5-FU)-treated] control groups. Mouse fibroblast cells (3T3) were used as normal cells. The mode of cell death was examined using morphological analysis via acridine orange (AO) and propidium iodide (PI) double staining. Cell cycle arrest was determined using flow cytometer, followed by annexin V-PI apoptosis detection kit. Results: MEDL demonstrated the most significant growth inhibition against MDA-MB-231 cells (IC50 22.4 µg/mL). PEEDL showed no cytotoxic effect. Induction of apoptosis by MEDL was evidenced via morphological analysis and acridine orange propidium iodide staining. MEDL could induce S phase cell cycle arrest after 72 h of incubation. Early apoptosis induction in MDA-MB-231 cells was confirmed by annexin V-FITC and PI staining. Significant increase in apoptotic cells were detected after 24 h of treatment with 15.07% cells underwent apoptosis, and the amount escalated to 18.24% with prolonged 48 h incubation. Conclusions: MEDL has potential as a potent cytotoxic agent against MDA-MB-231 adenocarcinoma. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment options due to its heterogeneity and the lack of well-defined molecular targets. In our endeavour towards the development of novel anti-TNBC agents, herein we report a one-pot three-component synthesis of novel spirooxindoles 6a-p, and evaluation of their potential anti-proliferative activity towards TNBC MDA-MB-231 cells. Spirooxindoles 6a, 6e and 6i emerged as the most potent analogues with IC50 = 6.70, 6.40 and 6.70 µM, respectively. Compounds 6a and 6e induced apoptosis in MDA-MB-231 cells, as evidenced by the up-regulation of the Bax and down-regulation of the Bcl-2, besides boosting caspase-3 levels. Additionally, 6e displayed significant increase in the percent of annexin V-FITC positive apoptotic cells from 1.34 to 44%. Furthermore, spirooxindoles 6e and 6i displayed good inhibitory activity against EGFR (IC50 = 120 and 150 nM, respectively). Collectively, these data demonstrated that 6e might be a potential lead compound for the development of effective anti-TNBC agents. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to evaluate the effects of REGγ knockdown on the proliferation, apoptosis and migration of multiple myeloma (MM) cells, and reveal the potential regulatory mechanisms. Methods: The expression of REGγ on myeloma cells of 28 MM patients was detected by Western blot. shRNA-REGγ-1 and shRNA-REGγ-2 were constructed to downregulate REGγ in RPMI-8226 cells. The proliferation, apoptosis and migration of transfected cells were analyzed by Cell Counting Kit 8 (CCK8), flow cytometry and transwell chamber, respectively. The expression of phosphorylated p65 (p-p65), p65, NF-kappa-B inhibitor ε (IkBε), matrix metalloproteinase 2 (MMP2), B-cell lymphoma xL (Bcl-xL) and X-linked inhibitor of apoptosis protein (XIAP) in transfected cells was detected by Western blot. Using cycloheximide (CHX), the half-life period of IkBε was detected by Western blot. Results: The expression of REGγ was positive in myeloma cells. The proliferation and migration of RPMI-8226 cells were significantly inhibited by shRNA-REGγ-1/shRNA-REGγ-2, while the apoptosis rates were significantly increased (p < 0.05). The expression of p-p65 and IkBε was significantly reduced in RPMI-8226 cells transfected with shRNA-REGγ-1/shRNA-REGγ-2. The degradation of IkBε was significantly lower in RPMI-8226 cells transfected with shRNA-REGγ-1 than the control (longer half-life period). Besides, the expression of MMP2, Bcl-xL and XIAP in RPMI-8226 cells was significantly inhibited by shRNA-REGγ-1/shRNA-REGγ-2. Discussion: Knockdown of REGγ may inhibit the proliferation and migration, and promote the apoptosis of RPMI-8226 cells possibly by downregulating NF-κB signal pathway. [ABSTRACT FROM AUTHOR]

Plants reputed to have cancer-inhibiting potential and putative active components derived from those plants have emerged as an exciting new field in cancer study. Some of these compounds have cancer-inhibiting potential in different clinical staging levels, especially metastasis. A few of them which stabilize cell-cell adhesions are controversial topics. This review article introduces some effective herbal compounds that target E-cadherin/β-catenin protein complex. In this article, at first, we briefly review the structure and function of E-cadherin and β-catenin proteins, Wnt signaling pathway, and its target genes. Then, effective compounds of the Teucrium persicum, Teucrium polium, Allium sativum (garlic), Glycine max (soy), and Brassica oleracea (broccoli) plants, which influence stability and cellular localization of E-cadherin/β-catenin complex, were studied. Based on literature review, there are some compounds in these plants, including genistein of soy, sulforaphane of broccoli, organosulfur compounds of garlic, and the total extract of Teucrium genus that change the expression of variety of Wnt target genes such as MMPs, E-cadherin, p21, p53, c-myc, and cyclin D1. So they may induce cell-cycle arrest, apoptosis and/or inhibition of Epithelial-Mesenchymal Transition (EMT) and metastasis. [ABSTRACT FROM AUTHOR]

A new series of quinazolinone compounds16–34incorporating isatin moieties was synthesized. The antitumor efficacy of the compounds against MDA-MB-231, a breast cancer cell line, and LOVO, a colon cancer cell line, was assessed. Compounds20,21,22,23,25, 27,28,29,30,31,32,33, and34displayed potent antitumor activity against MDA-MB-231 and LOVO cells (IC50: 10.38–38.67 μM and 9.91–15.77 μM, respectively); the comparative IC50values for 5-fluorouracil and erlotinib in these cells lines were 70.28 μM, 22.24 μM and 15.23 μM, 25.31 μM respectively. The EGFR-TK assay and induction of apoptosis for compound31were investigated to assess its potential cytotoxic activity as a representative example of the novel synthesized compounds. At a concentration of 10 μM, compound31exhibited efficient inhibitory effect against EGFR-TK and induced apoptosis in MDA-MB-231 cells. Furthermore, a molecular docking study for compound31and erlotinib was performed to verify the binding mode toward the EGFR kinase enzyme, and showed a similar interaction as that with erlotinib alone. Graphical Abstract:Compound31showed potent antitumor activity and efficient inhibitory effect against EGFR-TK and induced apoptosis of MDA-MB-231 cells at a concentration of 10 μM. [ABSTRACT FROM PUBLISHER]

Previous report of the vast effectiveness of opium derivatives in cancer therapy is leading us to see possible effects of these derivatives on cancer stem cells in order to find new agent for cancer therapy. In this study, cells were stained for CSC markers and sorted by magnetic beads. CSCs exhibit the characteristic CD44+/CD24−/low/ESA+phenotype. Noscapine and papaverine (alkaloids) showed anti-proliferative activity on MCF-7 and MDA-MB-231 cell lines. It was observed that noscapine has more cytotoxic effect on CSC derived from both cell lines compared with their parental cells. Papaverine has more cytotoxic effect on MCF-7 CSCs in comparison with parental cells, while CSCs population of MDA-MB-231 is more resistant to papaverine compared with MDA-MB-231 cells. Noscapine enhances apoptosis in MDA-MB-231 CSCs more than parent cells, while in MCF-7 CSCs the apoptosis is less than parent cells. Our results show that papverine is less active in terms of apoptotic effect on CSCs in both cell lines. Moreover, noscapine arrests MCF-7 and MDA-MB-231 CSCs cell cycle at G2/M phase, while papverine arrests cell cycle at G0/G1 phase. It was suggested different mechanism for apoptotic cytotoxicity. The results of this study show possible specific effects of noscapine on these breast cell lines CSCs. [ABSTRACT FROM AUTHOR]

Phellinus linteus(PL) is a medicinal mushroom due to its several biological properties, including anticancer activity. However, the mechanisms of its anticancer effect remain to be elucidated. We evaluated the inhibitory effects of the ethanolic extract from the PL combined with 5-FU on MDA-MB-231 breast cancer cell line and to determine the mechanism of cell death. Individually, PL extract and 5-FU significantly inhibited the proliferation of MDA-MB-231 cells in a dose-dependent manner. PL extract (30 mg/mL) in combination with 5-FU (10 μg/mL) synergistically inhibited MDA-MB-231 cells by 1.8-fold. PL did not induce apoptosis, as demonstrated by the DNA fragmentation assay, the sub-G1 population, and staining with annexin V-FITC and propidium iodide. The exposure of MDA-MB-231 cells to PL extracts resulted in several confirmed characteristics of autophagy, including the appearance of autophagic vacuoles revealed by monodansylcadaverine staining, the formation of acidic vesicular organelles, autophagosome membrane association of microtubule-associated protein light chain 3 (LC3) characterized by cleavage of LC3 and its punctuate redistribution, and ultrastructural observation of autophagic vacuoles by transmission electron microscopy. We concluded that PL extracts synergized with low doses of 5-FU to inhibit triple-negative breast cancer cell growth and demonstrated that PL extract can induce autophagy-related cell death. [ABSTRACT FROM PUBLISHER]

There is a growing interest in plant polyphenols (including flavanols) that exhibit pleiotropic biological activities such as antiinflammatory, antioxidant, and anticancer effects. Here, we report for the first time the inhibition of MDA-MB-231 breast cancer cell viability and invasiveness by an evening primrose flavanol preparation (EPFP). We observed a decrease in MDA-MB-231 viability of 50% vs. a control after 72 h of incubation with EPFP at a concentration of 58 μM gallic acid equivalents (GAE) and an inhibition of their invasiveness of 65% vs. a control at 75 μM GAE after 48 h of incubation. EPFP caused a 10-fold reduction in matrix metalloproteinase-9 (MMP-9) activity at 100 μM GAE. Furthermore, through modulation of mRNA expression, EPFP reduced the expression levels of the following proteins: antiapoptotic Bcl-2, angiogenic vascular endothelial growth factor (VEGF), and 2 transcription factors (c-Jun, c-Fos). Moreover, analysis by flow cytometry revealed that EPFP induced apoptosis in MDA-MB-231 cells. In conclusion, our data shows that EPFP inhibits cell viability by increasing apoptosis and decreases cell invasiveness by decreasing angiogenesis. [ABSTRACT FROM PUBLISHER]

Polyphenols are natural compounds of high structural diversity which translates into a very wide spectrum of biological activities, including chemoprevention. Here we report that a Japanese quince fruit flavanol preparation (JQFFP) caused favorable changes inBax/Bcl-2mRNA ratio, which rendered normal and cancer cells more resistant and more sensitive, respectively, to apoptosis. DU145 human prostate cancer cells were characterized by the most advantageousBax/Bcl-2ratio. The growth and invasiveness of MDA-MB-231 human breast cancer cells were strongly suppressed by JQFFP, which was accompanied with a decrease in MMP-9 activity and stimulation ofTIMP-1expression. Importantly, JQFFP did not decrease normal human prostate PNT1A cell number, whereasBax/Bcl-2ratio decreased which implies increased resistance to apoptosis. In conclusion, JQFFP exhibited a potent antiproliferative effect against cancer cells, inhibited their invasiveness, and decreased expression level of several genes involved in apoptosis, angiogenesis, and metastasis. [ABSTRACT FROM AUTHOR]

Gas permeable and biocompatible soft polymers are convenient for biological applications. Using the soft polymer poly(dimethylsiloxane) (PDMS), we established a straightforward technique for in-house production of self-adhesive and optical grade microculture devices. A gas permeable PDMS layer effectively protects against medium evaporation, changes in osmolarity, contamination and drug diffusion. These chip-based devices can be used effectively for long term mammalian cell culture and support a range of bioassays used in pharmacological profiling of anti-cancer drugs. Results obtained on a panel of hematopoietic and solid tumor cell lines during screening of investigative anti-cancer agents corresponded well to those obtained in a conventional cell culture on polystyrene plates. The cumulative correlation analysis of multiple cell lines and anti-cancer drugs showed no adverse effects on cell viability or cell growth retardation during microscale static cell culture. PDMS devices also can be custom modified for many bio-analytical purposes and are interfaced easily with both inverted and upright cell imaging platforms. Moreover, PDMS microculture devices are suitable for extended real time cell imaging. Data from the multicolor, real time analysis of apoptosis on human breast cancer MCF-7 cells provided further evidence that elimination of redundant centrifugation/washing achieved during microscale real time analysis facilitates preservation of fragile apoptotic cells and provides dynamic cellular information at high resolution. Because only small reaction volumes are required, such devices offer reduced use of consumables as well as simplified manipulations during all stages of live cell imaging. [ABSTRACT FROM AUTHOR]

There are conflicting reports with regard to the value of hot peppers and their primary active component compound, capsaicin, as an anticancer agent. We tested extracts from a number of peppers and found them to induce significant growth arrest and apoptosis in human breast and leukemia cancer cell lines in vitro with no significant effect on normal breast epithelial cells. Further, cell growth inhibition and cell death induction were positively correlated with the capsaicin content (based on the Scoville scale) of the peppers, and the hydroxyl radical scavenger thiourea significantly inhibited the activity of pepper extracts, suggesting the involvement of free radicals in mediating the biological activity of the pepper extracts. These results suggest a potential use of pepper extracts as anticancer agents. [ABSTRACT FROM AUTHOR]

Stearic acid (stearate) is an 18-carbon saturated fatty acid that has been shown to inhibit invasion and proliferation and induce apoptosis in various human cell types. The specificity of stearate-induced apoptosis for cancerous versus noncancerous breast cells has not been examined, and the mechanism underlying stearate-induced apoptosis is unknown. Morphological analysis, cell viability, and caspase-3 activity assays demonstrated that stearate activated apoptosis preferentially in cancerous breast cells in a time- and dose-dependent manner. Inhibition of de novo diacylgycerol synthesis or protein kinase C (PKC) blocked stearate-induced caspase-3 activity, indicating the involvement of a novel or classical PKC isozyme. To our knowledge this is the first study showing that stearate induces apoptosis preferentially in breast cancer cells and implicates protein kinase C in the signaling cascade. These results raise the possibility of dietary stearate having a beneficial role in the prevention or treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Objective Selective estrogen receptor modulators {SERMs) decrease the risk of developing breast cancer. As an antagonistic effect, SFRMs may aggravate or induce climacteric symptoms. Hormone therapy (HT) would be able to alleviate these symptoms. The present in vitro study tries to elucidate the effects of several HT preparations combined with SERMs on estrogen receptor-positive (ER+) (i.e. MCF-7 and T-47D) and -negative (ER-) (i.e. MDA-MB-231) human breast cancer cells in vitro. Methods We performed experiments with various HT preparations (estradiol (E2)/E2 + progesterone/E2 + dihydrodydrogesterone /E2 + norethisterone acetate/E2 + medroxyprogesterone acetate/tibolone) in the concentration of 10-6 mol/1 together with SERMs (raloxifene or tamoxifen) added to different breast cancer cell lines in vitro. After an incubation period of 144 h, proliferation and apoptosis were measured. The first was measured by quantification of the expression of cyclin DI mRNA, the latter by the Nicoletti method. Results This in vitro study clearly demonstrates differences in results if various HT preparations, combined with SERMs, are added to ER + and FR- breast cancer cell lines. Conclusions Adding estradiol/progestogens in combination with a SERM to estrogen receptor-positive breast cancer cell lines does not obligatorily lead to proliferation of tumor cells. Not all progestogens act equally. [ABSTRACT FROM AUTHOR]

Studies the effects of low levels of linoleic acids using an algal source of docosahexaenoic acid (DHA) in the growth of breast cancer cells and apoptosis in nude mice. Use of four isocaloric diets; Tumor growth rates; Changes in eicosanoid biosynthesis.