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Mushroom ß-D-glucans can be isolated from several species, including the widely consumed Agaricus bisporus. Besides immunomodulatory responses, some ß-D-glucans may exhibit direct antitumoral effects. It was previously observed that a ß-(1â6)-D-glucan (BDG16) has indirect cytotoxicity on triple-negative breast cancer cells. In this study, the cytotoxicity of this same glucan was observed on estrogen receptor-positive (ER+) breast cancer cells (MCF-7). Cell viability was determined by multiple methods to assess metabolic activity, lysosomal membrane integrity, and adhesion capacity. Assays to evaluate cell respiration, cell cycle, apoptosis, necroptosis, and oxidative stress were performed to determine the action of BDG16 on MCF-7 cells. A gradual and significant cell viability reduction was observed when the cells were treated with BDG16 (10-1000 µg/mL). This result could be associated with the inhibition of the basal state respiration after incubation with the ß-D-glucan. The cells showed a significant arrest in G1 phase population at 1000 µg/mL, with no induction of apoptosis. However, an increase in necrosis and necroptosis at the same concentration was observed. No difference in oxidative stress-related molecules was observed. Altogether, our findings demonstrate that BDG16 directly induces toxicity in MCF-7 cells, primarily by impairing mitochondrial respiration and promoting necroptosis. The specific mechanisms that mediate this action are being investigated.
Assuntos
Agaricus , Antineoplásicos , Apoptose , Neoplasias da Mama , Sobrevivência Celular , Estresse Oxidativo , Receptores de Estrogênio , Agaricus/química , Humanos , Células MCF-7 , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Sobrevivência Celular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , beta-Glucanas/farmacologia , beta-Glucanas/químicaRESUMO
The present work describes the extraction of a polyprenylated benzophenone-rich extract from Brazilian red propolis (ERPB), the development and validation of an RP-HPLC-UV method to characterize it, and its evaluation against breast cancer cell lines MCF-7 and MDA-MB-231, as well as the normal counterpart MCF-10A. A mixture of gutifferone E and xanthochymol (1+2), and isolated oblongifolin B (3) were used as chemical standards for ERPB and were also evaluated. The concentrations of 1+2 and 3 corresponded to 16.68% and 42.25% of the total content of the extract, respectively, and the validation parameters evaluated were satisfactorily met. The cytotoxic effects of ERPB were assessed, and the obtained IC50 values were 19.58 µg/mL (MCF-10A), 11.56 µg/mL (MCF-7), and 5.22 µg/mL (MDA-MB-231). In conclusion, ERPB exhibits promising cytotoxic effects on the tested breast cell lines. However, further investigation to elucidate its potential therapeutic applications and safety profile should be conducted.
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Graphene oxide (GOX) has become attractive due to its unique physicochemical properties. This nanomaterial can associate with other dendrimers, making them more soluble and allowing better interaction with biomacromolecules. The present study aimed to investigate, by real-time microscopy, the behavior of human breast cancer cells exposed to particles of materials based on graphene oxide. The MCF-7 cell line was exposed to GOX, GOX associated with Polypropylenimine hexadecaamine Dendrimer, Generation 3.0-DAB-AM-16 (GOXD) and GOX associated with polypropyleneimine-PAMAM (GOXP) in the presence or absence of fetal bovine serum (FBS). GOX, GOXD and GOXP were taken up by the cells in clusters and then the clusters were fragmented into smaller ones inside the cells. Real-time microscopy showed that the presence of FBS in the culture medium could allow a more efficient internalization of graphene materials. After internalizing the materials, cells can redistribute the clumps to their daughter cells. In conclusion, the present study showed that the particles can adhere to the cell surface, favoring their internalization. The presence of FBS contributed to the formation of smaller aggregates of particles, avoiding the formation of large ones, and thus transmitted a more efficient internalization of the materials through the interaction of the particles with the cell membrane.
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Graphene oxide (GOX) has become attractive due to its unique physicochemical properties. This nanomaterial can associate with other dendrimers, making them more soluble and allowing better interaction with biomacromolecules. The present study aimed to investigate, by real-time microscopy, the behavior of human breast cancer cells exposed to particles of materials based on graphene oxide. The MCF-7 cell line was exposed to GOX, GOX associated with Polypropylenimine hexadecaamine Dendrimer, Generation 3.0—DAB-AM-16 (GOXD) and GOX associated with polypropyleneimine—PAMAM (GOXP) in the presence or absence of fetal bovine serum (FBS). GOX, GOXD and GOXP were taken up by the cells in clusters and then the clusters were fragmented into smaller ones inside the cells. Real-time microscopy showed that the presence of FBS in the culture medium could allow a more efficient internalization of graphene materials. After internalizing the materials, cells can redistribute the clumps to their daughter cells. In conclusion, the present study showed that the particles can adhere to the cell surface, favoring their internalization. The presence of FBS contributed to the formation of smaller aggregates of particles, avoiding the formation of large ones, and thus transmitted a more efficient internalization of the materials through the interaction of the particles with the cell membrane.
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A series of structural analogs of aryl sulfonamide hybrid compounds were synthesised and their cytotoxic activity was evaluated against three human breast cancer cell lines (MCF-7, MDA-MB-231 and Hs 578T). The compounds were designed through electronic, hydrophobic and steric modifications using the chemical structure of N-{4-[(2-hydroxy-3-methoxy-5-propylphenyl)sulfamoyl]phenyl}acetamide (referred to as compound 7) as a starting point to then assess a structure-activity relationship (SAR) study. From the data generated, we observed that compounds 9, 10 and 11 (which have modifications in the substituents of the aryl sulfonamide), efficiently reduced the cell viability of MCF-7 and MDA-MB-231 cell cultures. Based on initial data, we selected compounds 10 and 11 for further investigations into their antiproliferative and/or cytotoxic profile against MDA-MB-231 cells, and we noted that compound 10 was the most promising compound in the series. Compound 10 promoted morphological changes and altered the dynamics of cell cycle progression in MDA-MB-231 cells, inducing arrest in G1/S transition. Taken together, these results show that the dihydroeugenol-aryl-sulfonamide hybrid compound 10 (which has an electron withdrawing nitro group) displays promising antiproliferative activity against MDA-MB-231 cell lines.
Assuntos
Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Sulfonamidas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células , Relação Estrutura-Atividade , Antineoplásicos/química , Linhagem Celular , Linhagem Celular Tumoral , Apoptose , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Aim: Investigate the heterogeneous tumor tissue organization and examine how this condition can interfere with the passive delivery of a lipid nanoemulsion in two breast cancer preclinical models (4T1 and Ehrlich). Materials & methods: The authors used in vivo image techniques to follow the nanoemulsion biodistribution and microtomography, as well as traditional histopathology and electron microscopy to evaluate the tumor structural characteristics. Results & conclusion: Lipid nanoemulsion was delivered to the tumor, vascular organization depends upon the subtumoral localization and this heterogeneous organization promotes a nanoemulsion biodistribution to the highly vascular peripherical region. Also, the results are presented with a comprehensive mathematical model, describing the differential biodistribution in two different breast cancer models, the 4T1 and Ehrlich models.
Assuntos
Neoplasias da Mama , Nanopartículas , Humanos , Feminino , Linhagem Celular Tumoral , Distribuição Tecidual , Nanopartículas/química , Lipídeos , Neoplasias da Mama/diagnóstico por imagem , Emulsões/químicaRESUMO
Abstract The main aim of the study is to quantify the cytotoxic property of the Fucoidan extracted from the Turbinaria conoides using the MTT assay with the standard fucose. Fucoidan was extracted using the soaked water method and it was determined using the HPLC procedure the obtained Test sample Fucoidan extracted from the Turbinaria conoides and standard fucose was subjected to the cytotoxicity assay against the MCF7 Human breast cancer cell line, A549 lung cancer cell line, and L929 normal mouse fibroblast cell line. From the results it was found that the Test sample showed good IC50 value for MCF7 cell line then A549 with an increasing concentration 24 hours incubation at 37°C The IC50 for MCF7 was 115.21 µg/ml and A549 396.46µg/ml and the Fucoidan extract was checked for its cytotoxicity against the normal mouse fibroblast cell line L929, Fucoidan was found non-lethal to the L929 mouse fibroblast normal cell line. Standard fucose also gave a significant result towards MCF7 and against the L929. This indicates that the Fucoidan extracted from Tubinaria conoides shows better anticancer potential in it. Hence its application can be further extended in the pharmacological fields.
Assuntos
Técnicas In Vitro/instrumentação , Citotoxinas/efeitos adversos , Células MCF-7 , Células A549 , Neoplasias da Mama/patologia , Linhagem Celular , Cromatografia Líquida de Alta Pressão/métodos , Concentração Inibidora 50 , Fibroblastos/classificação , Fucose/análogos & derivados , Neoplasias Pulmonares/patologiaRESUMO
The aim of this study was to evaluate the cytotoxic potential of Aristolochia foetida Kunth. Stems and leaves of A. foetida Kunth (Aristolochiaceae) have never been investigated pharmacologically. Recent studies of species of the Aristolochiaceae family found significant cytotoxic activities. Hexane, dichloromethane, ethyl acetate and methanol extracts were analyzed by 1H NMR and GC-MS to know the metabolites in each extract. In GC-MS analysis, the main compounds were methyl hexadecanoate (3); hexadecanoic acid (4); 2-butoxyethyl dodecanoate (9); ethyl hexadecanoate (20); methyl octadeca-9,12,15-trienoate (28) and (9Z,12Z,15Z)-octadeca-9,12,15-trienoic acid (40). The results showed a significant reduction in cell viability of the MCF-7 (breast cancer) cell line caused by organic extracts in a dose-dependent manner. The cytotoxicity activity of the dichloromethane extract from the stems (DSE) showed IC50 values of 45.9 µg/mL and the dichloromethane extract of the leaves (DLE) showed IC50 values of 47.3 µg/mL. DSE and DLE had the highest cytotoxic potential in an in vitro study against the MCF-7 cell line and non-tumor cells obtained from the bovine mammary epithelial (bMECs). DSE and DLE induced a loss in mitochondrial membrane potential (ΔΨm) and can cause cell death by apoptosis through the intrinsic pathway in the MCF-7 cell line. DSE and DLE are cytotoxic in cancer cells and cause late apoptosis. Higher concentrations of DSE and DLE are required to induce a cytotoxic effect in healthy mammary epithelial cells. This is the first report of the dichloromethane extract of A. foetida Kunth that induces late apoptosis in MCF-7 cancer cells and may be a candidate for pharmacological study against breast cancer.
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Black chickpea is a good source of bioactive compounds, particularly isoflavones. Sprouting improves nutraceutical value in chickpea seeds. This study aimed to explore the role of sprouting of black chickpea seeds on the synthesis of isoflavones and evaluate the impact of the soluble isoflavone on cellular antioxidant activity (CAA) and antiproliferative activity in breast cancer cells. Isoflavones were identified and quantified by HPLC-UV-MS. The CAA and antiproliferative activity were determined in HepG2 cells and MDA-MB-231 cancer cells, correspondingly. In sprouted black chickpea, six isoflavones (formononetin, biochanin-A, and its glycosides) were identified and the total isoflavones content increased (0.31 to 35.72 µgBA/mg of extract). The CAA was increased five times from 137.2 to 788.2 µMEQ/100 g of sample. The bioactive compounds in sprouted chickpea decreased the proliferation of MDA-MB-231 cell line. Also caused morphological changes such as cell shrinkage, rounding and nuclear fragmentation. The results herein suggest that bioactive compounds, as isoflavones, in sprouted black chickpea showed a potential antioxidant and antiproliferative activity. Therefore, it may be considered as a value-added product or ingredient for produce functional foods.
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A self-nanoemulsifying drug delivery system (SNEDDS) composed of ethyl oleate, Tween 80 and polyethylene glycol 600 was prepared as a new route to improve the efficacy of imatinib. The drug-loaded SNEDDS formed nanodroplets of ethyl oleate stabilized by Tween 80 and polyethylene glycol 600 with a diameter of 81.0±9.5 nm. The nanoemulsion-based delivery system was stable for at least two months, with entrapment efficiency and loading capacity of 16.4±0.1 and 48.3±0.2%, respectively. Imatinib-loaded SNEDDS was evaluated for the drug release profiles, and its effectiveness against MCF-7 cell line was investigated. IC50 values for the imatinib-loaded SNEDDS and an imatinib aqueous solution were 3.1 and 6.5 µg mL-1, respectively.
Assuntos
Técnicas In Vitro/métodos , Eficácia/classificação , Mesilato de Imatinib/efeitos adversos , Polietilenoglicóis/análise , Concentração Inibidora 50 , Células MCF-7/classificação , Liberação Controlada de Fármacos/efeitos dos fármacosRESUMO
Objective: Evaluate the value of imprint cytology in the intraoperative analysis of sentinel lymph node (SLN) in patients with breast cancer. Methods: An agreement study for the evaluation of the imprint cytology technique as a diagnostic test for intraoperative SLN among patients diagnosed with breast cancer from January 2007 to January 2017. Results: We studied 210 cases of breast cancer patients submitted to intraoperative sentinel node imprint cytology, aged between 24 and 86 years (mean age 59 years and median age 60 years). The sensitivity of the intraoperative study was 58.3% (95%CI 46.169.8%) and the specificity was 97.8% (95%CI 93.899.5). The positive predictive value (PPV) was 93.3% (95%CI 81.798.6) and the negative predictive value (NPV) was 81.8% (95%CI 75.187.4). From the analyzed variables, the presence of macrometastasis was the only one that significantly increased the sensitivity of the imprint to 73.2% (95%CI 59.784.2), while micrometastasis presented a sensitivity of only 6.3% (95%CI 0.230.2). Conclusion: The use of imprint cytology in the intraoperative SLN study showed good accuracy in predicting axillary status. However, the surgeon and pathologist are fully aware of the set of clinical and histological variables that can influence the sensitivity of the method.
Objetivo: Avaliar o valor do imprint citológico na análise intraoperatória do linfonodo sentinela (LS) em pacientes com câncer de mama. Métodos: Estudo de concordância para avaliação da técnica do imprint citológico como teste diagnóstico do LS no intraoperatório, entre pacientes com diagnóstico de câncer de mama, no período de janeiro de 2007 a janeiro de 2017. Resultados: Foram estudados 210 casos de pacientes com câncer de mama submetidas à citologia de impressão (IC) do linfonodo sentinela no intraoperatório, com idade entre 24 e 86 anos (média de 59 anos e mediana de 60 anos). A sensibilidade do estudo intraoperatório foi de 58,3% (IC95% 46,169,8) e a especificidade de 97,8% (IC95% 93,899,5). O valor preditivo positivo (VPP) foi de 93,3% (IC95% 81,798,6) e o valor preditivo negativo (VPN) de 81,8% (IC95% 75,187,4%). Das variáveis analisadas, a presença de macrometástase foi a única que aumentou significativamente a sensibilidade do imprint para 73,2% (IC95%, 59,784,2%), enquanto na micrometástase apresentou sensibilidade de apenas 6,3% (IC95% 0,230,2). Conclusão: A utilização do imprint citológico no estudo intraoperatório do LS apresentou boa acurácia na previsão do status axilar. Entretanto, é importante o pleno conhecimento, pelo cirurgião e patologista, do conjunto de variáveis clínicas e histológicas que podem influenciar a sensibilidade do método
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Drug repositioning refers to the identification of new therapeutic indications for drugs already approved. Albendazole and ricobendazole have been used as anti-parasitic drugs for many years; their therapeutic action is based on the inhibition of microtubule formation. Therefore, the study of their properties as antitumor compounds and the design of an appropriate formulation for cancer therapy is an interesting issue to investigate. The selected compounds are poorly soluble in water, and consequently, they have low and erratic bioavailability. In order to improve their biopharmaceutics properties, several formulations employing cyclodextrin inclusion complexes were developed. To carefully evaluate the in vitro and in vivo antitumor activity of these drugs and their complexes, several studies were performed on a breast cancer cell line (4T1) and BALB/c mice. In vitro studies showed that albendazole presented improved antitumor activity compared with ricobendazole. Furthermore, albendazole:citrate-ß-cyclodextrin complex decreased significantly 4T1 cell growth both in in vitro and in vivo experiments. Thus, new formulations for anti-parasitic drugs could help to reposition them for new therapeutic indications, offering safer and more effective treatments by using a well-known drug.
Assuntos
Antiparasitários/administração & dosagem , Ciclodextrinas/administração & dosagem , Reposicionamento de Medicamentos/métodos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Albendazol/administração & dosagem , Albendazol/análogos & derivados , Albendazol/química , Animais , Antiparasitários/química , Disponibilidade Biológica , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Ciclodextrinas/química , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/patologia , Difração de Raios X , beta-Ciclodextrinas/administração & dosagem , beta-Ciclodextrinas/químicaRESUMO
A novel heterometallic metal-porphyrinic framework (MPFs) built from Y and K ions as nods and meso-tetra(4-carboxyphenyl)porphyrin as linkers has been successfully synthesized and characterized. The single crystal X-ray diffraction indicated that this complex 1 exhibited a bilayered architecture of the porphyrins, which is seldom seen in MPFs. In addition, in vitro anticancer activity of complex 1 on three human breast cancer cells (BT474, SKBr-3 and ZR-75-30) was further determined.
Assuntos
Humanos , Porfirinas/química , Neoplasias da Mama/tratamento farmacológico , Estruturas Metalorgânicas/farmacologia , Estruturas Metalorgânicas/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Valores de Referência , Sais de Tetrazólio , Reprodutibilidade dos Testes , Cristalografia por Raios X , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , FormazansRESUMO
Breast cancer is the leading cause of cancer mortality in females worldwide. Studies based on gene expression profiles have identified different breast cancer molecular subtypes, such as luminal A and B cells, cancer cells that are estrogen receptor (ER) and/or progesterone receptor (PR) positive, human epidermal growth factor 2 (HER2)-enriched cells, cancer cells that exhibit an overexpression of the oncogene HER2, and triple-negative cells, cancer cells that are negative for ER, PR and HER2 expression. Immunohistochemistry is the most common type of method used for the identification of these molecular subtypes, through the identification of specific cell receptors. The present study aimed to evaluate the ER, PR and HER2 receptor expression in human breast cancer cell lines, and to classify the corresponding molecular subtype comparing two alternative methods. In the present study, a panel of human mammary carcinoma cell lines: BT-20; Hs578T; MCF-7; MCF-7/AZ; MDA-MB-231; MDA-MB-468; SKBR3; and T47D were used. Immunohistochemical and immunocytochemistry assays were used to characterize the breast cancer subtypes of these cell lines according to the expression of ER, PR and HER2 receptors. The results revealed the molecular characterization of this panel of breast cancer cell lines, using the differential expression of classical and clinically used markers in concordance with previous studies. In addition, these data are important for additional in vitro studies of these specific receptors.
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Thyroid hormones (TH) play a fundamental role in diverse processes, including cellular movement. Cell migration requires the integration of events that induce changes in cell structure towards the direction of migration. These actions are driven by actin remodeling and stabilized by the development of adhesion sites to extracellular matrix via transmembrane receptors linked to the actin cytoskeleton. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that promotes cell migration and invasion through the control of focal adhesion turnover. In this work, we demonstrate that the thyroid hormone triiodothyronine (T3) regulates actin remodeling and cell movement in breast cancer T-47D cells through the recruitment of FAK. T3 controls FAK phosphorylation and translocation at sites where focal adhesion complexes are assembled. This process is triggered via rapid signaling to integrin αV/ß3, Src, phosphatidylinositol 3-OH kinase (PI3K), and FAK. In addition, we established a cellular model with different concentration of T3 levels: normal, absence, and excess in T-47D breast cancer cells. We found that the expression of Src, FAK, and PI3K remained at normal levels in the excess of T3 model, while it was significantly reduced in the absence model. In conclusion, these results suggest a novel role for T3 as an important modulator of cell migration, providing a starting point for the development of new therapeutic strategies for breast cancer treatment.
Assuntos
Citoesqueleto de Actina/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Quinase 1 de Adesão Focal/metabolismo , Tri-Iodotironina/metabolismo , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Feminino , Adesões Focais/metabolismo , Humanos , Integrina alfaVbeta3/metabolismo , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Transporte Proteico , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: The aim of this study was to develop, characterize and assess the cytotoxic activity of pHsensitive (pHL-Gd), stealth pH-sensitive (SpHL-Gd), and conventional (convL-Gd) liposomes containing gadodiamide (Gd-DTPA-BMA). METHODS: Formulations were prepared by reverse-phase evaporation method and their physicochemical properties were evaluated by means of particle size, zeta potential, and Gd-DTPA-BMA entrapment. SpHL-Gd was considered being the most promising liposome, since it combines stealth and fusogenic characteristics that might contribute to achieve higher therapeutic efficiency. Their drug encapsulation percentages have been optimized satisfactorily. The addition of Gd-DTPA-BMA at 125 µmol/mL in the SpHL-Gd preparation allowed obtaining liposomes with appropriate encapsulation percentage (20.3 ± 0.1%) and entrapment (25.4 ± 0.1 µmol/mL). RESULTS: The cytotoxic studies on the 4T1 breast cancer cell line demonstrated that liposomes-loaded with Gd-DTPA-BMA inhibited cancer cell. pHL-Gd and SpHL-Gd liposomes showed higher activity than convL-Gd and free Gd-DTPA-BMA, indicating that the pH-sensitive characteristic was important to improve intracellular delivery. CONCLUSION: The presence of polyethylene glycol (PEG) in the SpHL-Gd formulation did not affect the pH-sensitivity and internalization. Therefore, the results of this study suggest the feasibility of liposomes containing Gd-DTPA-BMA as a new promising controlled delivery system.
Assuntos
Sistemas de Liberação de Medicamentos , Gadolínio DTPA/química , Lipossomos , Linhagem Celular Tumoral , Humanos , Tamanho da Partícula , PolietilenoglicóisRESUMO
BACKGROUND: We previously demonstrated that the activated leukocyte cell adhesion molecule (ALCAM/CD166) can interact with galectin-8 (Gal-8) in endothelial cells. ALCAM is a member of the immunoglobulin superfamily that promotes homophilic and heterophilic cell-cell interactions. Gal-8 is a "tandem-repeat"-type galectin, known as a matricellular protein involved in cell adhesion. Here, we analyzed the physical interaction between both molecules in breast cancer cells and the functional relevance of this phenomenon. METHODS: We performed binding assays by surface plasmon resonance to study the interaction between Gal-8 and the recombinant glycosylated ALCAM ectodomain or endogenous ALCAM from MDA-MB-231 breast cancer cells. We also analyzed the binding of ALCAM-silenced or control breast cancer cells to immobilized Gal-8 by SPR. In internalization assays, we evaluated the influence of Gal-8 on ALCAM surface localization. RESULTS: We showed that recombinant glycosylated ALCAM and endogenous ALCAM from breast carcinoma cells physically interacted with Gal-8 in a glycosylation-dependent fashion displaying a differential behavior compared to non-glycosylated ALCAM. Moreover, ALCAM-silenced breast cancer cells exhibited reduced binding to Gal-8 relative to control cells. Importantly, exogenously added Gal-8 provoked ALCAM segregation, probably trapping this adhesion molecule at the surface of breast cancer cells. CONCLUSIONS: Our data indicate that Gal-8 interacts with ALCAM at the surface of breast cancer cells through glycosylation-dependent mechanisms. GENERAL SIGNIFICANCE: A novel heterophilic interaction between ALCAM and Gal-8 is demonstrated here, suggesting its physiologic relevance in the biology of breast cancer cells.
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Antígenos CD/metabolismo , Neoplasias da Mama/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas Fetais/metabolismo , Galectinas/metabolismo , Mapas de Interação de Proteínas/genética , Antígenos CD/genética , Neoplasias da Mama/patologia , Adesão Celular/genética , Moléculas de Adesão Celular Neuronais/genética , Comunicação Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Células Endoteliais/metabolismo , Feminino , Proteínas Fetais/genética , Galectinas/genética , Glicosilação , Humanos , Ligação Proteica , Propriedades de SuperfícieRESUMO
It is well known the participation of oxidative stress in the induction and development of different pathologies including cancer, diabetes, neurodegeneration and respiratory disorders among others. It has been reported that oxidative stress may be induced by pesticides and it could be the cause of health alteration mediated by pollutants exposure. Large number of registered products containing chlorpyrifos (CPF) is used to control pest worldwide. We have previously reported that 50 µM CPF induces ROS generation and produces cell cycle arrest followed by cell death. The present investigation was designed to identify the pathway involved in CPF-inhibited cell proliferation in MCF-7 and MDA-MB-231 breast cancer cell lines. In addition, we determined if CPF-induced oxidative stress is related to alterations in antioxidant defense system. Finally we studied the molecular mechanisms underlying in the cell proliferation inhibition produced by the pesticide. In this study we demonstrate that CPF (50 µM) induces redox imbalance altering the antioxidant defense system in breast cancer cells. Furthermore, we found that the main mechanism involved in the inhibition of cell proliferation induced by CPF is an increment of p-ERK1/2 levels mediated by H2O2 in breast cancer cells. As PD98059 could not abolish the increment of ROS induced by CPF, we concluded that ERK1/2 phosphorylation is subsequent to ROS production induced by CPF but not the inverse.
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Antioxidantes/metabolismo , Proliferação de Células/efeitos dos fármacos , Clorpirifos/toxicidade , Inseticidas/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Células MCF-7 , Oxirredução , Fosforilação/efeitos dos fármacosRESUMO
Interleukin 1ß has been associated with tumor development, invasiveness and metastasis in various types of cancer. However, the molecular mechanisms underlying this association have not been clearly elucidated. The present study is the first to show, in breast cancer cells, that an IL-1ß/IL-1RI/ß-catenin signaling pathway induces ß-catenin accumulation due to GSK3ß inactivation by Akt phosphorylation. Translocation to the nucleus of accumulated ß-catenin and formation of the TCF/Lef/ß-catenin complex induce sequential expression of c-MYC, CCDN1, SNAIL1 and MMP2, leading to up-regulation of proliferation, migration and invasion; all of the processes shown to be required, in cancerous cells, to initiate transition from a non-invading to an invasive phenotype.
Assuntos
Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Interleucina-1beta/metabolismo , Transdução de Sinais , beta Catenina/metabolismo , Transporte Ativo do Núcleo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Invasividade Neoplásica , Fenótipo , Alcamidas Poli-Insaturadas/química , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Pterocarpans, a family of isoflavonoids found in the diverse Fabaceae, display potent cytotoxic activity over a panel of tumor cell lines, and among those tested, 2,3,9- trimethoxypterocarpan displays the most potent activity. This study evaluates the effects of 2,3,9-trimethoxypterocarpan and its related derivatives on cell cycle progression and microtubule function in select breast cancer cell lines (MCF7, T47d and HS578T). The pterocarpans, with the exception of 3,4-dihydroxy-9-methoxipterocarpan, induced increased frequencies of mitotic cells by inducing arrest in prometaphase. While microtubule organization in interphase cells was not modified during treatment, mitotic cells exhibited high frequencies of monastral spindles surrounded by condensed chromosomes. Immunofluorescence staining with an anti-γ-tubulin antibody showed double-dot labeling in the spindle polar region, suggesting that pterocarpan treatment blocked centrosome segregation. We found that this mitotic arrest was reversible when the cells were treated for up to 24 h followed by recovery in drug-free medium, but not after 48-h treatment followed by incubation in drug-free medium. In that case, treated cells typically underwent cell multinucleation and apoptosis.