RESUMEN
Hepatocellular carcinoma (HCC) is one of most common types of malignant tumours. Therefore, it is very important to identify powerful drugs and their antitumour mechanisms. Corilagin has a significant antitumour potential and lower toxicity in normal cells in vitro. The IC50 values of corilagin for normal Chang-liver cells and the HCC cell lines Bel7402 and SMMC7721 were 131.4, 24.5 and 23.4 µM, respectively, in the methyl thiazolyl tetrazolium (MTT) assay. MHCC97-H xenografts in Balb/c mice intraperitoneally injected with 30 mg/kg corilagin for 5 weeks showed a 47.3% inhibition of tumour growth in vivo. Furthermore, data from flow cytometry and Western blot analyses of cell cycle and cell cycle-related proteins suggest that corilagin arrests SMMC7721 cells at the G2/M phase by downregulating p-Akt and cyclin B1/cdc2 and upregulating p-p53 and p21(Cip1) . In conclusion, corilagin is a potential antitumour drug that is effective in retarding the growth of HCC, which is correlated with the activation of p-p53-p21(Cip1) -cdc2/cyclin B1.
Asunto(s)
Carcinoma Hepatocelular/patología , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Glucósidos/farmacología , Neoplasias Hepáticas/patología , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Animales , Proteína Quinasa CDC2/metabolismo , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Cisplatino/farmacología , Ciclina B1/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Glucósidos/química , Glucósidos/uso terapéutico , Humanos , Taninos Hidrolizables , Neoplasias Hepáticas/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Biológicos , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The intestinal metabolite of ginseng saponin, compound K (CK), has various chemopreventive and chemotherapeutic activities, including anti-tumor activity. However, the functional mechanisms through which CK attenuates metastatic growth in hepatocellular carcinoma (HCC) remain unclear. Here, using multiple IN VITRO and IN VIVO models, we reported that CK strongly attenuated colony formation, adhesion, and invasion of HCC cells IN VITRO and dramatically inhibited spontaneous HCC metastatic growth IN VIVO. At the molecular level, immunofluorescence and Western blotting analysis confirmed that inhibition of metastatic growth of HCC induced by CK treatment caused a time-dependent decrease in nuclear NF- κB p65 and a concomitant increase in cytosolic NF- κB p65, indicating that CK suppressed the activation of the NF- κB pathway. Meanwhile, our study showed that the inhibition of matrix metalloproteinase2/9 (MMP2/9) expression caused by CK treatment was associated with NF- κB p65 nuclear export. Taken together, our results not only revealed that NF- κB p65 nuclear export and the reduction of MMP2/9 expression were associated with the metastatic inhibition induced by CK, but also suggested that CK may become a potential cytotoxic drug in the prevention and treatment of HCC.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Ginsenósidos/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Inhibidores de la Metaloproteinasa de la Matriz , FN-kappa B/fisiología , Animales , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/secundario , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Ginsenósidos/aislamiento & purificación , Ginsenósidos/farmacología , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Metástasis de la Neoplasia , Panax/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéuticoRESUMEN
This study aims to investigate the inhibitory effect on proliferation and metastasis of 20-O-(beta-D-glucopyranosyl)-20(S)-protopanaxadiol (IH901) on ECV304 cell line. MTT assay was used to examine the effect of cell proliferation inhibition and the adhesive ability of ECV304 cells to artificial basement membrane. Morphology of cell apoptosis was observed with phase contrast microscope. Apoptosis rate and cell cycle were detected by flow cytometry (FCM). Cell migration was measured by wound healing assay. ELISA kit was used to detect VEGF and bFGF. Caspases were detected by Western blotting. Results indicated that ginseng saponin IH901 can downregulate the expression of growth promoting protein VEGF and bFGF, and upregulate pro apoptosis protein cleaved caspase-9 and cleaved caspase-3. The increase in the apoptotic sub-G1 fraction is in a dose-dependent manner, and cell cycle arrests in the G0/G1 phase was detected by FCM. Morphological examination of IH901-treated samples showed cells with chromatin condensation, cell shrinkage, and all typical characteristics of apoptotic cells. Therefore, IH901 dramatically suppresses cell proliferation and adhesion and migration of ECV304 cell line.
Asunto(s)
Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Panax , Sapogeninas/farmacología , Adhesión Celular/efectos de los fármacos , Línea Celular , Células Endoteliales de la Vena Umbilical Humana/citología , Humanos , Saponinas/farmacologíaRESUMEN
Corilagin, a gallotannin, is one of the major active components of many ethnopharmacological plants and exhibits antitumor, anti-inflammatory and antioxidative properties. In recent years, corilagin has provoked much attention due to its antitumor activity, yet the mechanisms attributed to its anticancer actions are largely unknown. In our previous research, our group reported that corilagin could inhibit the proliferation of hepatocellular carcinoma (HCC) cells by inducing G2/M phase arrest. In the present study, observation of the morphological changes showed that corilagin induced the apoptosis of HCC cells as determined by AO/EB and Hoechst 33258 staining assays. Furthermore, flow cytometric analysis was carried out to calculate the apoptotic rate which was 24.1% following treatment with corilagin (37.5 µM). At the molecular level, mitochondrial membrane potential assay and western blot analysis showed that the mitochondrial transmembrane potential was reduced and the rate of release of cytochrome c was increased, which led to the activation of caspase-9, caspase-3 and cleavage of PARP in the cytoplasm indicating activation of the mitochondrial apoptotic pathway. Moreover, following treatment with corilagin, we noted upregulation of Fas and FasL and activation of caspase-8 which represented activation of the death receptor pathway, and we also observed downregulation of Bcl-2 and survivin which was also attributed to the antitumor effect of corilagin. These results suggest that corilagin significantly induced the apoptosis of HCC cells through both the mitochondrial apoptotic pathway and the death receptor pathway, and corilagin is a potential complementary anticancer herbal drug for HCC therapy.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Glucósidos/farmacología , Taninos Hidrolizables/farmacología , Neoplasias Hepáticas/metabolismo , Mitocondrias/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Caspasas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Corilagin, a gallotannin, is one of the major active components of many ethnopharmacological plants. It was isolated from Caesalpinia coriaria (Jacq.) Willd. (dividivi) by Schmidt in 1951 for the first time. In the past few decades, corilagin was reported to exhibit anti-tumor, anti-inflammatory and hepatoprotective activities, etc. However, little attention was paid to its pharmacological properties due to the complicated and inefficient extract method. In recent years, with the development of extraction technology corilagin was much easier to obtain than before. Thus, people return to pay attention to its anti-tumor, hepatoprotective, and anti-inflammatory activities, particularly as an anti-tumor agent candidate. Our research team had focused on the distribution, preparation and anti-tumor activity of corilagin since 2005. We found corilagin showed good anti-tumor activity on hepatocellular carcinoma and ovarian cancer. What's more, corilagin showed a low level of toxicity toward normal cells and tissues. Due to the extensive attention that corilagin has received, we present a systematic review of the pharmacological effects of corilagin. In this review, we summarized all the pharmacological effects of corilagin with a focus on the molecular mechanism of anti-tumor activity and show you how corilagin affected the signaling pathways of tumor cells as well as its physicochemical properties, distribution and preparation methods.
Asunto(s)
Glucósidos/farmacología , Taninos Hidrolizables/farmacología , Fitoterapia , Animales , Antibacterianos/efectos adversos , Antibacterianos/química , Antibacterianos/farmacología , Antiinflamatorios/efectos adversos , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antineoplásicos/efectos adversos , Antineoplásicos/química , Antineoplásicos/farmacología , Glucósidos/efectos adversos , Glucósidos/química , Humanos , Taninos Hidrolizables/efectos adversos , Taninos Hidrolizables/químicaRESUMEN
Recent metabolomics research revealed a new ginseng ginsenoside IH901 that is synthesized by intestinal microbial transformation in oral administration of ginseng. IH901 shows various biological activities, including anti-tumor, anti-inflammatory, anti-diabetic, and anti-aging. In recent years, great effort has been made to prepare IH901 by microbial and enzymatic transformation in a large scale. In this paper, we reviewed the biotransformation pathways both in vivo and in vitro and bioactive properties of rare ginsenoside IH901.
Asunto(s)
Ginsenósidos/metabolismo , Ginsenósidos/farmacocinética , Mucosa Intestinal/metabolismo , Panax/química , Sapogeninas/metabolismo , Biotransformación , Humanos , Intestinos/microbiologíaRESUMEN
20-O-(beta-D-glucopyranosyl)-20(S)-protopanaxadiol (IH-901), a novel intestinal bacterial metabolite of ginseng protopanaxadiol saponins, is reported to induce apoptosis in a variety of cancer cells. We purified the compound and measured its in vitro anti-tumor activity. IH-901 inhibited cell growth of human hepatocellular carcinoma SMMC7721 cells in a dose- and time-dependent manner. We also found that IH-901 induced apoptotic cell death concurrent with cell cycle arrest in G0-G1 phase in SMMC7721 cells. At the molecular level, we show that IH-901 upregulates cytochrome c, p53, and Bax expression, and downregulates pro-caspase-3 and pro-caspase-9 expressions in a dose-dependent manner, while the levels of Bcl-2 and Bcl-X(L) were unchanged in IH-901-treated SMMC7721 cells. These results provide significant insight into the anticarcinogenic action of IH-901.