RESUMEN
BACKGROUND: Recent studies have demonstrated that side population (SP) cells isolated from various cancer cell lines and primary tumors possess stem cell-like properties. Sesamin, a food-derived agent, possesses anti-cancer activities both in vitro and in vivo. The present study was designed to determine whether sesamin also have effects on cancer stem-like SP cells from gallbladder cancer (GBC). METHODS: In this study, we sorted SP cells by flow cytometry. SP cells were cultured and treated with sesamin. Tumor-sphere formation, colony formation, Matrigel invasion and tumorigenic potential were determined. Expression of nuclear NF-κB, IL-6, p-Stat3, Twist, E-cadherin and Vimentin was measured by Western blot, immunofluorescence staining or RT-PCR analysis. Nuclear NF-κB activity and IL-6 protein level were assessed with ELISA. Xenograft tumors were generated in nude mice. RESULTS: After treated with sesamin, SP cells differentiated into cells expressing the epithelial marker (E-cadherin). Sesamin effectively affected SP cells stem cell-like characteristics (i.e., tumor-sphere formation, colony-formation, Matrigel invasion), weakened the drug-resistance of SP cells and inhibited tumor growth both in vitro and in vivo. Treatment with sesamin significantly reduced the expression of nuclear NF-κB, IL-6, p-Stat3, Twist and Vimentin (a mesenchymal marker) in SP cells. Nuclear NF-κB activity and IL-6 level were also decreased after treatment with sesamin. CONCLUSION: Food-derived sesamin directs the epithelial differentiation of cancer stem-like SP cells from GBC, which is associated with attenuation of NF-κB-IL-6-Stat3-Twist signal pathway.
Asunto(s)
Dioxoles/farmacología , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Neoplasias de la Vesícula Biliar/patología , Lignanos/farmacología , Células Madre Neoplásicas/efectos de los fármacos , Células de Población Lateral/efectos de los fármacos , Análisis de Varianza , Animales , Cadherinas/metabolismo , Carcinoma/tratamiento farmacológico , Carcinoma/metabolismo , Carcinoma/patología , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Neoplasias de la Vesícula Biliar/metabolismo , Humanos , Interleucina-6/metabolismo , Ratones , Ratones Desnudos , FN-kappa B/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Células de Población Lateral/metabolismo , Células de Población Lateral/patología , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The objective of our study was to examine the hepatic protective mechanism of Ginkgo biloba extract (GBE) in rats with obstructive jaundice (OJ). Twenty rats underwent bile duct ligation and received daily intraperitoneal injections of either control saline or Ginkgo biloba extract for 14 days. Ten sham-operated rats had their bile duct exposed but not ligated or sectioned. Serum alanine transaminase (ALT) was analyzed for liver function tests and liver damage was further assessed by histologic examination. The levels of endothelin 1 (ET-1) and nitric oxide (NO) in blood and liver homogenate were measured. The serum alanine transaminase was elevated in the bile duct ligation rats (BDL rats); GBE could signiï¬cantly lower serum transaminase level and ameliorate liver histological damage. ET-1 and NO levels in both plasma and liver tissue were also elevated in common bile duct (CBD)-ligated rats, but this increase was significantly decreased by GBE treatment. Moreover, the degree of liver damage severity positively correlates with high levels of ET-1 and NO. GBE mediated the liver protective effect at least in part by suppressing overproduction of ET-1 and NO and restoring a proper balance between ET-1 and NO to some extent.