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1.
Mol Biol Rep ; 47(2): 843-853, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31848915

RESUMO

The goal of this survey is to evaluate the anti-proliferative effects of the hydroalcholic extract of Blepharis persica seeds and its synergic effect on doxorubicin (DOX) in human colon cancer (HT-29) and gastric cancer cell (AGS) lines. 70% Ethanol was used for extraction of B. persica seed. Aluminum-chloride colorimetric and Folin-Ciocalteu reagent methods were used to measure total flavonoid and total phenolic contents of the extract respectively. Gas chromatography-mass spectrometry (GC-MS) analysis of the B. persica extract was performed on GC-MS equipment after silylation. HT-29, AGS, and human fibroblast (SKM) cell lines were treated by different concentration of the B. persica extract, (DOX) and the combination of extraction and DOX. The cytotoxicity was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay while the apoptosis induction was monitored using flowcytometry by annexin-V FITC/PI double-staining. The changes in expression levels of BAX and BCL-2 were determined using Real-Time RT-qPCR. GC-MS analysis of the hydroalcoholic extract from B. persica seeds revealed 24 major components. The MTT assay revealed the cytotoxicity against three cell lines and also it was shown that 125 ng/mL of DOX and 0.625 mg/mL of B. persica extract had synergistic behavior against HT29 cell line. These results showed B. persica extract induced apoptosis in AGS and HT29 cells and its extract caused dose-dependent increase in up-regulation of BAX level (p < 0.05) and down-regulation of BCL2 (p < 0.05). B. persica showed the synergistic effect in combination with DOX on HT29 cell line. These findings demonstrated a basis for further studies on the characterization and mechanistic evaluation of the bioactive compounds of B. persica extract which had antiproliferative effects on cancer cell lines.


Assuntos
Acanthaceae/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Extratos Vegetais/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Células HT29/efeitos dos fármacos , Humanos , Sementes/metabolismo , Neoplasias Gástricas/metabolismo
2.
Mutat Res ; 845: 402980, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31561898

RESUMO

TiO2 particles are widely used in products for everyday consumption, such as cosmetics and food; their possible adverse effects on human health must therefore be investigated. The aim of this study was to document in vitro impact of the food additive E171, i.e. TiO2, and of TiO2 nanoparticles, on a co-culture of Caco-2 and HT29-MTX cells, which is an in vitro model for human intestine. Cells were exposed to TiO2 particles three days after seeding, i.e. while they were not fully differentiated. Cell viability, reactive oxygen species (ROS) levels and DNA integrity were assessed, by MTT assay, DCFH-DA assay, alkaline and Fpg-modified comet assay and 8-oxo-dGuo measurement by HPLC-MS/MS. The mRNA expression of genes involved in ROS regulation, DNA repair via base-excision repair, and endoplasmic reticulum stress was assessed by RT-qPCR. Exposure to TiO2 particles resulted in increased intracellular ROS levels, but did not impair cell viability and did not cause any oxidative damage to DNA. Only minor changes in mRNA expression were detected. Altogether, this shows that E171 food additive and TiO2 nanoparticles only produce minor effects to this in vitro intestinal cell model.


Assuntos
Células CACO-2/efeitos dos fármacos , Aditivos Alimentares/toxicidade , Células HT29/efeitos dos fármacos , Titânio/toxicidade , 8-Hidroxi-2'-Desoxiguanosina/análise , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Aditivos Alimentares/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estresse Oxidativo , Tamanho da Partícula , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
3.
J Microbiol Biotechnol ; 29(4): 571-576, 2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-30955254

RESUMO

Microenvironmental stress, which is naturally observed in solid tumors, has been implicated in anticancer drug resistance. This tumor-specific stress causes the degradation of topoisomerase IIα, rendering cells resistant to topoisomerase IIα-targeted anticancer agents. In addition, microenvironmental stress can induce the overexpression of 78kDa glucose regulated protein (GRP78), which can subsequently block the activation of apoptosis induced by treatment with anticancer agents. Therefore, inhibition of topoisomerase IIα degradation and reduction in GRP78 expression may be effective strategies for inhibiting anticancer drug resistance. In this study, we investigated the active compound arctigenin, which inhibited microenvironmental stress-induced etoposide resistance in HT-29 cells. Arctigenin was also highly toxic to etoposide-resistant HT-29 cells, with an IC50 value of 10 µM for colony formation. We further showed that arctigenin inhibited the degradation of topoisomerase IIα and reduced the expression of GRP78. Thus, these results suggest that arctigenin is a novel therapeutic agent that inhibits resistance to etoposide associated with microenvironmental stress conditions.


Assuntos
Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Etoposídeo/farmacologia , Furanos/antagonistas & inibidores , Células HT29/efeitos dos fármacos , Lignanas/antagonistas & inibidores , Estresse Fisiológico , Microambiente Tumoral/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaio de Unidades Formadoras de Colônias , DNA Topoisomerases Tipo II , Furanos/química , Células HT29/citologia , Proteínas de Choque Térmico/metabolismo , Humanos , Lignanas/química
4.
Med Sci Monit ; 24: 9488-9496, 2018 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-30594943

RESUMO

BACKGROUND Ginkgo biloba extract EGb 761 is a putative antioxidant and has been used for thousands of years to treat a variety of ailments, including cancer. While it is known that cell behavior can be modulated by long non-coding RNAs (lncRNAs), the contributions of lncRNAs in EGb 761-induced anti-cancer effects are largely unknown. MATERIAL AND METHODS Colon cancer cell lines HT29 and HCT116 were used in this study. RT-qPCR was used to detect the relative expression of lincRNA-p21 in colon cancer cells. Wound-healing assay and Matrigel Transwell assay were performed to investigate the migration and invasion of colon cancer cells. Immunoprecipitation and Western blot experiments were used to verify ubiquitination and the interaction between lincRNA-p21 and E-cadherin, or E-cadherin and b-transducin repeat containing (BTRC) E3 ubiquitin protein ligase. RESULTS Cell function assay verified that treatment with EGb 761 suppressed the migratory and invasive abilities of colon cancer cells in a dose-dependent manner via the suppression of E-cadherin expression level. lincRNA-p21 was upregulated in colon cancer cells after treatment with EGb 761, and knockdown of lincRNA-p21 reversed the EGb 761-induced anti-metastatic effect. Furthermore, lincRNA-p21 was localized in cytoplasm of colon cells and regulated E-cadherin expression at a post-transcriptional level. Specifically, lincRNA-p21 promotes E-cadherin stability by preventing the interaction between BTRC and E-cadherin, which leads to the inhibition of E-cadherin ubiquitination. CONCLUSIONS We demonstrated that lincRNA-p21 mediates the anti-cancer effect of Ginkgo biloba extract EGb 761 by stabilizing E-cadherin protein in colon cancer, which may help define the functional role of EGb 761 in cancer treatment.


Assuntos
Neoplasias do Colo/genética , Extratos Vegetais/uso terapêutico , RNA Longo não Codificante/genética , Antioxidantes , Caderinas/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Células HT29/efeitos dos fármacos , Humanos , Invasividade Neoplásica/genética , RNA Longo não Codificante/metabolismo
5.
J Acoust Soc Am ; 144(5): EL374, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30522320

RESUMO

A scaling subtraction method was proposed to analyze the radio frequency data from cancer cell samples exposed to an anti-cancer drug and to estimate a nonlinear parameter. The nonlinear parameter was found to be well correlated (R2 = 0.62) to the percentage of dead cells in apoptosis and necrosis. The origin of the nonlinearity may be related to a change in contacts between cells, since the nonlinear parameter was well correlated to the average total coordination number of binary packings (R2 ≥ 0.77). These results suggest that the scaling subtraction method may be used to early quantify chemotherapeutic treatment efficiency.


Assuntos
Apoptose/fisiologia , Neoplasias do Colo/patologia , Células HT29/efeitos dos fármacos , Ultrassonografia/métodos , Adenocarcinoma , Algoritmos , Apoptose/efeitos dos fármacos , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/tratamento farmacológico , Inibidores Enzimáticos/administração & dosagem , Citometria de Fluxo/métodos , Células HT29/patologia , Humanos , Monitorização Fisiológica , Dinâmica não Linear , Estaurosporina/administração & dosagem
6.
Mol Biol Rep ; 45(6): 1621-1626, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30293192

RESUMO

The evaluation of cytotoxic and apoptotic activities of silver nanoparticles (Ag-NPs) synthesized by aqueous extract of Prosopis farcta was investigated against lung (A549) and colon (HT-29) cell lines. The cytotoxic activity of nanoparticles was performed using MTT assay, while their apoptotic activity was tested using TUNEL method. The obtained results of MTT showed that the cell viability of A549 was dependent on the nanoparticles concentration and incubation time. Therefore, although the cytotoxic effect increased as the Ag-NPs concentration and incubation time heightened, yet the viability of HT-29 cells seems to be dependent only on the incubation time. The apoptotic results of the nanoparticles showed more than 50% of apoptosis on A549 and HT-29 cell lines, which in this case, HT-29 demonstrated 100% apoptosis at concentrations of more than 400 µg/ml. It seems that Ag-NPs synthesized using P. farcta extract can serve as anti-cancer agent in the treatment many cancers through creating or discovering new drug forms.


Assuntos
Células A549/efeitos dos fármacos , Células HT29/efeitos dos fármacos , Nanopartículas Metálicas/efeitos adversos , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Extratos Vegetais/farmacologia , Prosopis/efeitos adversos , Prata/efeitos adversos , Prata/metabolismo , Espectrofotometria Ultravioleta , Difração de Raios X
7.
Microb Pathog ; 123: 183-189, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30017942

RESUMO

Colorectal cancer is the third most common cause of cancer-related death in the world which genetic and environmental agents are responsible for cancer. When cells detach from the tumor and invade surrounding tissues, the tumor is malignant and may form secondary tumors at other locations in a process called metastasis. Probiotics are the largest group of inhabitation bacteria in the colon. Gut microbiota has a central role in prevented the risk colon cancer. Probiotics are beneficial microorganisms, like Lactic acid bacteria and Lactobacilli bacteria which are using in the dairy industry. Probiotics nisin are having the most important category of safe usage. In this study LS180, SW48, HT29 and Caco2 was cultured and treated with different dose of nisin. Cell proliferation was assayed with MTT. The expression of CEA, CEAM6 and MMP2F genes was analyzed with Real-time PCR. Protein expression of CEA was evacuated with ELISA. Our result was shown that the 40-50 IU/mL nisin could suppress proliferation of LS180. Cell proliferation of SW48, HT29, Caco2 cells was decreased in 250-350 IU/mL concentration of nisin. The gene expression of CEA, CEAM6, MMP2F was significantly down-regulated with nisin treatment (p < 0.001, p < 0.01). Also, after cells treated with nisin, CEA protein expression was down regulated (p < 0.01). In conclusion, nisin could suppressed metastatic process via down-regulation of CEA, CEAM6, MMP2F, MMP9F genes. We suggested the new treatment strategies beyond Probiotics, which play a role in the prevention local tumor invasion, metastasis and recurrence.


Assuntos
Antibacterianos/farmacologia , Bacteriocinas/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Nisina/farmacologia , Células CACO-2/efeitos dos fármacos , Antígeno Carcinoembrionário/genética , Antígeno Carcinoembrionário/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Células HT29/efeitos dos fármacos , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Nisina/administração & dosagem , Probióticos/farmacologia , Proteínas/genética , Proteínas/metabolismo
8.
Nat Commun ; 8(1): 1834, 2017 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-29184140

RESUMO

Normal epithelial cells are stably connected to each other via the apical junctional complex (AJC). AJCs, however, tend to be disrupted during tumor progression, and this process is implicated in cancer dissemination. Here, using colon carcinoma cells that fail to form AJCs, we investigated molecular defects behind this failure through a search for chemical compounds that could restore AJCs, and found that microtubule-polymerization inhibitors (MTIs) were effective. MTIs activated GEF-H1/RhoA signaling, causing actomyosin contraction at the apical cortex. This contraction transmitted force to the cadherin-catenin complex, resulting in a mechanosensitive recruitment of vinculin to cell junctions. This process, in turn, recruited PDZ-RhoGEF to the junctions, leading to the RhoA/ROCK/LIM kinase/cofilin-dependent stabilization of the junctions. RhoGAP depletion mimicked these MTI-mediated processes. Cells that normally organize AJCs did not show such MTI/RhoA sensitivity. Thus, advanced carcinoma cells require elevated RhoA activity for establishing robust junctions, which triggers tension-sensitive reorganization of actin/adhesion regulators.


Assuntos
Junções Aderentes/metabolismo , Moléculas de Adesão Celular/metabolismo , Adesão Celular/fisiologia , Neoplasias do Colo/metabolismo , Proteínas do Citoesqueleto/metabolismo , Células HT29/fisiologia , Junções Intercelulares/fisiologia , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/ultraestrutura , Fatores de Despolimerização de Actina/metabolismo , Actinas/metabolismo , Actomiosina/metabolismo , Junções Aderentes/ultraestrutura , Fenômenos Biomecânicos , Células CACO-2 , Caderinas/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Células Epiteliais/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Células HT29/citologia , Células HT29/efeitos dos fármacos , Humanos , Quinases Lim/metabolismo , Microtúbulos , Miosina Tipo II/metabolismo , Nocodazol/farmacologia , Transdução de Sinais , Vinculina/metabolismo , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
9.
Artigo em Inglês | MEDLINE | ID: mdl-28713773

RESUMO

Cytolethal distending toxins (CDTs) are common among pathogenic bacteria of the human and animal microbiota. CDTs exert cytopathic effets, via their active CdtB subunit. No clear description of those cytopathic effects has been reported at the cellular level in the target organs in vivo. In the present study, xenograft mouse models of colon and liver cell lines were set up to study the effects of the CdtB subunit of Helicobacter hepaticus. Conditional transgenic cell lines were established, validated in vitro and then engrafted into immunodeficient mice. After successful engraftment, mice were treated with doxycyclin to induce the expression of transgenes (red fluorescent protein, CdtB, and mutated CdtB). For both engrafted cell lines, results revealed a delayed tumor growth and a reduced tumor weight in CdtB-expressing tumors compared to controls. CdtB-derived tumors showed γ-H2AX foci formation, an increase in apoptosis, senescence, p21 and Ki-67 nuclear antigen expression. No difference in proliferating cells undergoing mitosis (phospho-histone H3) was observed. CdtB intoxication was also associated with an overexpression of cytokeratins in cells at the invasive front of the tumor as well as an increase in ploidy. All these features are hallmarks of endoreplication, as well as aggressiveness in cancer. These effects were dependent on the histidine residue at position 265 of the CdtB, underlying the importance of this residue in CdtB catalytic activity. Taken together, these data indicate that the CdtB triggers senescence and cell endoreplication leading to giant polyploid cells in these xenograft mouse models.


Assuntos
Envelhecimento/efeitos dos fármacos , Toxinas Bacterianas/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Distrofias Hereditárias da Córnea/metabolismo , Endorreduplicação/efeitos dos fármacos , Helicobacter hepaticus/metabolismo , Intestinos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Animais , Apoptose , Toxinas Bacterianas/metabolismo , Ciclo Celular/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Doxiciclina/farmacologia , Células Epiteliais , Células HT29/efeitos dos fármacos , Xenoenxertos , Histonas/metabolismo , Humanos , Antígeno Ki-67/metabolismo , Proteínas Luminescentes , Camundongos , Microbiota
10.
Int J Nanomedicine ; 12: 2657-2672, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28435250

RESUMO

DNA nanostructures prepared by self-assembly possess good stability, high biocompatibility, and low immunogenicity as drug delivery vehicles. In this work, DNA tetrahedron (TD) was constructed and modified with SL2B aptamer (S) and folic acid (F). TD possessed a small diameter (~6 nm) and entered into the nucleus quickly. SL2B aptamer can inhibit cancer cell growth by disturbing vascular endothelial growth factor/Notch signaling pathways. To explore the effect of SL2B number on colorectal cancer inhibition, SL2B multimers (dimer, trimer, and tetramer) were constructed by functionalization of TD with different numbers of SL2B. One SL2B per TD was the most efficient anticancer strategy and showed significantly better anticancer efficacy than SL2B, probably due to the enhanced stability of SL2B by TD. Doxorubicin (DOX) is a potent anticancer agent that can intercalate into DNA double strands. Results showed that TD could facilitate DOX entrance into the nucleus and the intracellular delivery of DOX was further enhanced by functionalization of SL2B and F. DOX-intercalated TD modified with two F and two S (DOX@TD-2F2S) could cause sufficient HT-29 cell inhibition at a much lower DOX concentration. In sum, DOX@TD-2F2S exhibited a synergic anticancer biological effect with chemotherapy and can be a promising strategy for treating colorectal cancer.


Assuntos
Aptâmeros de Nucleotídeos/química , Neoplasias Colorretais/tratamento farmacológico , Ácido Fólico/administração & dosagem , Nanoestruturas/administração & dosagem , Aptâmeros de Nucleotídeos/administração & dosagem , DNA/química , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Estabilidade de Medicamentos , Ácido Fólico/química , Ácido Fólico/farmacologia , Células HT29/efeitos dos fármacos , Humanos , Substâncias Intercalantes/administração & dosagem , Substâncias Intercalantes/química , Terapia de Alvo Molecular , Nanoestruturas/química
11.
Nutr Cancer ; 69(4): 663-673, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28353361

RESUMO

Methionine (Met) is involved in one-carbon de novo nucleotide synthesis and is an essential amino acid for cell survival. The impact of lactate calcium salt (CaLa) on the Met metabolism was investigated to evaluate the enhanced antitumor effect of methotrexate (MTX) on colorectal cancer (CRC) cells. Met dependency relating to homocysteine (Hcy) and betaine was investigated in human CRC cells (HCT-116 and HT-29) using a viability assay and liquid chromatography-mass spectrometry. Expression of betaine transporter-1 (BGT-1) following treatment with MTX alone or with CaLa was determined by Western blot. Enhanced antitumor effect due to malfunction of Met synthesis was confirmed. CRC cell viability decreased in Met-restricted medium, but was maintained after Hcy and betaine treatment while overcoming Met restriction. BGT-1 expression was downregulated following the treatment of dose-increased CaLa, whereas there was no effect on BGT-1 expression after MTX treatment. CaLa in combination with MTX induced reduced Met synthesis when CRC cell viability was reduced. The results indicated that CaLa-mediated BGT-1 downregulation inhibits Met synthesis by disrupting betaine homeostasis. CaLa raised the antitumor effect of MTX via secondary role in the inhibition of the de novo nucleotide synthesis. Combination therapy of MTX and CaLa could maximize the effectiveness of CRC treatment.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Metionina/metabolismo , Betaína/administração & dosagem , Betaína/metabolismo , Betaína/farmacologia , Compostos de Cálcio/administração & dosagem , Compostos de Cálcio/farmacologia , Proteínas de Transporte/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Proteínas da Membrana Plasmática de Transporte de GABA , Células HCT116/efeitos dos fármacos , Células HT29/efeitos dos fármacos , Humanos , Lactatos/administração & dosagem , Lactatos/farmacologia , Metotrexato/administração & dosagem , Metotrexato/farmacologia , Terapia de Alvo Molecular
12.
J Microbiol Biotechnol ; 27(4): 694-700, 2017 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-28173695

RESUMO

Clostridium difficile, which causes pseudomembranous colitis, releases toxin A and toxin B. These toxins are considered to be the main causative agents for the disease pathogenesis, and their expression is associated with a marked increase of apoptosis in mucosal epithelial cells. Colonic epithelial cells are believed to form a physical barrier between the lumen and the submucosa, and abnormally increased mucosal epithelial cell apoptosis is considered to be an initial step in gut inflammation responses. Therefore, one approach to treating pseudomembranous colitis would be to develop agents that block the mucosal epithelial cell apoptosis caused by toxin A, thus restoring barrier function and curing inflammatory responses in the gut. We recently isolated an antimicrobial peptide, Periplanetasin-2 (Peri-2, YPCKLNLKLGKVPFH) from the American cockroach, whose extracts have shown great potential for clinical use. Here, we assessed whether Peri-2 could inhibit the cell toxicity and inflammation caused by C. difficile toxin A. Indeed, in human colonocyte HT29 cells, Peri-2 inhibited the toxin A-induced decrease in cell proliferation and ameliorated the cell apoptosis induced by this toxin. Moreover, in the toxin A-induced mouse enteritis model, Peri-2 blocked the mucosal disruption and inflammatory response caused by toxin A. These results suggest that the American cockroach peptide Peri-2 could be a possible drug candidate for addressing the pseudomembranous colitis caused by C. difficile toxin A.


Assuntos
Anti-Infecciosos/farmacologia , Toxinas Bacterianas/metabolismo , Enterotoxinas/metabolismo , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/patologia , Peptídeos/antagonistas & inibidores , Periplaneta/química , Animais , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Clostridium difficile/metabolismo , Clostridium difficile/patogenicidade , Colo/efeitos dos fármacos , Colo/patologia , Modelos Animais de Doenças , Enterite/tratamento farmacológico , Enterocolite Pseudomembranosa/tratamento farmacológico , Enterocolite Pseudomembranosa/microbiologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Células HT29/efeitos dos fármacos , Humanos , Íleo/efeitos dos fármacos , Íleo/patologia , Inflamação , Interleucina-6/análise , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Camundongos , Peptídeos/administração & dosagem , Peptídeos/síntese química , Espécies Reativas de Oxigênio/análise , Transdução de Sinais
13.
Food Chem Toxicol ; 102: 63-75, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28159593

RESUMO

The present study investigated potential modulatory effects of low doses of nano-sized titanium dioxide (TiO2) on intestinal cells in vivo and in vitro. After short-term exposure to TiO2 nanoparticles in rats, histopathological analysis of intestinal tissues indicated a gender-specific effect with increased length of intestinal villi in male rats only. Moreover the intestinal tissue showed nanoparticle deposition as revealed by ICP-MS determination of titanium. Increased serum testosterone levels were also detected. Considering the male-specific effects detected in vivo, the TiO2 nanoparticle interaction with intestinal cells was further characterized in vitro and the modulating effect of testosterone and a hormone-induced growth factor, namely Insulin-like Growth Factor 1 (IGF-1), was also assessed. Cytotoxicity assays and analysis of Reactive Oxygen Species (ROS) production showed neither cellular alteration nor oxidative stress for nanoparticles at low concentrations, even though they were able to penetrate intestinal cells, as revealed by electron microscopy. Cell treatments with nanoparticles in association with testosterone or IGF-1 showed increased cell proliferation, compared to nanoparticles or testosterone/IGF-1 alone. Since long-term intake of TiO2 nanoparticles at low doses is a relevant scenario for human exposure, attention should be given to the potential modulating activity of this nanomaterial on cell proliferation.


Assuntos
Intestinos/efeitos dos fármacos , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/toxicidade , Titânio/administração & dosagem , Titânio/toxicidade , Administração Oral , Animais , Relação Dose-Resposta a Droga , Difusão Dinâmica da Luz , Feminino , Células HT29/efeitos dos fármacos , Humanos , Intestinos/citologia , Masculino , Nanopartículas Metálicas/química , Microscopia Eletrônica de Varredura , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Testosterona/farmacologia , Titânio/química , Testes de Toxicidade/métodos
14.
Chem Biol Drug Des ; 89(3): 443-455, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27717183

RESUMO

A novel class of tetrahydroisoquinoline derivatives was designed and synthesized as antitumor agents and evaluated for their in vitro and in vivo biological activities. The antiproliferative activities of all the target compounds on HUVEC, MCF-7, and HT-29 were evaluated. Compared with colchicine (1.04 × 10-2  µm), 17d and 17e exhibited outstanding activity on MCF-7 with IC50 values 0.26 × 10-2  µm and 0.89 × 10-3 µm in cell cytotoxicity assay. The tubulin polymerization assay demonstrated that 17d and 17e exhibited better inhibition rate. In the MCF-7-xenograft mouse model that was treated with 17d and 17e by intraperitoneal injection, the tumor weight was decreased at same rate with tamoxifen, and relative tumor proliferation rates were 59.48% and 41.33%, while tamoxifen was 45.08% with a daily dose of 20 mg/kg, which were demonstrated potent in vivo efficacy.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Tetra-Hidroisoquinolinas/química , Animais , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células HT29/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos , Podofilotoxina/química , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Food Chem ; 218: 249-255, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-27719906

RESUMO

Tyramine and histamine are the biogenic amines (BA) most commonly found at high concentrations in food; they may even appear together at toxic concentrations. The present work examines, via real-time cell analysis, whether histamine and tyramine show synergistic toxicity towards intestinal cell cultures. Employing a constant equipotency ratio, their interaction was examined via the combination index (CI) method of Chou & Talalay. Co-treatment with tyramine and histamine was associated with a stronger cytotoxic effect than was treatment with either BA or on its own. Indeed, a synergistic interaction (CI<1) was observed in the range of concentrations found in foods. The results also show that histamine, at concentrations below the legal limit, increases the cytotoxicity of tyramine at concentrations frequently reached in some foods. The synergistic cytotoxicity of tyramine and histamine should be taken into account when establishing legal limits designed to ensure consumer safety.


Assuntos
Aminas Biogênicas/toxicidade , Células Epiteliais/efeitos dos fármacos , Histamina/toxicidade , Intestinos/citologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Análise de Alimentos , Células HT29/efeitos dos fármacos , Humanos , Intestinos/efeitos dos fármacos , Tiramina/toxicidade
16.
Int J Nanomedicine ; 11: 6229-6238, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27920529

RESUMO

The purpose of this study was to develop a novel synthetic high-density lipoprotein (sHDL) nanoparticle delivery system for 10-hydroxycamptothecin (HCPT) for treatment of colon carcinoma. HDL is recognized by scavenger receptor B-I (SR-BI) over-expressed in colon carcinomas 5- to 35-fold relative to the human fibroblasts. The sHDL nanoparticles were composed of apolipoprotein A-I mimic peptide (5A) and contained 0.5%-1.5% (w/w) of HCPT. An optimized HCPT-sHDL formulation exhibited 0.7% HCPT loading with 70% efficiency with an average size of 10-12 nm. Partitioning of HCPT in the sHDL lipid membrane enhanced drug stability in its active lactone form, increased solubilization, and enabled slow release. Cytotoxicity studies in HT29 colon carcinoma cells revealed that the IC50 of HCPT-sHDL was approximately 3-fold lower than that of free HCPT. Pharmacokinetics in rats following intravenous administration showed that the area under the serum concentration-time curve (AUC0-t) and Cmax of HCPT-HDL were 2.7- and 6.5-fold higher relative to the values for the free HCPT, respectively. These results suggest that sHDL-based formulations of hydrophobic drugs are useful for future evaluation in treatment of SR-BI-positive tumors.


Assuntos
Camptotecina/análogos & derivados , Sistemas de Liberação de Medicamentos/métodos , Lipoproteínas HDL/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Apolipoproteína A-I/química , Camptotecina/administração & dosagem , Camptotecina/química , Camptotecina/farmacocinética , Estabilidade de Medicamentos , Células HT29/efeitos dos fármacos , Humanos , Lactonas/química , Lipoproteínas HDL/administração & dosagem , Nanopartículas/toxicidade , Ratos Sprague-Dawley
17.
Bioconjug Chem ; 27(12): 2943-2953, 2016 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-27998073

RESUMO

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide, especially in developed countries. Although patients' overall survival has been improved by either conventional chemotherapy or newly developed anti-angiogenesis treatment based on its highly vascularized feature, the relatively low therapeutic efficacy and severe side effects remain big problems in clinical practice. In this study, we describe an easy method to construct a novel matrix metalloproteinase-2 (MMP-2) responsive nanocarrier, which can load hydrophobic agents (camptothecin and sorafenib) with high efficiency to exert synergistic efficacy for CRC treatment. The drug-containing nanoparticles can particularly respond to the MMP-2 and realize the controlled release of payloads at the tumor site. Moreover, both in vitro and in vivo studies have demonstrated that this responsive nanoparticle exhibits much higher therapeutic efficacy than that of single antitumor agents or combined drugs coadministrated in traditional ways.


Assuntos
Inibidores da Angiogênese/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Metaloproteinase 2 da Matriz/metabolismo , Nanopartículas , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Camptotecina/administração & dosagem , Camptotecina/química , Camptotecina/farmacocinética , Neoplasias Colorretais/metabolismo , Liberação Controlada de Fármacos , Células HT29/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Nanopartículas/química , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacologia , Técnicas Fotoacústicas/métodos , Ratos Sprague-Dawley , Sorafenibe , Distribuição Tecidual , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Phytomedicine ; 23(13): 1680-1690, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27823633

RESUMO

BACKGROUND: Quercetin is a major dietary flavonoid found in a various fruits, vegetables, and grains. Although the inhibitory effects of quercetin have previously been observed in several types of cancer cells, the anti-metastatic effect of quercetin on colorectal metastasis has not been determined. PURPOSE: This study investigated whether quercetin exhibits inhibitory effect on colorectal lung metastasis. STUDY DESIGN: The effects of quercetin on cell viability, mitogen-activated protein kinases (MAPKs) activation, migration, invasion, epithelial-mesenchymal transition (EMT) and lung metastasis were investigated. METHODS: We investigated the effect of quercetin on metastatic colon cancer cells using WST assay, Annexin V assay, real-time RT-PCR, western blot analysis and gelatin zymography. The anti-metastatic effect of quercetin in vivo was confirmed in a colorectal lung metastasis model. RESULTS: Quercetin inhibited the cell viability of colon 26 (CT26) and colon 38 (MC38) cells and induced apoptosis through the MAPKs pathway in CT26 cells. Expression of EMT markers, such as E-, N-cadherin, ß-catenin, and snail, were regulated by non-toxic concentrations of quercetin. Moreover, the migration and invasion abilities of CT26 cells were inhibited by quercetin through expression of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) regulation. Quercetin markedly decreased lung metastasis of CT26 cells in an experimental in vivo metastasis model. CONCLUSION: In conclusion, this study demonstrates for the first time that quercetin can inhibit the survival and metastatic ability of CT26 cells, and it can subsequently suppress colorectal lung metastasis in the mouse model. These results indicate that quercetin may be a potent therapeutic agent for the treatment of metastatic colorectal cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Colorretais/patologia , Neoplasias Pulmonares/tratamento farmacológico , Quercetina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HT29/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Metaloproteinases da Matriz/metabolismo , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/metabolismo
19.
Anticancer Res ; 36(9): 4537-43, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27630293

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs, and the deregulated expression of miRNAs is associated with tumor development. Among these, the miR-17-92 cluster, including six mature miRNAs, is known as an oncogenic miRNA cluster because expression of the miR-17-92 cluster is frequently elevated in a variety of malignant tumors. MATERIALS AND METHODS: We investigated whether a mitogen-activated protein kinase kinase (MEK) inhibitor, PD0325901, suppresses expression of the miR-17-92 cluster in HT-29 human colon cancer cells and MIA PaCa-2 pancreatic cancer cells. RESULTS: PD0325901 inhibited cell growth with G1-phase arrest and suppressed expression of the miR-17-92 cluster. Furthermore, phosphatase and tensin homolog (PTEN), which is a target molecule of the miR-17-92 cluster, was up-regulated by PD0325901. The exogenous expression of miR-17 slightly, but significantly reduced G1-phase arrest by PD0325901. CONCLUSION: These results raise the possibility that a MEK inhibitor causes G1-phase arrest, at least partially, through suppression of the miR-17-92 cluster.


Assuntos
Pontos de Checagem do Ciclo Celular , Neoplasias do Colo/enzimologia , Regulação Neoplásica da Expressão Gênica , MAP Quinase Quinase Quinases/antagonistas & inibidores , MicroRNAs/genética , Benzamidas/química , Ciclo Celular , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células , Difenilamina/análogos & derivados , Difenilamina/química , Regulação para Baixo , Inibidores Enzimáticos/química , Fase G1 , Células HT29/efeitos dos fármacos , Humanos , MAP Quinase Quinase Quinases/metabolismo , Família Multigênica , Mutação , PTEN Fosfo-Hidrolase/metabolismo
20.
Int J Nanomedicine ; 11: 1947-58, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27226714

RESUMO

Colon cancer is the third most common cancer in the world, with drug resistance and metastasis being the major challenges to effective treatments. To overcome this, combination therapy with different chemotherapeutics is a common practice. In this study, we demonstrated that paclitaxel (PTX) together with BEZ235 exhibited a synergetic inhibition effect on colon cancer cell growth. Furthermore, nanoemulsion (NE)-loaded PTX and BEZ235 were more effective than the free drug, and a combination treatment of both NE drugs increased the efficiency of the treatments. BEZ235 pretreatment before adding PTX sensitized the cancer cells further, suggesting a synergistic inhibition effect through the phosphatidylinositol-3-kinases/protein kinase B/mammalian target of rapamycin pathway. The 50% inhibitory concentrations for BEZ235 were 127.1 nM and 145.0 nM and for PTX 9.7 nM and 9.5 nM for HCT-116 and HT-29 cells, respectively. When loaded with NE the 50% inhibitory concentrations for BEZ235 decreased to 52.6 nM and 55.6 nM and for PTX to 1.9 nM and 2.3 nM for HCT-116 and HT-29 cells, respectively. Combination treatment with 10 nM NE-BEZ235 and 0.6 nM and 1.78 nM NE-PTX could kill 50% of HCT-116 and HT-29, respectively. The cell death caused by the treatment was through apoptotic cell death, which coincided with decreased expression of anti-apoptotic protein B-cell lymphoma 2. Our data indicate that the combination therapy of PTX with the phosphatidylinositol-3-kinases/protein kinase B/mammalian target of rapamycin dual inhibitor BEZ235 using NE delivery may hold promise for a more effective approach for colon cancer treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias do Colo/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Neoplasias do Colo/patologia , Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Células HCT116/efeitos dos fármacos , Células HT29/efeitos dos fármacos , Humanos , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Nanocompostos/administração & dosagem , Paclitaxel/administração & dosagem , Paclitaxel/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinolinas/administração & dosagem , Quinolinas/farmacologia
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