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1.
Medicine (Baltimore) ; 98(36): e17009, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31490383

RESUMO

Erythrina corallodendron L., a kind of landscape tree, has long been used as a traditional medicine. In this study, the composition of essential oil extracted from the leaves was analysed by GC-MS (gas chromatograph-mass spectrometer), with linalool identified as the main compound. Its cytotoxicity against MDA-MB-231, MCF-7 and HMLE cells was examined by MTT and cloning assays. Transwell and wound-healing assays were used to examine the inhibition of migration and invasion. Western blot, qRT-PCR and immunofluorescence staining were used to measure the mRNA and protein expression of factors related to EMT (snail, slug, E-cadherin, N-cadherin and vimentin). The essential oil of Erythrina corallodendron leaves was found to inhibit the proliferation, migration and invasion of breast cancer cells in a dose-dependent manner. The findings of this study suggest that the essential oil of E. corallodendron leaves may merit further investigation as a potential clinical or adjuvant drug for treating breast cancer migration and invasion.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/análise , Neoplasias da Mama/tratamento farmacológico , Erythrina/química , Óleos Voláteis/uso terapêutico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Células MCF-7 , Óleos Voláteis/química , Óleos Voláteis/isolamento & purificação , Óleos Voláteis/farmacologia , Fitoterapia , Folhas de Planta/química
2.
Toxicol Lett ; 316: 49-59, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520698

RESUMO

Epidemiological studies have established the correlations between PM2.5 and a wide variety of pulmonary diseases. However, their underlying pathogeneses have not been clearly elucidated yet. In the present study, the epithelial-mesenchymal transition (EMT) phenotype with enhanced proliferation and migration activity of human pulmonary epithelial cell line BEAS-2B was observed after exposure to low dose PM2.5 exposure (50 µg/ml) for 30 passages. Then, epithelial cells derived-exosomal micro-RNA (miRNA) and intracellular total RNA were extracted, and the differentially expressed exosomal miRNAs (DE-Exo-MiRs) as well as differentially expressed protein coding genes (DEGs) were identified by RNA sequencing (RNA-seq) and transcriptome analysis. We found that chronic PM2.5 exposure stimulated the release of pulmonary epithelium derived exosomes. 45 DE-Exo-MiRs including 32 novelly predicted miRNAs and 843 DEGs between PM2.5 exposed group and the normal control were detected. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that DEGs were significantly enriched in extracellular matrix organization, focal adhesion and cancer related terms. Besides, the enrichment analyses on 7774 mRNA targets of 27 DE-Exo-MiRs predicted by MiRanda software also revealed the potential regulatory role of exosomal miRNAs in pathways in cancer, Wingless/Integrated (Wnt) signaling pathway, focal adhesion related genes and other multiple pathogenic pathways. Moreover, the interactive exosomal miRNA-mRNA pair networks were constructed using Cytoscape software. Our results provided a novel basis for a better understanding of the mechanisms of chronic PM2.5 exposure induced pulmonary disorders including pulmonary fibrosis and cancer, in which exosomal miRNAs (Exo-MiRs) potentially functions by dynamically regulating gene expressions.


Assuntos
Células Epiteliais/efeitos dos fármacos , Exossomos/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Pulmão/efeitos dos fármacos , MicroRNAs/genética , Material Particulado/toxicidade , RNA Mensageiro/genética , Transcriptoma/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Biologia Computacional , Bases de Dados Genéticas , Células Epiteliais/metabolismo , Células Epiteliais/ultraestrutura , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Exossomos/genética , Exossomos/metabolismo , Exossomos/patologia , Redes Reguladoras de Genes , Humanos , Pulmão/metabolismo , Pulmão/ultraestrutura , MicroRNAs/metabolismo , Tamanho da Partícula , RNA Mensageiro/metabolismo , Medição de Risco , Fatores de Tempo , Testes de Toxicidade Crônica
3.
Shanghai Kou Qiang Yi Xue ; 28(3): 225-230, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31489406

RESUMO

PURPOSE: To investigate the mechanism of ANXA1 in TPF chemotherapy of oral squamous cell carcinoma (OSCC). METHODS: ANXA1 overexpression and low-expression cell lines were constructed. The role of ANXA1 in TPF chemotherapy was analyzed by cell proliferation, cytotoxicity test, real-time PCR and Western blot, and the mechanism of ANXA1 in TPF chemotherapy through EMT (epithelial-mesenchymal transition) pathway was discussed. The data were analyzed with SPSS 18.0 software package. RESULTS: After overexpression of ANXA1, cell growth rate decreased, cell cycle slowed down, sensitivity to TPF-induced drugs decreased, and EMT occurred in OSCC. After underexpression of ANXA1, cell growth rate increased, cell cycle accelerated, sensitivity to TPF chemotherapeutic drugs increased, and reverse EMT occurred in OSCC. CONCLUSIONS: In TPF chemotherapy of OSCC, overexpression of ANXA1 results in EMT of cells, which leads to decreased chemosensitivity.


Assuntos
Anexina A1 , Antineoplásicos , Carcinoma de Células Escamosas , Transição Epitelial-Mesenquimal , Neoplasias Bucais , Anexina A1/metabolismo , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética
4.
J Agric Food Chem ; 67(35): 9789-9795, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31373816

RESUMO

Pulmonary fibrosis is a chronic lung disease characterized by abnormal accumulation of the extracellular matrix (ECM). Chronic damage of the alveolar epithelium leads to a process called "epithelial-mesenchymal transition" (EMT) and increases synthesis and deposition of ECM proteins. Therefore, inhibition of EMT might be a promising therapeutic approach for the treatment of pulmonary fibrosis. ß-Sitosterol is one of the most abundant phytosterols in the plant kingdom and the major constituent in corn silk, which is derived from the stigma and style of maize (Zea mays). In this study, we elucidated that ß-sitosterol inhibited transforming growth factor-ß1 (TGF-ß1)-induced EMT and consequently had an antifibrotic effect. ß-Sitosterol (1-10 µg/mL) significantly downregulated the TGF-ß1-induced fibrotic proteins, such as collagen, fibronectin, and α-smooth muscle actin in human alveolar epithelial cells (p < 0.01). After 24 h, relative wound density (RWD) was increased in TGF-ß1 treated group (82.16 ± 5.70) compare to the control group (64.63 ± 2.21), but RWD was decreased in ß-sitosterol cotreated group (10 µg/mL: 71.54 ± 7.39; 20 µg/mL: 65.69 ± 6.42). In addition, the changes of the TGF-ß1-induced morphological shape and protein expression of EMT markers, N-cadherin, vimentin, and E-cadherin, were significantly blocked by ß-sitosterol treatment (p < 0.01). The effects of ß-sitosterol on EMT were found to be associated with the TGF-ß1/Snail pathway, which is regulated by Smad and non-Smad signaling pathways. Taken together, these findings suggest that ß-sitosterol can be used to attenuate pulmonary fibrosis through suppression of EMT by inhibiting the TGF-ß1/Snail pathway.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Extratos Vegetais/farmacologia , Alvéolos Pulmonares/efeitos dos fármacos , Fibrose Pulmonar/fisiopatologia , Sitosteroides/farmacologia , Zea mays/química , Actinas/genética , Actinas/metabolismo , Células Epiteliais Alveolares/citologia , Células Epiteliais Alveolares/metabolismo , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular , Fibronectinas/genética , Fibronectinas/metabolismo , Humanos , Extratos Vegetais/química , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/fisiopatologia , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
5.
Life Sci ; 234: 116781, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31430455

RESUMO

Cancer stem cells (CSCs) are a population of self-renewal cells with high tumorigenic potency. CSCs can adopt easily with changes in the nearby milieu, and are more resistant to conventional therapies than other cells within a tumor. CSC resistance can be induced secondary to radio- and chemotherapy, or even after chemotherapy secession. A combination of both intrinsic and extrinsic factors is contributed to CSC-mediated therapy resistance. CSCs represent protective autophagy and efficient cell cycling, along with highly qualified epithelial-mesenchymal transition (EMT) regulators, reactive oxygen species (ROS) scavengers, drug transporters, and anti-apoptotic and DNA repairing systems. In addition, CSCs develop cross-talking and share some characteristics with other cells within the tumor microenvironment (TME) being more intense in higher stage tumors, and thereby sophisticating tumor-targeted therapies. TME, in fact, is a nest for aggravating resistance mechanisms in CSCs. TME is exposed constantly to the nutritional, metabolic and oxygen deprivation; these conditions promote CSC adaptation. This review is aimed to discuss main (intrinsic and extrinsic) mechanisms of CSC resistance and suggest some strategies to revoke this important promoter of therapy failure.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Células-Tronco Neoplásicas/patologia , Animais , Antineoplásicos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos da radiação , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos da radiação , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos da radiação
6.
Oncol Rep ; 42(4): 1451-1458, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364732

RESUMO

Epithelial­mesenchymal transition (EMT) is closely related to tumor metastasis, and offers insight into novel strategies for cancer treatment. HMQ­T­F2 (F2) is a taspine derivative, which has excellent anticancer activity in human cervical cancer. The present study aimed to evaluate the effect of F2 on in vitro migration of HeLa cells. The present data demonstrated that F2 inhibited migration of HeLa cells by negatively regulating the Wnt signaling pathway and reversing EMT. F2 not only mediated Frizzled8, p­LRP6 and LRP6 expression, but also downregulated the phosphorylation of GSK3ß, and concurrently decreased the nucleus protein expression of MMP2, MMP3, MMP7, MMP9, and c­Myc. In addition, the expression of N­cadherin, vimentin, Snail and HIF­1α were downregulated and that of E­cadherin was upregulated after F2 treatment. F2 was also associated with the downregulation of the PI3K/Akt/mTOR signaling pathways. Notably, F2 induced HeLa cell accumulation at the S phase and cell apoptosis. These results provide evidence that F2 inhibits HeLa cell migration, proliferation and promotes apoptosis. It also reverses EMT, potentially via the PI3K/Akt signaling pathway. Therefore, F2 may be a potential therapeutic reagent against cervical cancer.


Assuntos
Alcaloides/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo , Alcaloides/química , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Fase S/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/patologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo
7.
Cancer Sci ; 110(10): 3315-3327, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385407

RESUMO

Despite advances and refinements in surgery and perioperative chemotherapy, there are still unmet medical needs with respect to radical cystectomy for muscle-invasive bladder cancer (MIBC). We investigated the potential benefit of supplementary granulocyte macrophage colony-stimulating factor (GM-CSF) to chemoimmunotherapy with programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis blockade and standard neoadjuvant chemotherapy in bladder cancer. We inoculated 2 × 105 MBT2 cells s.c. in C3H mice to create a syngeneic animal model of local recurrence (LR). When the tumor diameter reached 12 mm, the mice were allocated randomly as follows: (i) non-treated control (vehicle only); (ii) anti-mPD-L1 monotherapy; (iii) mGM-CSF monotherapy; (iv) anti-mPD-L1 plus mGM-CSF; (v) gemcitabine and cisplatin (GC); (vi) GC plus anti-mPD-L1; (vii) GC plus mGM-CSF; and (viii) GC plus anti-mPD-L1 plus mGM-CSF. After completing 2-week neoadjuvant therapy, tumors were resected for resection margin evaluation and immunohistochemical staining and blood was collected for flow cytometry and ELISA. Operative wounds were sutured, and the operative site was monitored to detect LR. Addition of anti-mPD-L1 and mGM-CSF to neoadjuvant GC chemotherapy enhanced the antitumor effect and reduced positive resection margins (50% vs 12.5%). Combination of GC, anti-mPD-L1, and mGM-CSF resulted in longer LR-free survival and cancer-specific survival compared to those in other groups. These effects involved an immunotherapy-related decrease in oncological properties such as tumor invasion capacity and epithelial-mesenchymal transition. mGM-CSF significantly decreased the accumulation of myeloid-derived suppressor cells in both the blood and tumor microenvironment and blood interleukin-6 levels. Supplementary GM-CSF to neoadjuvant GC plus PD-L1 blockade could decrease LR after radical surgery by immune modulation in the blood and tumor microenvironment.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Antígeno B7-H1/antagonistas & inibidores , Cisplatino/administração & dosagem , Desoxicitidina/análogos & derivados , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Recidiva Local de Neoplasia/terapia , Neoplasias da Bexiga Urinária/terapia , Animais , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Terapia Combinada , Cistectomia , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Margens de Excisão , Camundongos , Terapia Neoadjuvante , Recidiva Local de Neoplasia/imunologia , Distribuição Aleatória , Análise de Sobrevida , Resultado do Tratamento , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Bioengineered ; 10(1): 282-291, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31311401

RESUMO

Transforming growth factor (TGF)-ß1 plays a crucial role in the epithelial-to-mesenchymal transition (EMT) in many cancer types and in thyroid cancers. Epigallocatechin-3-gallate (EGCG), the most important ingredient in the green tea, has been reported to possess antioxidant and anticancer activities. However, the cellular and molecular mechanisms explaining its action have not been completely understood. In this study, we found that EGCG significantly suppresses EMT, invasion and migration in anaplastic thyroid carcinoma (ATC) 8505C cells in vitro by regulating the TGF-ß/Smad signaling pathways. EGCG significantly inhibited TGF-ß1-induced expression of EMT markers (E-cadherin reduction and vimentin induction) in 8505C cells in vitro. Treatment with EGCG completely blocked the phosphorylation of Smad2/3, translocation of Smad4. Taken together, these results suggest that EGCG suppresses EMT and invasion and migration by blocking TGFß/Smad signaling pathways.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Catequina/análogos & derivados , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais/efeitos dos fármacos , Células Epiteliais da Tireoide/efeitos dos fármacos , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Antígenos CD/genética , Antígenos CD/metabolismo , Caderinas/antagonistas & inibidores , Caderinas/genética , Caderinas/metabolismo , Catequina/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Humanos , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Células Epiteliais da Tireoide/metabolismo , Células Epiteliais da Tireoide/patologia , Fator de Crescimento Transformador beta1/farmacologia , Vimentina/agonistas , Vimentina/genética , Vimentina/metabolismo
9.
Life Sci ; 232: 116617, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260685

RESUMO

AIM: To investigate the effects and underlying mechanisms of taxifolin on proliferation, migration and invasion of highly aggressive breast cancer in vitro and in vivo. MAIN METHODS: The antineoplastic activity of taxifolin was evaluated in MDA-MB-231 and 4 T1 cells by crystal violet assay and colony formation assay. The effects of taxifolin on migration and invasion were determined by wound healing assay and Transwell assay, respectively. mRNA and protein expression of genes were assayed respectively with qRT-PCR and western blot, and the protein expression and location was also detected by immunofluorescence and immunohistochemistry. ß-catenin overexpression was performed with adenovirus infection. The effects of taxifolin on growth and metastasis of breast cancer in vivo were investigated in BALB/c mice bearing 4T1 xenografts. KEY FINDINGS: We found that taxifolin had the potential to inhibit proliferation, migration and invasion of highly aggressive breast cancer cells in a dose-dependent manner. In addition, taxifolin promoted the MET process, the reversed process of EMT, as evaluated by EMT markers and EMT-transcriptional factors in breast cancer cell lines. Meanwhile, the protein and mRNA expressions of ß-catenin were dose-dependently downregulated by taxifolin, and overexpression of ß-catenin by adenoviruses abrogated these beneficial effects of taxifolin above-mentioned. Furthermore, within a 4T1 xenograft mouse model, taxifolin markedly inhibited the growth of primary tumors and reduced lung metastasis of breast cancer. SIGNIFICANCE: Our findings provide a theoretical foundation for the possibility of taxifolin used as a promising agent in the clinical treatment of highly aggressive breast cancer patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quercetina/análogos & derivados , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Quercetina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismo
10.
Cancer Sci ; 110(9): 2834-2845, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31278880

RESUMO

Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously used in the treatment of diabetes, have been shown to have anticancer effects in various cancers, including breast, lung and prostate cancers. However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and SW1463 rectal cancer cells were more resistant to ionizing radiation and 5-fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor-ß/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X-linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor ß receptor 2-mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor-ß/Smad signaling.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Metformina/farmacologia , Fenformin/farmacologia , Neoplasias Retais/terapia , Transdução de Sinais/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Quimiorradioterapia/métodos , Colo/patologia , Neoplasias do Colo/patologia , Neoplasias do Colo/terapia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos da radiação , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Masculino , Metformina/uso terapêutico , Camundongos , Camundongos Nus , Recidiva Local de Neoplasia , Fenformin/uso terapêutico , Neoplasias Retais/patologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos da radiação , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Chem Biol Interact ; 309: 108725, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31238027

RESUMO

Tumor recurrence and metastasis decrease the survival rate of colorectal cancer (CRC) patients. Menadione reduces the numbers and incidences of 1,2-dimethylhydrazine induced colon tumors in mouse but the mechanism of anticancer activity of menadione in colorectal cancer is not very clear. Since Wnt signaling is constitutively active in CRC and it aggravates the epithelial mesenchymal transition (EMT), the regulation of EMT and Wnt signaling by menadione (vitamin K3) was investigated in CRC cells. Menadione showed cytotoxicity against human CRC cells (SW480 and SW620) and human primary colon cancer cells but was relatively ineffective against the cells from human normal colon (CRL-1790) and human primary colon epithelial cells. Menadione suppressed invasion, migration and epithelial-mesenchymal transition in human CRC cells by upregulating the expression of E-cadherin (CDH1), ZO-1 and downregulating that of N-cadherin (CDH2), Vimentin (VIM), ZEB1, MMP2 and MMP9. Menadione decreased TOPFlash/FOPFlash luciferase activity and expression of several downstream targets of Wnt signaling and coactivators such as ß-catenin (CTNNB1), TCF7L2, Bcl9l, p300 (EP300) and cyclin D1 (CCND1) was suppressed. Menadione induced differentiation and increased apoptotic cell population in SubG0 phase of cell cycle in SW480 and SW620 cells. The ability of menadione to suppress EMT, migration, invasion, Wnt signaling, cell proliferation and induce Sub G0 arrest, highlights its potential to be considered for intensive preclinical and clinical investigation in CRC.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Vitamina K 3/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Caderinas/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Ciclina D1/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Metaloproteinase 2 da Matriz/metabolismo
12.
J Agric Food Chem ; 67(26): 7274-7280, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31244200

RESUMO

Bioactivity-guided separation led to the isolation of six novel phenanthrenes, spiranthesphenanthrenes A-F (1-6), together with 19 known compounds, including seven phenanthrenes (7-13), one bibenzyl compound (14), five flavonoids (15-16 and 20-22), and six simple phenolic compounds (17-19 and 23-25), from the petroleum ether (PE) and ethyl acetate (EtOAc) extracts of Spiranthes sinensis (Pers.) Ames, an edible medicinal plant named "panlongshen" in Chinese that is popularly used in medicinal foods and herbal teas. The structures of the obtained compounds were identified on the basis of extensive NMR spectroscopy and HR-ESI-MS analyses. The cytotoxicities of the phenanthrenes (1-13), the bibenzyl compound (14) , and the flavonoids (15-16 and 20-22) toward SGC-7901, HepG2, and B16-F10 cell lines were examined in vitro. Compounds 1 and 7 exhibited moderate cytotoxic activities toward all of the selected cancer cell lines, and their IC50 values ranged from 19.0 ± 7.3 to 30.2 ± 5.6 µM. Spiranthesphenanthrene A (1) exhibited higher cytotoxic activity than the positive control cisplatin toward the B16-F10 cell line (IC50 = 19.0 ± 7.3 µM). A wound healing assay revealed the inhibition of the migration of B16-F10 cancer cells in a time- and dose-dependent pattern by treatment with 2.5, 5, and 10 µM solutions of compound 1 for 24 and 48 h, respectively. Western blots revealed that compound 1 obviously increased the level of the E-cadherin protein (an epithelial marker) and decreased the levels of the vimentin and N-cadherin proteins (mesenchymal markers). Furthermore, the level of the transcription factor Snail was also obviously decreased by compound 1 in a dose-dependent manner. Taken together, compound 1 inhibits the migration of B16-F10 cancer cells, which may be closely related to the inhibition of the epithelial-mesenchymal transition. Compound 1 represents a promising drug candidate for the prevention of tumor metastasis.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Orchidaceae/química , Fenantrenos/química , Fenantrenos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Fenantrenos/isolamento & purificação , Extratos Vegetais/isolamento & purificação
13.
Cancer Sci ; 110(8): 2442-2455, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31148345

RESUMO

The human prolyl isomerase PIN1, best known for its association with carcinogenesis, has recently been indicated in the disease of pancreatic ductal adenocarcinoma (PDAC). However, the functions of PIN1 and the feasibility of targeting PIN1 in PDAC remain elusive. For this purpose, we examined the expression of PIN1 in cancer, related paracarcinoma and metastatic cancer tissues by immunohistochemistry and analyzed the associations with the pathogenesis of PDAC in 173 patients. The functional roles of PIN1 in PDAC were explored in vitro and in vivo using both genetic and chemical PIN1 inhibition. We showed that PIN1 was upregulated in pancreatic cancer and metastatic tissues. High PIN1 expression is significantly association with poor clinicopathological features and shorter overall survival and disease-free survival. Further stratified analysis showed that PIN1 phenotypes refined prognostication in PDAC. Inhibition of PIN1 expression with RNA interference or with all trans retinoic acid decreased not only the growth but also the migration and invasion of PDAC cells through regulating the key molecules of multiple cancer-driving pathways, simultaneously resulting in cell cycle arrest and mesenchymal-epithelial transition in vitro. Furthermore, genetic and chemical PIN1 ablation showed dramatic inhibition of the tumorigenesis and metastatic spread and then reduced the tumor burden in vivo. We provided further evidence for the use of PIN1 as a promising therapeutic target in PDAC. Genetic and chemical PIN1 ablation exerted potent antitumor effects through blocking multiple cancer-driving pathways in PDAC. More potent and specific PIN1 targeted inhibitors could be exploited to treat this aggressive cancer.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Peptidilprolil Isomerase de Interação com NIMA/genética , Metástase Neoplásica/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Ductal Pancreático/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Neoplasias Pancreáticas/patologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
14.
Planta Med ; 85(9-10): 755-765, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31185503

RESUMO

Antcin-A (ATA) is a steroid-like phytochemical isolated from the fruiting bodies of a precious edible mushroom Antrodia cinnamomea. We previously showed that ATA has strong anti-inflammatory and anti-tumor effects; however, other possible bioactivities of this unique compound remain unexplored. In the present study, we aimed to investigate the modulation of epithelial-to-mesenchymal transition (EMT), anti-migration, and anti-invasive potential of ATA against human breast cancer cells in vitro. Human breast cancer cell lines, MCF-7 and MDA-MB-231, were incubated with ATA for 24 h. Wound healing, trans-well invasion, western blot, q-PCR, F-actin staining, and immunofluorescence assays were performed. We found that treatment with ATA significantly blocked EMT processes, as evidenced by upregulation of epithelial markers (E-cadherin and occludin) and downregulation of mesenchymal markers (N-cadherin and vimentin) via suppression of their transcriptional repressor ZEB1. Next, we found that ATA could induce miR-200c, which is a known player of ZEB1 repression. Further investigations revealed that ATA-mediated induction of miR-200c is associated with transcriptional activation of p53, as confirmed by the fact that ATA failed to induce miR-200c or suppress ZEB1 activity in p53 inhibited cells. Further in vitro wound healing and trans-well invasion assays support that ATA could inhibit migratory and invasive potentials of breast cancer cells, and the effect was likely associated with induced phenotypic modulation. Taken together, the present study suggests that antcin-A could be a lead phyto-agent for the development of anti-metastatic drug for breast cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Esteroides/farmacologia , Proteína Supressora de Tumor p53/genética , Antígenos CD/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Caderinas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , MicroRNAs/genética , Fator de Crescimento Transformador beta1/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
15.
Phytother Res ; 33(7): 1934-1942, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31172618

RESUMO

Theacrine, a purine alkaloid structurally similar to caffeine, has recently become of interest as a potential therapeutic compound. Here, we investigated the antimetastatic potential of theacrine on human breast cancer MDA-MB-231 cells. We observed that theacrine can reverse epithelial-to-mesenchymal transition (EMT), which resulted in a decrease in the levels of mesenchymal markers (Fibronectin, Vimentin, N-cadherin, Twist, and Snail) and an increase in the levels of epithelial markers (Occludin and E-cadherin) in the cells. Additionally, theacrine attenuates TGF-ß-induced EMT, cell adhesion, migration, and invasion in MDA-MB-231 cells. Overall, our results suggest that theacrine may inhibit the breast cancer cell metastasis by reversing the EMT process.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Ácido Úrico/análogos & derivados , Neoplasias da Mama/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Fibronectinas/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Proteína 1 Relacionada a Twist/metabolismo , Ácido Úrico/farmacologia , Vimentina/metabolismo
16.
Life Sci ; 230: 197-207, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31150688

RESUMO

AIMS: Increased amounts of protein, in particular albumin within renal tubular cells (TBCs), induce the expression of inflammatory and fibrogenic mediators, which are adverse prognostic factors in tubulointerstitial fibrosis and diabetic nephropathy (DN). We sought to assess the participation of the thiol-linked tertiary structure of albumin in the mechanism of protein toxicity in a model of TBCs. MATERIALS AND METHODS: Cultured human renal proximal tubular cells, HK-2, were exposed to isolated albumin from patients with and without DN (Stages 0, 1 and 4). The magnitude of change of the albumin tertiary structure, cell viability (LDH leakage), apoptosis (Annexin V), transdifferentiation and reticulum endoplasmic stress (Western blot and flow cytometry) and lysosomal enzyme activity were assessed. KEY FINDINGS: We found that albumin from Stage 4 patients presented >50% higher thiol-dependent changes of tertiary structure compared to Stages 0 and 1. Cells incubated with Stage 4 albumin displayed 5 times less viability, accompanied by an increased number of apoptotic cells; evidence of profibrogenic markers E-cadherin and vimentin and higher expression of epithelial-to-mesenchymal transition markers α-SMA and E-cadherin and of endoplasmic reticulum stress protein GRP78 were likewise observed. Moreover, we found that cathepsin B activity in isolated lysosomes showed a significant inhibitory effect on albumin from patients in advanced stages of DN and on albumin that was intentionally modified. SIGNIFICANCE: Overall, this study showed that thiol-dependent changes in albumin's tertiary structure interfere with the lysosomal proteolysis of renal TBCs, inducing molecular changes associated with interstitial fibrosis and DN progression.


Assuntos
Nefropatias Diabéticas/metabolismo , Lisossomos/fisiologia , Albumina Sérica Humana/fisiologia , Adulto , Idoso , Albuminas/metabolismo , Apoptose/efeitos dos fármacos , Caderinas/metabolismo , Linhagem Celular , Sobrevivência Celular , Transdiferenciação Celular , Nefropatias Diabéticas/fisiopatologia , Estresse do Retículo Endoplasmático , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Fibrose , Humanos , Túbulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Estrutura Terciária de Proteína/fisiologia , Albumina Sérica Humana/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vimentina/metabolismo
17.
Cell Physiol Biochem ; 53(1): 141-156, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31237760

RESUMO

BACKGROUND/AIMS: Previous research has indicated that the currently available histone deacetylase inhibitors (HDACis) are not effective as monotherapies against oral squamous cell carcinoma (OSCC). However, HDACis act synergistically with other therapeutic agents to exert significant antitumor activities. Thus, a strategy to develop chemotherapeutic agents by combining several active groups based on histone deacetylase (HDAC) into a single molecule as a conjugate that modulates multiple cellular pathways may be useful for the treatment of OSCC. METHODS: The novel inhibitor Roxyl-ZR was prepared by organic synthesis and its anticancer effects on OSCC were investigated by cell metabolism (n=5), colony formation (n=3), cell cycle (n=3), cell apoptosis (n=3), wound healing (n=3), transwell migration (n=3), and 5-bromo-2'-deoxyuridine staining (n=3) assays in vitro and in in vivo xenograft mice models (4 mice/group for subcutaneous xenograft and 3 mice/group for orthotopic xenograft ). The abundance of Ki67, Bcl-2, and p-STAT3 was detected by immunohistochemistry staining (n=4). Apoptotic cells in the tumor tissues of mice were detected by terminal deoxynucleotidyl transferase dUTP nickend labeling assay (n=3). The abundance of related proteins levels were evaluated by western blot (n=3). E-cadherin expression was detected by an immunofluorescence assay (n=3). RESULTS: Compared with the approved HDACi, conjugated Roxyl-ZR exhibited significantly higher antitumor effects in OSCC cells. Roxyl-ZR suppressed OSCC cell proliferation by inducing the reduction of S phase and inducing caspase-dependent apoptosis by down-regulating Bcl-2 expression. Moreover, Roxyl-ZR attenuated the epithelial-mesenchymal transition, which is closely associated with migration and invasion. In addition, Roxyl-ZR inhibited OSCC xenograft mice models and showed low toxicity. The mechanism underlying the Roxyl-ZR-enhanced sensitivity to HDACi may be attributed to the inhibition of key regulators of JAK1-STAT3 signaling pathway. CONCLUSION: HDAC-cyclin-dependent kinase conjugates represent a novel approach to the development of OSCC treatment. Our findings may open a new avenue for the development of novel inhibitors for the treatment of OSCC.


Assuntos
Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Benzimidazóis/síntese química , Benzimidazóis/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Janus Quinase 1/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transplante Heterólogo
18.
Int J Mol Sci ; 20(9)2019 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-31035577

RESUMO

Cataracts are the leading cause of blindness worldwide. Although surgery is a successful method to restore vision loss due to cataracts, post-surgical complications can occur, such as secondary cataracts, also known as posterior capsular opacification (PCO). PCO arises when lens epithelial cells (LEC) are left behind in the capsular bag following surgery and are induced to undergo epithelial to mesenchymal transition (EMT). Following EMT, LEC morphology and phenotype are altered leading to a loss of transparency and vision. Transforming growth factor (TGF)-ß-induced signaling through both canonical, TGF-ß/Smad, and non-canonical, ß-catenin/Wnt and Rho/ROCK/MRTF-A, pathways have been shown to be involved in lens EMT, and thus PCO. However, the interactions between these signaling pathways in the lens have not been thoroughly explored. In the current study we use rat LEC explants as an ex vivo model, to examine the interplay between three TGF-ß-mediated pathways using α-smooth muscle actin (α-SMA) as a molecular marker for EMT. We show that Smad3 inhibition via SIS3 prevents nuclear translocation of ß-catenin and MRTF-A, and α-SMA expression, suggesting a key role of Smad3 in regulation of MRTF-A and ß-catenin nuclear transport in LECs. Further, we demonstrate that inhibition of ß-catenin/CBP interaction by ICG-001 decreased the amount of phosphorylated Smad3 upon TGF-ß stimulation in addition to significantly decreasing the expression levels of TGF-ß receptors, TBRII and TBRI. Overall, our findings demonstrate interdependence between the canonical and non-canonical TGF-ß-mediated signaling pathways controlling EMT in the lens.


Assuntos
Transição Epitelial-Mesenquimal , Cristalino/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , beta Catenina/metabolismo , Animais , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Ligação Proteica , Transporte Proteico , Ratos , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/genética , Fator de Crescimento Transformador beta/farmacologia , beta Catenina/genética
19.
Ecotoxicol Environ Saf ; 180: 192-201, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31085430

RESUMO

As a main marine phycotoxin, okadaic acid (OA) is mainly responsible for diarrheic shellfish poisoning (DSP), through specifically inhibiting phosphatase (PP1 and PP2A). It has been shown that isotope labelled-OA could cross the placental barrier in mice. However, it remains obscure how OA exposure could affect the formation of neural crest cells (NCCs), especially cranial NCCs in early embryo development. Here, we explored the effects of OA exposure on the generation of neural crest cells during embryonic development using the classic chick embryo model. We found that OA exposure at 100 nM (80.5 µg/L) could cause craniofacial bone defects in the developing chick embryo and delay the development of early chick embryos. Immunofluorescent staining of HNK-1, Pax7, and Ap-2α demonstrated that cranial NCC generation was inhibited by OA exposure. Double immunofluorescent staining with Ap-2α/PHIS3 or Pax7/c-Caspase3 manifested that both NCC proliferation and apoptosis were restrained by OA exposure. Furthermore, the expression of Msx1 and BMP4 were down-regulated in the developing chick embryonic neural tubes, which could contribute the inhibitive production of NCCs. We also discovered that expression of EMT-related adhesion molecules, such as Cadherin 6B (Cad6B) and E-cadherin, was altered following OA exposure. In sum, OA exposure negatively affected the development of embryonic neural crest cells, which in turn might result in cranial bone malformation.


Assuntos
Inibidores Enzimáticos/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Crista Neural/efeitos dos fármacos , Ácido Okadáico/toxicidade , Animais , Apoptose/efeitos dos fármacos , Caderinas/metabolismo , Embrião de Galinha , Regulação para Baixo , Desenvolvimento Embrionário/efeitos dos fármacos , Crista Neural/citologia , Crista Neural/embriologia , Tubo Neural/efeitos dos fármacos , Tubo Neural/metabolismo , Crânio/anormalidades
20.
Biol Pharm Bull ; 42(5): 685-691, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061311

RESUMO

Ursolic acid (UA), a natural pentacyclic triterpenoid, is a promising compound for cancer prevention and therapy. However, its mechanisms of action have not been well elucidated in colorectal cancer cells. Here, using cultured human colon cancer cell lines SW620 and HCT116, this assay demonstrates that UA reduces cell viability, inhibits cell clone formation, and induces caspase-3 mediated apoptosis. Additional experiments show that UA inhibits cell migration and epithelial-mesenchymal transition (EMT), including E-cadherin, Vimentin, Integrin, Twist, and Zeb1 biomakers. These results suggest that UA inhibits cell proliferation, invasion, and metastasis in colorectal cancer cells by affecting mechanisms that regulate EMT. Taken together, the results suggested that the anti-proliferation and anti-metastasis activities of UA was through EMT inhibition in colorectal cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos
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