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1.
Cancer Sci ; 111(3): 783-794, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31912579

RESUMO

Aberrant activation of the Wnt/ß-catenin signaling pathway has been observed in a wide range of human tumors. Deregulation of the pathway is closely linked to various aspects of human carcinogenesis such as cell viability, regulation of cell cycle, epithelial-mesenchymal transition, and maintenance of stemness. In addition, recent studies have disclosed the involvement of Wnt signaling in immune evasion of tumor cells. The accumulation of ß-catenin in the nucleus is a common feature of cancer cells carrying defects in the pathway, which leads to the continuous activation of T-cell factor (TCF)/LEF transcription factors. Consequently, a genetic program is switched on, leading to the uncontrolled growth, prolonged survival, and acquisition of mesenchymal phenotype. As ß-catenin/TCF serves as a signaling hub for the pathway, ß-catenin/TCF-dependent transcriptional activity is a relevant readout of the pathway. To date, a wide variety of synthetic TCF/LEF reporters has been developed, and high-throughput screening (HTS) using these reporters has made significant contributions to the discovery of Wnt inhibitors. Indeed, HTS led to the identification of chemical probes targeting porcupine, a membrane bound O-acyltransferase, and CREB-binding protein, a transcriptional coactivator. This review focuses on various screening strategies for the discovery of Wnt inhibitors and their mode of action to help the creation of new concepts for assay/screening methods.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/antagonistas & inibidores , Animais , Ensaios de Triagem em Larga Escala/métodos , Humanos , Fatores de Transcrição/genética , Via de Sinalização Wnt/genética , beta Catenina/genética
2.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1130-1131: 121829, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31670104

RESUMO

S011-2111 is a semicarbazone and chalcone hybrid demonstrating antiproliferative tumor cell-selective effects along with unique antimetastatic potential by mitigating PP2A-ß-catenin signalling pathway. The present study envisaged to explore the in vitro and in vivo pharmacokinetics of S011-2111. A sensitive and selective liquid chromatography-tandem mass spectrometry bioanalytical method was developed and validated to determine S011-2111. It has high permeability across intestinal membrane as observed in in situ single-pass intestinal perfusion study. It has high plasma protein binding and poor aqueous solubility. It was rapidly partitioning into plasma of blood, where it was moderately stable. In mice liver microsomal stability study, S011-2111 was stable against cytochrome P450 enzymes but undergoes rapid glucuronidation with intrinsic clearance of 148.6 ±â€¯48.3 µL/min/mg. Following 100 mg/kg oral dosing of S011-2111, the compound was detectable in the plasma samples up to 24 h with a maximum plasma concentration of 45 ±â€¯16.5 ng/mL at 2.4 ±â€¯0.1 h and absolute bioavailability of 1.68%. Knowledge from this research will assist in further development of S011-2111 as an anti-cancer agent.


Assuntos
Cromatografia Líquida/métodos , Inibidores Enzimáticos , Proteína Fosfatase 2/antagonistas & inibidores , Espectrometria de Massas em Tandem/métodos , beta Catenina/antagonistas & inibidores , Animais , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Eritrócitos , Feminino , Absorção Intestinal , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray/métodos
3.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370265

RESUMO

Osteosarcoma and Ewing sarcoma are the most common malignant primary bone tumors mainly occurring in children, adolescents and young adults. Current standard therapy includes multidrug chemotherapy and/or radiation specifically for Ewing sarcoma, associated with tumor resection. However, patient survival has not evolved for the past decade and remains closely related to the response of tumor cells to chemotherapy, reaching around 75% at 5 years for patients with localized forms of osteosarcoma or Ewing sarcoma but less than 30% in metastatic diseases and patients resistant to initial chemotherapy. Despite Ewing sarcoma being characterized by specific EWSR1-ETS gene fusions resulting in oncogenic transcription factors, currently, no targeted therapy could be implemented. It seems even more difficult to develop a targeted therapeutic strategy in osteosarcoma which is characterized by high complexity and heterogeneity in genomic alterations. Nevertheless, the common point between these different bone tumors is their ability to deregulate bone homeostasis and remodeling and divert them to their benefit. Therefore, targeting different actors of the bone tumor microenvironment has been hypothesized to develop new therapeutic strategies. In this context, it is well known that the Wnt/ß-catenin signaling pathway plays a key role in cancer development, including osteosarcoma and Ewing sarcoma as well as in bone remodeling. Moreover, recent studies highlight the implication of the Wnt/ß-catenin pathway in angiogenesis and immuno-surveillance, two key mechanisms involved in metastatic dissemination. This review focuses on the role played by this signaling pathway in the development of primary bone tumors and the modulation of their specific microenvironment.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Osteossarcoma/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Adolescente , Neoplasias Ósseas/genética , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/mortalidade , Osso e Ossos , Criança , Humanos , Metástase Linfática , Terapia de Alvo Molecular/métodos , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Neovascularização Patológica/mortalidade , Neovascularização Patológica/prevenção & controle , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/imunologia , Osteossarcoma/genética , Osteossarcoma/imunologia , Osteossarcoma/mortalidade , Proteínas Proto-Oncogênicas c-ets/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/imunologia , Proteína EWS de Ligação a RNA/antagonistas & inibidores , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/imunologia , Sarcoma de Ewing/genética , Sarcoma de Ewing/imunologia , Sarcoma de Ewing/mortalidade , Análise de Sobrevida , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Via de Sinalização Wnt/efeitos dos fármacos , Adulto Jovem , beta Catenina/antagonistas & inibidores , beta Catenina/genética , beta Catenina/imunologia
4.
Drug Des Devel Ther ; 13: 2235-2247, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371920

RESUMO

Purpose: Jatrorrhizine (JAT) is a natural protoberberine alkaloid, possesses detoxification, bactericidal and hypoglycemic activities. However, its anti-cancer mechanism is not clear. This study aimed to investigate the mechanism of JAT through which inhibits colorectal cancer in HCT-116 and HT-29 cells. Methods: MTT assay and colony formation assay were used to check the cell proliferation ability. Cell apoptosis and cell cycle were measured by Hoechst 33342 staining and flow cytometry, respectively. Cell migration and invasion were detected by scratch wound healing assay and trans-well assay, respectively. Further, expression of related proteins was examined via Western blotting and the in vivo anti-cancer effect of JAT was confirmed by nude mice xenograft model. Results: The research showed that JAT inhibited the proliferation of HCT-116 and HT-29 cells with IC50 values of 6.75±0.29 µM and 5.29±0.13 µM, respectively, for 72 hrs. It has also showed a time dependently, cell cycle arrested in S phase, promoted cell apoptosis and suppressed cell migration and invasion. In addition, JAT inhibited Wnt signaling pathway by reducing ß-catenin and increasing GSK-3ß expressions. Increased expression of E-cadherin, while decreased N-cadherin, indicating that JAT treatment suppressed the process of cell epithelial-mesenchymal transition (EMT). In HCT-116 nude mice xenograft model, JAT inhibited tumor growth and metastasis, and induced apoptosis of tumor cells. Conclusion: This study demonstrated that JAT efficiently inhibited colorectal cancer cells growth and metastasis, which provides a new point for clinical treatment of colorectal cancer.


Assuntos
Antineoplásicos/farmacologia , Berberina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/antagonistas & inibidores , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Berberina/química , Berberina/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células HT29 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Relação Estrutura-Atividade , Cicatrização/efeitos dos fármacos , beta Catenina/metabolismo
5.
J Orthop Surg Res ; 14(1): 258, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412883

RESUMO

BACKGROUND: Failed back surgery syndrome (FBSS) is a common complication after the laminectomy. Epidural fibrosis is the major cause of lower back pain and other complications. Numerous studies have shown that apigenin (API) could treat various fibrotic diseases by regulating various signaling pathways, whereas no study has discussed whether API can inhibit fibroblast proliferation and reduce epidural fibrosis after the laminectomy by regulating Wnt3a/ß-catenin signaling pathway. METHODS: Human fibroblasts were cultured and treated with API in different concentrations for 24 h. CCK-8 detection and EdU incorporation assay were performed to detect cell viability and cell proliferation. Western blotting analysis was applied to detect expressions of proliferative proteins, Wnt3a, and its downstream proteins. Moreover, the Wnt3a gene was overexpressed in fibroblasts to define the relationship between Wnt3a/ß-catenin signaling pathway and fibroblast proliferation. Wnt3a overexpressed fibroblasts were treated with API to verify if it could reverse the effects of API treatment. Twenty-four Sprague-Dawley rats were randomly divided into four groups. Laminectomy was performed and the rats were gavaged with different doses of API or 5% sodium carboxyl methyl cellulose (CMC-Na) solution for 1 month. The abilities of API to inhibit fibroblast proliferation and to reduce epidural fibrosis were evaluated using histological and immunohistochemical analysis. RESULTS: CCK-8 detection and EdU incorporation assay demonstrated that API could inhibit the viability and proliferation rate of fibroblasts in a concentration-dependent manner. The Western blotting analysis revealed that API could inhibit the expressions of PCNA, cyclinD1, Wnt3a, and its downstream proteins. The overexpression of Wnt3a in fibroblasts could upregulate the expressions of proliferative proteins such as PCNA and cyclinD1. The inhibitory effect of API on PCNA, Wnt3a, and its downstream proteins was partially reversed by overexpression of Wnt3a. Moreover, the results of the histological and immunohistochemical analysis revealed that API could reduce the epidural fibrosis in rats by inhibiting fibroblast proliferation in a dose-dependent manner. CONCLUSIONS: API can inhibit fibroblast proliferation and reduce epidural fibrosis by suppressing Wnt3a/ß-catenin signaling pathway, which can be adopted as a new option to prevent epidural fibrosis after the laminectomy.


Assuntos
Apigenina/farmacologia , Espaço Epidural/metabolismo , Fibroblastos/metabolismo , Proteína Wnt3A/metabolismo , beta Catenina/metabolismo , Animais , Apigenina/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Espaço Epidural/efeitos dos fármacos , Espaço Epidural/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Fibrose/patologia , Células HEK293 , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Proteína Wnt3A/antagonistas & inibidores , beta Catenina/antagonistas & inibidores
6.
Anticancer Res ; 39(7): 3661-3667, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262892

RESUMO

BACKGROUND/AIM: To explore the possibility of a selective small-molecule ß-catenin inhibitor, CWP232228, as a potential therapeutic drug in the treatment of colorectal cancer (CRC). MATERIALS AND METHODS: The effect of CWP2228 on HCT116 cells was analysed in vitro via flow cytometry, western immunoblotting, and luciferase reporter assays. NOD-scid IL2Rgammanull mice were employed for an in vivo xenograft study to validate the in vitro studies. RESULTS: CWP232228 treatment decreased the promoter activity and nuclear expression of ß-catenin and induced a significant cytotoxic effect in HCT116 cells. CWP232228 treatment induced apoptosis and cell-cycle arrest in the G1 phase of the cell cycle. Furthermore, CWP232228 decreased the expression of aurora kinase A, c-Myc, cyclin D1 and microphthalmia-associated transcription factor. Lastly, CWP232228 also inhibited the growth of xenografted colon cancer cells in mice. CONCLUSION: Collectively, CWP232228 may be used as a potential therapeutic drug in CRC.


Assuntos
Antineoplásicos/farmacologia , Compostos Azabicíclicos/farmacologia , Neoplasias do Colo/metabolismo , Organofosfatos/farmacologia , beta Catenina/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Compostos Azabicíclicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Células HCT116 , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Organofosfatos/uso terapêutico , Carga Tumoral/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos
7.
Drug Des Devel Ther ; 13: 2009-2019, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354246

RESUMO

Background: miR-29a, a downstream factor of Wnt/ß-catenin signaling, promotes the activity of the Wnt/ß-catenin signaling in a positive feedback loop. Our previous work showed that 5,7,3',4'-tetramethoxyflavone (TMF), a major constituent from Murraya exotica L., exhibited chondroprotective activity by inhibiting the activity of Wnt/ß-catenin signaling. Purpose: To investigate whether TMF showed the inhibitory effects on miR-29a/ß-catenin signaling by up regulation of Foxo3a expression. Methods: Rat knee OA models were duplicated by using Hulth's method. TMF (5 µg/mL and 20 µg/mL) was used for administration to cultured cells, which were isolated from the rat cartilages. Analysis of chondrocytes apoptosis, gene expression, and protein expression were conducted. In addition, miR-29a mimics and pcDNA3.1(+)-Foxo3a vector were used for transfection, luciferase reporter assay for detecting the activity of Wnt/ß-catenin signaling, and co-immunoprecipitation for determining proteins interaction. Results: TMF down regulated miR-29a/ß-catenin signaling activity and cleaved caspase-3 expression and up regulated Foxo3a expression in OA rat cartilages. In vitro, miR-29a mimics down regulated the expression of Foxo3a and up regulated the activity of Wnt/ß-catenin signaling and cleaved caspase-3 expression. TMF ameliorated miR-29a/ß-catenin-induced chondrocytes apoptosis by up regulation of Foxo3a expression. Conclusion: TMF exhibited chondroprotective activity by up regulating Foxo3a expression and subsequently inhibiting miR-29a/Wnt/ß-catenin signaling activity.


Assuntos
Condrócitos/efeitos dos fármacos , Proteína Forkhead Box O3/metabolismo , Luteolina/farmacologia , MicroRNAs/antagonistas & inibidores , Osteoartrite/tratamento farmacológico , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/antagonistas & inibidores , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Luteolina/administração & dosagem , MicroRNAs/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Ratos , Regulação para Cima/efeitos dos fármacos , beta Catenina/metabolismo
8.
Int J Mol Sci ; 20(15)2019 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-31357721

RESUMO

Combinatorial therapeutic strategies using siRNA and small molecules to eradicate tumors are emerging. Targeting multiple signaling pathways decreases the chances of cancer cells switching and adapting new signaling processes that may occur when using a single therapeutic modality. Aberrant functioning of Notch-1, Wnt/ß-catenin, and STAT3 proteins and their crosstalk signaling pathways have been found to be involved in tumor survival, drug resistance, and relapse. In the current study, we describe a therapeutic potential of single and combinations of siRNA designed for silencing Notch-1, Wnt/ß-catenin, and STAT3 in MCF7_DoxS (wild type) and MCF7_DoxR (doxorubicin resistant) breast cancer cells. The MCF7_DoxR cells were developed through treatment with a gradual increase in doxorubicin concentration, the expression of targeted genes was investigated, and the expression profiling of CD44/CD24 of the MCF7_DoxS and MCF7_DoxR cells were detected by flow cytometry. Both MCF7_DoxS and MCF7_DoxR breast cancer cells were treated with single and combinations of siRNA to investigate synergism and were analyzed for their effect on cell proliferation with and without doxorubicin treatment. The finding of this study showed the overexpression of targeted genes and the enrichment of the CD44-/CD24+ phenotype in MCF7_DoxR cells when compared to MCF7_DoxS cells. In both cell lines, the gene silencing efficacy showed a synergistic effect when combining STAT3/Notch-1 and STAT3/Notch-1/ß-catenin siRNA. Interestingly, the chemosensitivity of MCF7_DoxS and MCF7_DoxR cells to doxorubicin was increased when combined with siRNA treatment. Our study shows the possibility of using single and combinations of siRNA to enhance the chemosensitivity of cancer cells to conventional antitumor chemotherapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Receptor Notch1/genética , Fator de Transcrição STAT3/genética , beta Catenina/genética , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Antígeno CD24/genética , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Inativação Gênica/efeitos dos fármacos , Humanos , Receptores de Hialuronatos/genética , Células MCF-7 , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , RNA Interferente Pequeno/antagonistas & inibidores , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , beta Catenina/antagonistas & inibidores
9.
Biotechnol Appl Biochem ; 66(5): 787-793, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31169325

RESUMO

Evidence suggests that Weichang'an (WCA) inhibited the metastasis of colorectal cancer (CRC) in vitro and downregulates oncogenic ß-catenin; more intriguingly, we also found an upregulation of ARHGAP25 in this process. This study aimed to investigate the mechanisms by which WCA regulated CRC metastasis in vitro. Here, HCT116 cells were transfected with siRNAs to interfere ARHGAP25 expression. WCA decoction, XAV939 (a specific Wnt/ß-catenin pathway inhibitor), and LiCl (an activator for Wnt/ß-catenin pathway) were used for treatment. Cell migratory and invasive capacities were determined using Transwell chamber. The activation of Wnt/ß-catenin pathway was assessed by determining the expression of MMP7, MMP9, ZEB1, and ß-catenin. The study suggests that WCA inhibited the migration and invasion of HCT116 cells and suppressed the activation of Wnt/ß-catenin pathway, as evidenced by retarding MMP7, MMP9, ZEB1, and ß-catenin. However, siRNA-ARHGAP25 resulted in the opposite. In siRNA-ARHGAP25-transfected HCT116 cells, WCA (0.4 mg/mL) induced the antimetastatic effects and the inactivation of Wnt/ß-catenin pathway was remarkably reversed with additional LiCl treatment. Our study concludes that inhibiting Wnt/ß-catenin pathway while promoting ARHGAP25 was the mechanism, whereby WCA retarded migration and invasion of CRC in vitro.


Assuntos
Movimento Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Proteínas Ativadoras de GTPase/metabolismo , Regulação para Cima/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/química , Proteínas Ativadoras de GTPase/genética , Células HCT116 , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Relação Estrutura-Atividade , beta Catenina/metabolismo
10.
Environ Pollut ; 252(Pt A): 216-226, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31151060

RESUMO

Microcystins (MCs) have been shown to be carcinogenic by animal and cellular experiments and found to be associated with the development of human hepatocellular carcinoma (HCC) through epidemiological studies. However, the molecular mechanism of microcystin-LR (MC-LR) induced HCC is still unclear. This study is determined to clarify the role and mechanism of LHX6 in MC-LR-induced hepatocarcinogenesis. Using the previously established MC-LR-induced malignant transformation model in L02 cells, we screened out LHX6, homeobox gene that was significantly changed. We found that LHX6 was significantly down-regulated in MC-LR treated L02 cells and the liver tissue of rats treated for 35 weeks with 10 µg/kg body weight of MC-LR. Expression of LHX6 in human tumor tissue was significantly down-regulated in high MC-LR-exposure group. LHX6 was hypermethylated in MC-LR treated L02 cells and up-regulated after treatment with 10 µM of 5-aza-2'-deoxycytidine. Furthermore, overexpression of LHX6 inhibited proliferation, invasion and migration of malignantly transformed L02 cells in vitro and in vivo, while knockdown of LHX6 resulted in an opposite phenotype. In addition, we found that up-regulation of P53 and Bax resulted in apoptosis, and that down-regulation of CTNNB1 and MMP7 led to migration of MC-LR treated L02 cells. Blockade of P53 and CTNNB1 by its inhibitor significantly diminished the effect of LHX6. These genes were working together during the process of MC-LR-induced hepatocarcinogenesis. Our study demonstrated for the first time that LHX6 gene expression is regulated by DNA methylation and can inhibit the proliferation, invasion and migration through Wnt/ß-catenin and P53 signaling pathways during the MC-LR-induced hepatocarcinogenesis. This result may suggest that LHX6 gene can be used as a potential target gene and a biomarker for liver cancer treatment.


Assuntos
Carcinoma Hepatocelular/induzido quimicamente , Transformação Celular Neoplásica/induzido quimicamente , Proteínas com Homeodomínio LIM/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Microcistinas/toxicidade , Proteínas do Tecido Nervoso/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Metilação de DNA/efeitos dos fármacos , Decitabina/farmacologia , Epigênese Genética , Humanos , Proteínas com Homeodomínio LIM/genética , Metaloproteinase 7 da Matriz/metabolismo , Proteínas do Tecido Nervoso/genética , Ratos , Transdução de Sinais , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismo
11.
Drug Des Devel Ther ; 13: 1449-1460, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118579

RESUMO

Background: Colorectal cancer (CRC) is a common form of cancer associated with a high mortality rate and poor prognosis. Given the limited efficacy of current therapies for CRC, interest in novel therapeutic agents isolated from natural sources has increased. We studied the anticancer properties of isobavachalcone (IBC), a flavonoid isolated from the herb Psoralea corylifolia, which is used in traditional Chinese medicine, in an in vitro model of CRC. Materials and methods: Cell viability and growth of CRC cells were determined by Cell Counting Kit-8 and colony formation assays following treatment with varying concentrations of IBC, respectively. Apoptosis was examined by 4',6-diamidino-2-phenylindole staining and flow cytometry with Annexin V/propidium iodide double staining. Western blot analysis was used to analyze expression of apoptosis-associated protein pathway and the AKT/GSK-3ß/ß-catenin signaling pathway. Results: Initial experiments showed that IBC inhibited proliferation and colony formation of human CRC cell lines in dose- and time-dependent manners. The antiproliferative effect of IBC resulted from induction of apoptosis, as evidenced by morphological changes in the nucleus, flow cytometry analysis, upregulation of cleaved caspase-3 and cleaved PARP, changes in the ratio of the anti-apoptotic protein Bcl-2 and the pro-apoptotic protein Bax, translocation of Bax from the cytosol to the mitochondria, and decreased expression of two inhibitors of apoptosis family proteins, XIAP, and survivin. Western blot analysis of signaling pathway proteins demonstrated that IBC downregulated Wnt/ß-catenin signaling, which has previously been associated with CRC, by inhibiting the AKT/GSK-3ß signaling pathway. Conclusion: This study demonstrated that IBC inhibited cell proliferation and induced apoptosis through inhibition of the AKT/GSK-3ß/ß-catenin pathway in CRC. These results suggest the potential of IBC as a novel therapeutic agent for the treatment of CRC.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Chalconas/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Psoralea/química , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalconas/química , Chalconas/isolamento & purificação , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificação , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismo
12.
Cell Biol Int ; 43(8): 931-939, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31124219

RESUMO

Phosphoinositide 3-kinase (PI3K) signaling is frequently deregulated in breast cancer and plays a critical role in tumor progression. However, resistance to PI3K inhibitors in breast cancer has emerged, which is due to the enhanced ß-catenin nuclear accumulation. Until now, the mechanisms underlying PI3K inhibition-induced ß-catenin nuclear accumulation remains largely unknown. In the present study, we found inhibition of PI3K with LY294002 promoted ß-catenin nuclear accumulation in MCF-7 and MDA-MB-231 breast cancer cells. Combining PI3K inhibitor LY294002 with XAV-939, an inhibitor against ß-catenin nuclear accumulation, produced an additive anti-proliferation effect against breast cancer cells. Subsequent experiments suggested ß-catenin nuclear accumulation induced by PI3K inhibition depended on the feedback activation of epidermal growth factor receptor (EGFR) signaling pathway in breast cancer cells. Inhibition of EGFR phosphorylation with Gefitinib enhanced anti-proliferation effect of PI3K inhibitor LY294002 in MCF-7 and MDA-MB-231 cells. Taken together, our findings may elucidate a possible mechanism explaining the poor outcome of PI3K inhibitors in breast cancer treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Cromonas/farmacologia , Gefitinibe/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Morfolinas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Células MCF-7 , beta Catenina/antagonistas & inibidores
13.
Anticancer Res ; 39(5): 2447-2451, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092438

RESUMO

BACKGROUND/AIM: The insulin-like growth factor 1 (IGF1) signaling pathway as an aging mechanism related to p53 in human melanogenesis remains unclear. The aim of this study was to investigate the relationship between p53 and IGF1 signaling pathway in young, senescent and H2O2-treated cells. MATERIALS AND METHODS: The protein and gene expression in young, senescent and H2O2-treated cells were analyzed using western blot and reverse transcription polymerase chain reaction (RT-PCR) assays, respectively. RESULTS: The expression levels of (phosphoinositide 3-kinases) PI3K, v-akt murine thymoma viral oncogene homolog 1 (AKT1), mammalian target of rapamycin, ß-catenin (CTNNB1), acetylated p53 (ac-p53), p53 and p-p21 proteins, related to IGF1 and p53 signaling pathways, were higher in senescent and H2O2-treated cells than those of young cells. Furthermore, AKT reduced melanogenesis through microphthalmia-associated transcription factor (MITF) inactivation by the inhibition of CTNNB1. The gene expression levels of PI3K, TP53 and catalase (CAT) in senescent and H2O2-treated cells were increased compared to young cells. CONCLUSION: p53 protein plays a key role in the aging of melanocytes via IGF1 signaling pathways.


Assuntos
Envelhecimento/genética , Proliferação de Células/genética , Fator de Crescimento Insulin-Like I/genética , Proteína Supressora de Tumor p53/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Catalase/genética , Proliferação de Células/efeitos dos fármacos , Senescência Celular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/toxicidade , Melanócitos/metabolismo , Melanócitos/patologia , Camundongos , Fator de Transcrição Associado à Microftalmia/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , beta Catenina/antagonistas & inibidores , beta Catenina/genética
14.
Br J Cancer ; 120(9): 941-951, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30944457

RESUMO

BACKGROUND: Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signalling pathway and are attractive targets for cancer therapy. These agents continue to be investigated in KRAS mutant colon cancer but are met with significant resistance. Clinical investigations have demonstrated that these strategies are not well tolerated by patients. METHODS: We investigated a biomarker of response for MEK inhibition in KRAS mutant colon cancers by LC-MS/MS analysis. We tested the MEK inhibitor in PIK3CA wild(wt) and mutant(mt) colon cancer cells. In addition, we tested the combinational effects of MEK and TNKS inhibitor in vitro and in vivo. RESULTS: We identified ß-catenin, a key mediator of the WNT pathway, in response to MEK inhibitor. MEK inhibition led to a decrease in ß-catenin in PIK3CA wt colon cancer cells but not in mt. Tumour regression was promoted by combination of MEK inhibition and NVP-TNS656, which targets the WNT pathway. Furthermore, inhibition of MEK promoted tumour regression in colon cancer patient-derived xenograft models expressing PIK3CA wt. CONCLUSIONS: We propose that inhibition of the WNT pathway, particularly ß-catenin, may bypass resistance to MEK inhibition in human PIK3CA mt colon cancer. Therefore, we suggest that ß-catenin is a potential predictive marker of MEK inhibitor resistance.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/genética , beta Catenina/metabolismo , Acetamidas/farmacologia , Animais , Biomarcadores Farmacológicos/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias do Colo/metabolismo , Farmacorresistência Viral , Humanos , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 3/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Pirimidinonas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/antagonistas & inibidores
15.
Chem Biol Interact ; 305: 148-155, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-30929997

RESUMO

Accumulating evidence has documented that ataxia-telangiectasia group D complementing gene (ATDC) is aberrantly expressed in various cancers and is associated with cancer development and progression. However, little is known about the role of ATDC in glioma tumorigenesis. In this study, we aimed to explore the biological function and regulatory mechanism of ATDC in glioma. We found that ATDC expression was highly upregulated in glioma cell lines. Knockdown of ATDC significantly inhibited the growth and invasion of glioma cells. In contrast, overexpression of ATDC markedly promoted the growth and invasion of glioma cells. Moreover, our results showed that inhibition of ATDC reduced the expression levels of Dishevelled 2 (Dvl2) and ß-catenin and impeded the activation of Wnt/ß-catenin signaling, whereas overexpression of ATDC showed the opposite effect. Knockdown of Dvl2 significantly blocked the promotion effect of ATDC overexpression on activation of Wnt/ß-catenin signaling. In addition, silencing of ß-catenin partially reversed the oncogenic effect of ATDC overexpression in glioma cells. Taken together, out study reveals an oncogenic role of ATDC that drives the growth and invasion of glioma by modulating the Wnt/Dvl2/ß-catenin signaling pathway, suggesting a potential therapeutic target for treatment of glioma.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Proteínas Desgrenhadas/metabolismo , Glioma/metabolismo , Glioma/patologia , Humanos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Regulação para Cima , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismo
16.
Biochem Pharmacol ; 164: 205-215, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30991049

RESUMO

Endothelial to mesenchymal transition (EndMT), where endothelial cells acquire mesenchymal characteristics has been implicated in several cardiopulmonary, vascular and fibrotic diseases. The most commonly studied molecular mechanisms involved in EndMT include TGFß, Notch, interleukin, and interferon-γ signaling. As of today, the contributions of Akt1, an important mediator of TGFß signaling and a key regulator of endothelial barrier function to EndMT remains unclear. By using the ShRNA based gene silencing approach and endothelial-specific inducible Akt1 knockdown (ECKOAkt1) mice, we studied the role of Akt1 in EndMT in vitro and pathological vascular remodeling in vivo. Stable, Akt1 silenced (ShAkt1) human microvascular endothelial cells (HMECs) indicated increased expression of mesenchymal markers such as N-cadherin and α-SMA, phosphorylation of Smad2/3, cellular stress via activation of p38 MAP Kinase and the loss of endothelial nitric oxide synthase (eNOS) accompanied by a change in the morphology of HMECs in vitro and co-localization of endothelial and mesenchymal markers promoting EndMT in vivo. EndMT as a result of Akt1 loss was associated with increased expression of TGFß2, a potent inducer of EndMT and mesenchymal transcription factors Snail1, and FoxC2. We observed that hypoxia-induced lung vascular remodeling is exacerbated in ECKOAkt1 mice, which was reversed by pharmacological inhibition of ß-catenin. Thus, we provide novel insights into the role of Akt1-mediated ß-catenin signaling in EndMT and pathological vascular remodeling, and present ß-catenin as a potential target for therapy for various cardiopulmonary diseases involving vascular remodeling.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Remodelação Vascular/fisiologia , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Indóis/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pirróis/farmacologia , Remodelação Vascular/efeitos dos fármacos
17.
Kaohsiung J Med Sci ; 35(7): 393-400, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31001900

RESUMO

Vascular calcification (VC) plays as a critical role on cardiovascular disease (CVD) and acts as a notable risk factor in cardiovascular system. Vascular smooth muscle cells (VSMCs) calcification can be triggered by high phosphate treatment; however, the explicit mechanism remains unclear. In the present study, we isolated VSMCs from primary rat artery, applied ß-GP (ß-glycerophosphate) for inducing VSMCs calcification in vitro to explore the mechanism of phosphate-induced calcification in VSMCs. Alizarin red staining was performed to assess the mineralization in VSMCs. Calcium deposition experiment was taken to evaluate the calcium content. ALP staining was determined to assess the ALP activity. The recombinant adenoviruses were constructed for the overexpression of Klotho and FGF23, respectively. qRT-PCR and western blot analysis were subjected to measure the expression of Klotho/FGF23 and correlated genes among Wnt7b/ß-catenin pathway. We found that the calcium content was obviously increased and Alizarin red staining was positive in calcification group exposure with high phosphate in a time-dependent manner. The expression of Klotho and FGF23 was significantly decreased in the calcification group. However, overexpression of Klotho and FGF23 markedly reversed VSMCs calcification stimulating with high phosphate treatment. Moreover, Wnt7b/ß-catenin inhibitor DKK1 could partly attenuate the effect of high phosphate on calcified VSMCs. These findings demonstrated that Klotho/FGF23 axis could modulate high phosphate-induced VSMCs calcification via Wnt7b/ß-catenin signaling pathway. Our findings unravel that Klotho/FGF23- Wnt7b/ß-catenin axis functions as a crucial role in the VSMCs calcification.


Assuntos
Fatores de Crescimento de Fibroblastos/genética , Glucuronidase/genética , Glicerofosfatos/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Calcificação Vascular/genética , Proteínas Wnt/genética , beta Catenina/genética , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Aorta/citologia , Aorta/metabolismo , Cálcio/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Glucuronidase/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Masculino , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/farmacologia , Transdução de Sinais , Proteínas Wnt/antagonistas & inibidores , Proteínas Wnt/metabolismo , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismo
18.
Phytomedicine ; 57: 352-363, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30831484

RESUMO

BACKGROUND: Nerigoside (NG), a cardenolide isolated from a commonfolk medicine, Nerium oleander Linn. (Apocynaceae), has not been explored for its biological effects. To date, cardenolides have received considerable attention in pharmacology studies due to their direct effects of apoptosis-induction or growth-inhibitory against tumor in vitro and in vivo. Whether and how NG exerts anticancer effects against colorectal cancer remains to be elucidated. PURPOSE: The aim of this study was to investigate the anticancer effect of NG in human colorectal cancer cells. METHODS: To test anticancer effect, we compared potency of NG in two colorectal cancer cell lines, HT29 and SW620 by WST-1 and colony proliferation assays. And we investigated mechanism of anticancer activities by analyzing players in apoptotic and ERK/GSK3ß/ß-catenin signaling pathways in HT29 and SW620 cells treated with NG. RESULTS: In this study, we showed that NG markedly suppressed the cell viability and colony formation of colorectal cancer cells HT29 and SW620, with no significant toxic effect on non-cancer cells NCM460. Annexin V-FITC/PI and CFSE labeling results revealed that NG suppressed cell proliferation in low concentration, along with reducing expression of PCNA, while NG induced apoptosis in high concentration,. Meanwhile, NG significantly arrested cell migration by reversal of EMT and cell cycle on G2/M. Then, we found that the ERK and GSK3ß/ß-catenin signaling pathway were noticeably blocked in CRC cells after treatment with NG. According to western blot, NG upregulated the expression of p-GSK3ß/GSK3ß and decreased especially the expression of ß-catenin in nuclear. In addition, Wnt signaling and its target genes were suppressed in response to NG. Then, the Ser9 phosphorylation of GSK3ß can be reduced / raised by GÖ 6983 / LiCl, respectively. Thus, we further confirmed that the GSK3ß/ß-catenin axis is involved in NG-prevented cell proliferation. CONCLUSION: NG inhibited the growth of colorectal cancer cells by suppressing ERK/GSK3ß/ß-catenin signaling pathway. And the GSK3ß/ß-catenin axis is involved in preventing cell proliferation and migration by NG-treatment. These results suggest that NG may be used to treat colorectal cancer, with better outcome by combining with GSK3ß inhibitor to block Wnt pathway.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Glicogênio Sintase Quinase 3 beta/metabolismo , beta Catenina/metabolismo , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Células HT29 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Nerium/química , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , beta Catenina/antagonistas & inibidores
19.
Nanoscale ; 11(18): 8760-8775, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-30793730

RESUMO

Delivery of genetic medicines, such as small interfering RNA (siRNA), by lipid nanoparticles (LNPs) is a promising approach towards the treatment of diseases, such as solid tumors. However, in vitro and in vivo nanoparticle delivery efficiency is influenced by the formation of a protein corona in biological media. In this study, we have formulated four types of EnCore nanoparticles (F1 to F4) with a similar composition, but different polyethylene glycol (PEG) conjugated lipid chain lengths (carbon 14 vs. carbon 18) and molar ratios (6% vs. 3%). These LNPs showed dramatic differences in cellular delivery and transfection in hepatocellular carcinoma (HepG2) cells in the absence and presence of fetal bovine serum (FBS). The presence of proteins inhibited the cellular uptake of C18 (3%) nanoparticles, while it facilitated the cellular uptake of C14 nanoparticles. Among the adsorbed proteins from FBS, apolipoprotein E, but not apolipoprotein A1, affected the cellular uptake of the carbon 14 LNPs. Additionally, surface PEG was one of the determinants for the protein corona amount and composition. Finally, different serum to LNP volume ratios resulted in different protein enrichment patterns. Overall, the results showed a correlation between surface chemistry of LNPs and the protein corona composition suggesting a potential use for targeted delivery.


Assuntos
Proteínas Sanguíneas/química , Lipídeos/química , Nanopartículas/química , Coroa de Proteína/química , Interferência de RNA , Apolipoproteína A-I/química , Células Hep G2 , Humanos , RNA Interferente Pequeno/química , RNA Interferente Pequeno/metabolismo , Propriedades de Superfície , Transfecção/métodos , beta Catenina/antagonistas & inibidores , beta Catenina/genética , beta Catenina/metabolismo
20.
PLoS One ; 14(2): e0212538, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30794613

RESUMO

Autophagy targets cellular components for lysosomal-dependent degradation in which the products of degradation may be recycled for protein synthesis and utilized for energy production. Autophagy also plays a critical role in cell homeostasis and the regulation of many physiological and pathological processes and prompts this investigation of new agents to effect abnormal autophagy in hepatocellular carcinoma (HCC). 2,5-Dichloro-N-(2-methyl-4-nitrophenyl) benzenesulfonamide (FH535) is a synthetic inhibitor of the Wnt/ß-catenin pathway that exhibits anti-proliferative and anti-angiogenic effects on different types of cancer cells. The combination of FH535 with sorafenib promotes a synergistic inhibition of HCC and liver cancer stem cell proliferation, mediated in part by the simultaneous disruption of mitochondrial respiration and glycolysis. We demonstrated that FH535 decreased HCC tumor progression in a mouse xenograft model. For the first time, we showed the inhibitory effect of an FH535 derivative, FH535-N, alone and in combination with sorafenib on HCC cell proliferation. Our study revealed the contributing effect of Wnt/ß-catenin pathway inhibition by FH535 and its derivative (FH535-N) through disruption of the autophagic flux in HCC cells.


Assuntos
Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Sulfonamidas/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Nus , Sorafenibe/administração & dosagem , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/antagonistas & inibidores , beta Catenina/genética , beta Catenina/metabolismo
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