RESUMEN
(-)-Epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, has been shown to inhibit the proliferation of a variety of tumor cells. Epidemiological studies have shown that drinking green tea can reduce the incidence of nasopharyngeal carcinoma (NPC), yet the underlying mechanism is not well understood. In this study, the inhibitory effect of EGCG was tested on a set of Epstein Barr virus-negative and -positive NPC cell lines. Treatment with EGCG inhibited the proliferation of NPC cells but did not affect the growth of a non-malignant nasopharyngeal cell line, NP460hTert. Moreover, EGCG treated cells had reduced migration and invasive properties. The expression of the cell adhesion molecules E-cadherin and ß-catenin was found to be up-regulated by EGCG treatment, while the down-regulation of matrix metalloproteinases (MMP)-2 and MMP-9 were found to be mediated by suppression of extracellular signal-regulated kinase (ERK) phosphorylation and AP-1 and Sp1 transactivation. Spheroid formation by NPC cells in suspension was significantly inhibited by EGCG. Oral administration of EGCG was capable of suppressing tumor growth in xenografted mice bearing NPC tumors. Treatment with EGCG was found to elevate the expression of p53 and p21, and eventually led to apoptosis of NPC cells via caspase 3 activation. The nuclear translocation of NF-κB and ß-catenin was also suppressed by EGCG treatment. These results indicate that EGCG can inhibit the proliferation and invasiveness, and induce apoptosis, of NPC cells, making it a promising agent for chemoprevention or adjuvant therapy of NPC.
Asunto(s)
Apoptosis/efectos de los fármacos , Catequina/análogos & derivados , Moléculas de Adhesión Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Gelatinasas/metabolismo , Animales , Cadherinas/metabolismo , Carcinoma , Caspasa 3/metabolismo , Catequina/farmacología , Catequina/uso terapéutico , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Ratones , Ratones SCID , FN-kappa B/metabolismo , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/enzimología , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Transducción de Señal/efectos de los fármacos , Esferoides Celulares/efectos de los fármacos , Trasplante Heterólogo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Epstein-Barr virus (EBV) has been associated with several human malignancies including nasopharyngeal carcinoma (NPC). Reactivation of latent EBV has been considered to contribute to the carcinogenesis of NPC. Blocking the EBV lytic cycle has been shown effective in the treatment of EBV-associated diseases. We have searched for natural dietary compounds inhibiting EBV reactivation in NPC cells. Among them, sulforaphane (SFN) was found to be effective in the inhibition of EBV reactivation in latent EBV-positive NPC cells, NA and HA. SFN is a histone deacetylase (HDAC) inhibitor and has been recognized as an antioxidant and antitumor compound for chemoprevention. However, its antiviral effect is less well elucidated. In this study, after determination of the cytotoxicity of SFN on various epithelial cells, we showed that SFN treatment inhibits EBV reactivation, rather than induction, by detection of EBV lytic gene expression in EBV-positive NPC cells. We also determined that the number of cells supporting the EBV lytic cycle is decreased using immunofluorescence and flow cytometric analysis. Moreover, we have found that this inhibitory effect decreases virus production. To elucidate the inhibitory mechanism of SFN on the EBV lytic cycle, luciferase reporter assays were carried out on the Zta and Rta promoters. The results show that SFN inhibits transactivation activity of the EBV immediate-early gene Rta but not Zta. Together, our results suggest that SFN has the capability to inhibit EBV lytic cycle and the potential to be taken as a dietary compound for prevention of EBV reactivation.
Asunto(s)
Herpesvirus Humano 4/efectos de los fármacos , Isotiocianatos/farmacología , Neoplasias Nasofaríngeas/virología , Antivirales/farmacología , Carcinoma , Suplementos Dietéticos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/virología , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Infecciones por Virus de Epstein-Barr/prevención & control , Infecciones por Virus de Epstein-Barr/virología , Regulación Viral de la Expresión Génica/efectos de los fármacos , Genes Inmediatos-Precoces , Herpesvirus Humano 4/patogenicidad , Herpesvirus Humano 4/fisiología , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Proteínas Inmediatas-Precoces/genética , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/tratamiento farmacológico , Regiones Promotoras Genéticas , Sulfóxidos , Transactivadores/genética , Transactivadores/metabolismo , Células Tumorales Cultivadas , Activación Viral/efectos de los fármacosRESUMEN
BACKGROUND: A case-control study was conducted to evaluate the role of adult diet on nasopharyngeal carcinoma (NPC) in Taiwan. METHODS: A total of 375 incident NPC cases and 327 controls matched to the cases on sex, age, and residence were recruited between July 1991 and December 1994. A structured questionnaire inquiring complete dietary history, socio-demographic characteristics, and other potential confounding factors was used in the personal interview. Unconditional logistic regression analysis was used to estimate multivariate-adjusted odds ratio (OR(adj)) with 95% confidence interval (CI) after accounting for known risk factors. RESULTS: Fresh fish (OR(adj), 0.56; 95% CI, 0.38-0.83 for the highest vs. lowest tertile of intake), green tea (OR(adj), 0.61; 95% CI, 0.40-0.91 for drinking ≥1 times/week vs. never) and coffee (OR(adj), 0.56; 95% CI, 0.37-0.85 for drinking ≥0.5 times/week vs. never) were inversely associated with the NPC risk. No association with NPC risk was observed for the intake of meats, salted fish, fresh vegetables, fruits and milk. Intake of vitamin A from plant sources was associated with a decreased NPC risk (OR(adj), 0.62; 95% CI, 0.41-0.94 for the highest vs. lowest tertile). CONCLUSION: The study findings suggest that certain adult dietary patterns might protect against the development of NPC.
Asunto(s)
Café , Ingestión de Líquidos , Peces , Neoplasias Nasofaríngeas/epidemiología , Plantas/química , Té , Vitaminas , Adulto , Anciano , Animales , Carcinoma , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/prevención & control , Factores de Riesgo , Taiwán/epidemiologíaRESUMEN
BACKGROUND: Persistent activation of hepatic stellate cells (HSC-T6) has been known to cause liver fibrosis. In this study, our objective was to investigate the effects of chebulagic acid and chebulinic acid, two hydrolysable tannins of tropical almond (Terminalia chebula) fruits, on collagen synthesis and signal transduction in transforming growth factor-ß1-stimulated HSC-T6 cells. The expression of Smad2, Smad3, Smad4, collagen I(α1)/III, and plasminogen activator inhibitor 1 (PAI-1) mRNAs was determined by reverse-transcription polymerase chain reaction and their protein levels were assessed by western blotting. RESULTS: Results showed that chebulagic acid and chebulinic acid at 20 µmol L(-1) exhibited cytotoxic and anti-proliferative effects on HSC-T6 cells. They also significantly decreased the expression of Smd2, Smad3 and Smad4, and the synthesis of collagen, procollagen I (α1) and III, as well as suppressing the activation of PAI-1; these events consequently facilitated the resolution of fibrosis. CONCLUSION: These results indicate that both chebulagic acid and chebulinic acid possess antifibrotic activity, and their mechanism of action could be through the inhibition of the Smad pathway.