RESUMEN
Total glucoside of paeony (TGP), extracted from the root of Paeonia Lactiflora, has been known to show anti-inflammatory, anti-oxidative, hepato-protective and immuno-regulatory activities. The aim of this present study was to determine the anti-tumor effect of TGP against N-nitrosodiethylamine (DEN)-induced hepatocellular carcinoma (HCC) in rats, and to find the related mechanisms. Rat HCC model was established by intragastrically administrating with DEN (8 mg/kg). We found the number of tumor nodules and the index of liver and spleen were increased in the model group compared with the normal group, and was significantly decreased by TGP. Additionally, TGP obviously improved the hepatic pathological lesions induced by DEN, and decreased the elevated levels of serum alanine aminotransferase (ALT), glutamic oxalacetic transaminase (AST), alkaline phosphatase (ALP) and alpha fetoprotein (AFP) by DEN. Moreover, TGP decreased the level of B cell-activating factor (BAFF) and the proportion of IL-10-producing regulatory B cells (Bregs), and the decrease of BAFF by TGP is positively correlated to the decrease of IL-10-producing Bregs by TGP. These results suggest that TGP had a good therapeutic action on DEN-induced HCC rats, which might be due to its down-regulation of Bregs through reducing the level of BAFF.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Linfocitos B Reguladores/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Glucósidos/uso terapéutico , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Paeonia , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Animales , Antineoplásicos Fitogénicos/farmacología , Aspartato Aminotransferasas/sangre , Factor Activador de Células B/sangre , Linfocitos B Reguladores/inmunología , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Dietilnitrosamina , Regulación hacia Abajo , Glucósidos/farmacología , Interleucina-10/inmunología , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/inmunología , Neoplasias Hepáticas Experimentales/patología , Masculino , Fitoterapia , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: Evidence suggests that paeoniflorin may be involved in anticancer activities. Here, we have investigated the effects of paeoniflorin and correlative mechanisms on anti-invasion and anti-metastasis in human hepatocellular carcinoma (HCC) cell lines. MATERIALS AND METHODS: In the current study, we have applied 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay to determine the proliferative effect of HepG2 and Bel-7402, two human hepatoma cell lines, and we have established a boyden chamber assay, a wound healing assay and cell adhesion assay to detect and quantify the invasion, metastasis and adhesion of both HepG2 and Bel-7402. In addition, we have analyzed the protein expression of matrix metalloproteinas (MMP)-9, E-cadherin (E-cad) and extracellular signal-regulated kinase (ERK) in both cell lines through western blot analysis. RESULTS: Paeoniflorin (6. 25-200 µM) had inhibitory effect on the growth of HepG2 and Bel-7402 cell lines, and reduced significantly invasion, metastasis and adhesion of HCC cell lines. In addition, paeoniflorin decreased the expression of MMP-9 and ERK in HepG2 and Bel-7402 cells, and increased expression of E-cad in both cell lines. CONCLUSIONS: Paeoniflorin is effective anti-metastatic and anti-invasive agent for suppressing HCC invasion and metastasis (Fig. 5, Ref. 30).
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Glucósidos/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Monoterpenos/uso terapéutico , Cadherinas/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/secundario , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Inmunoglobulina G/farmacología , Neoplasias Hepáticas/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Melfalán/farmacología , Invasividad Neoplásica/patología , Invasividad Neoplásica/fisiopatología , Invasividad Neoplásica/prevención & control , Paeonia , Fosfotransferasas/metabolismo , Fitoterapia , Preparaciones de Plantas/farmacología , Células Tumorales CultivadasRESUMEN
Tumor multidrug resistance (MDR) can result from overexpression of drug transporters and deregulation of cellular signaling transduction. New agents and strategies are required for overcoming MDR. Here, we report that tanshinone-1, a bioactive ingredient in traditional Chinese medicine, directly killed MDR tumor cells and their corresponding parental cells, which was potentiated by inhibition of secondary activation of signaling networks. Tanshinone-1 was slightly more potent at inducing cytotoxicity and apoptosis in MDR cells than in corresponding parental cells. Tanshinone-1-induced MDR cell killing was independent of the function and expression of drug transporters but was partially correlated with the phosphatase-dependent reduction of phospho-705-Stat3, which secondarily activated p38-, AKT-, and ERK-involved signaling networks. Cotreatments with p38, AKT, and ERK inhibitors potentiated the anti-MDR effects of tanshinone-1. Our study presents a model for MDR cell killing using a compound of natural origin. This model could lead to new therapeutic strategies for targeting signaling network(s) in MDR cancers as well as new strategies for multitarget design.