RESUMO
Currently, 5-Fluorouracil (5-FU) based chemotherapy is the primary option for colorectal cancer after surgery, whereas chemotherapy resistance related mortality is observed in a large proportion of patients. Anemoside B4 (AB4) is a triterpene saponin, which exhibits a considerable activity in oncotherapy. In this study, we explored the efficacy of AB4 in FU-based chemotherapy in colorectal cancer cells and the underlying molecular mechanisms. Our results indicated a significant synergistic activity of AB4 in 5-FU treated colorectal cancer cells. Furthermore, AB4 treatment eliminated colorectal cancer stem cells by promoting apoptotic cell death in 5-FU resistant colorectal cancer cells. Mechanically, AB4 activated caspase-9 pathway in 5-FU resistant colorectal cancer cells. Elevated Src activity induced cell apoptosis and cancer stem cells elimination effects in AB4 treated colorectal cancer cells. In conclusion, AB4 showed promising sensitization effect in the FU-based chemotherapy of colorectal cancer. Our study may pave a way to ameliorate FU-based chemotherapeutic efficiency in colorectal cancer.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/uso terapêutico , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Saponinas/uso terapêutico , Animais , Caspase 9/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Células HCT116/efeitos dos fármacos , Humanos , Camundongos Nus , Transplante de Neoplasias , Células-Tronco Neoplásicas/efeitos dos fármacosRESUMO
The axons of the adult mammalian brain and spinal cord fail to regenerate after injury, and it has been suggested that Nogo-66 could prevent CNS axon repair. However, the mechanism of Nogo-66 inhibiting neurite outgrowth remains unknown. Our previous results indicated that protein kinase B (PKB) is involved in the inhibition of the neurite outgrowth by Nogo-66. Glycogen synthase kinase-3ß (GSK-3ß) is implicated in many processes in the nervous system, including differentiation, specification, polarity, plasticity and axon growth. In addition, GSK-3ß is one of the most important molecules downstream of PKB. In the present study, we report on the role of GSK-3ß signaling on Nogo-66-treated mouse neuroblastoma N2a cells. Nogo-66 reduced the phosphorylation of GSK-3ß at Ser9 in N2a cells. In contrast, pretreatment with SB216763, a specific inhibitor of GSK-3ß, resulted in an amelioration of neurite outgrowth by Nogo-66, compared with the Nogo-66 alone group (P<0.05). Moreover, we performed RNA interference experiments to knock down GSK-3ß expression levels in N2a cells via transient transfection of shRNA plasmids. The inhibition of neurite outgrowth by Nogo-66 was subdued in shRNA cells, compared to the non-RNAi cells (P<0.05). Taken together, these data suggest that GSK-3ß is involved in the inhibition by Nogo-66 of neurite outgrowth in N2a cells.
Assuntos
Quinase 3 da Glicogênio Sintase/metabolismo , Proteínas da Mielina/fisiologia , Regeneração Nervosa/fisiologia , Inibição Neural/genética , Neuritos/metabolismo , Neurogênese/fisiologia , Receptores de Superfície Celular/fisiologia , Animais , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Proteínas Ligadas por GPI/fisiologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/genética , Glicogênio Sintase Quinase 3 beta , Indóis/farmacologia , Maleimidas/farmacologia , Camundongos , Regeneração Nervosa/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Neuritos/patologia , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Neurogênese/efeitos dos fármacos , Receptor Nogo 1 , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Interferência de RNA/efeitos dos fármacos , RNA Interferente Pequeno/genéticaRESUMO
In May (spring) and October (autumn) 2005, the effects of grazing on the zoobenthos community in Chongming Dongtan wetland of Shanghai were investigated. A total of 3 transects including 90 sampling plots were set up. Transects I and II were in feeding area, and transect III was in non-pasture area. All of these three transects were set in mid-tidal zone. 13 zoobenthos species were observed, with 7 species of arthropod, 4 species of mollusk, and 2 species of annelid. In spring, there were 6, 8 and 10 species in transects I , II and III while in autumn, the species number was 6, 8 and 12, respectively. The mean abundance of zoobenthos community in all transects was higher in autumn than in spring, and transect III had the highest mean abundance and biomass both in autumn and spring. Transect III also had the highest evenness, richness and diversity, indicating that grazing could change the species distribution of zoobenthos, and affect their abundance and biomass to different degree. Grazing had made certain negative effects on the biodiversity of zoobenthos community in Chongming Dongtan wetland.
