RESUMEN
Glioblastoma is a common malignant brain tumor and it is refractory to therapy because it usually contains a mixture of cell types. The tumor necrosis factor-related apoptosis inducing ligand (TRAIL) has been shown to induce apoptosis in a range of tumor cell types. Previously, we found that two human glioblastoma cell lines are resistant to TRAIL, while lovastatin sensitizes these glioblastoma cells to TRAIL-induced cell death. In this study, we investigated the mechanisms underlying the TRAIL-induced apoptosis in human glioblastoma cell lines by lovastatin. Furthermore, we have confirmed the anti-tumor effect of combination therapy with lovastatin and TRAIL in the subcutaneous brain tumor model. We showed that lovastatin significantly up-regulated the expression of death receptor 5 (DR5) in glioblastoma cell lines as well as in tumor-bearing mice with peri-tumoral administration of lovastatin. Further study in glioblastoma cell lines suggested that lovastatin treatment could inhibit NF-κB and Erk/MAPK pathways but activates JNK pathway. These results suggest that lovastatin sensitizes TRAIL-induced apoptosis by up-regulation of DR5 level via NF-κB inactivation, but also directly induces apoptosis by dysregulation of MAPK pathway. Our in vivo study showed that local peri-tumoral co-injection of lovastatin and TRAIL substantially reduced tumor growth compared with single injection of lovastatin or TRAIL in subcutaneous nude mice model. This study suggests that combined treatment of lovastatin and TRAIL is a promising therapeutic strategy to TRAIL-resistant glioblastoma.
Asunto(s)
Glioblastoma/tratamiento farmacológico , Glioblastoma/enzimología , Lovastatina/uso terapéutico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , FN-kappa B/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/uso terapéutico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Glioblastoma/patología , Células HEK293 , Humanos , Lovastatina/administración & dosificación , Lovastatina/farmacología , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Biológicos , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Tejido Subcutáneo/efectos de los fármacos , Tejido Subcutáneo/patología , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
A new conjugate polymer was prepared by an efficient thiol-ene coupling of one carborane with a linear PEG chain (Mn = 2,000 g/mol), and each carborane was further labeled with a fluorescence rhodamine dye. Such a novel polymer can associate in water to form narrowly distributed spherical vesicles, which were characterized using a range of methods, including laser light scattering, confocal laser scanning microscopy, and TEM. The vesicular structure is potentially multifunctional in biomedical applications, namely, serving as a boron neutron capture therapy (BNCT) agent, a hydrophilic drug carrier, and a diagnostic imaging fluorescent probe. As expected, either cleaving the thiol-ene linked PEO chain by esterase or destroying carborane by neutron irradiation results in a dismantlement of such a vesicle structure to release its encapsulated drugs. Its potential biomedical applications have been evaluated in vitro and in vivo. Our preliminary results reveal that these small vesicles can be quickly taken up by cells and have an enhanced stability in the bloodstream so that their targeting to specific cancer cells becomes feasible.
Asunto(s)
Terapia por Captura de Neutrón de Boro/métodos , Diagnóstico por Imagen/métodos , Portadores de Fármacos/química , Animales , Boro , Preparaciones de Acción Retardada , Humanos , Masculino , Ratones , Microscopía Confocal , Microscopía Electrónica de Transmisión , Microscopía FluorescenteRESUMEN
Primitive neural stem cells (NSCs) define an early stage of neural induction, thus provide a model to understand the mechanism that controls initial neural commitment. In this study, we investigated primitive NSCs derived from mouse embryonic stem cells (ESCs). By genome-wide transcriptional profiling, we revealed their unique signature and depicted the molecular changes underlying critical cell fate transitions during early neural induction at a global level. Together with qRT-PCR analysis, our data illustrated that primitive NSCs retained expression of key pluripotency genes Oct4 and Nanog, while exhibiting repression of other pluripotency-related genes Zscan4, Foxp1 and Dusp9 and up-regulation of neural markers Sox1 and Hes1. The early differentiation feature in primitive NSCs was also supported by their intermediate characters on cell cycle profiles. Moreover, re-plating primitive NSCs back to ESC culture condition could reverse them back to ESC stage, as shown by reversible regulation of marker genes, cell cycle profile changes and enhanced embryoid body formation. In addition, our microarray analysis also identified genes differentially expressed in primitive NSCs, and loss-of-function analysis demonstrated that Hes1 and Ccdc141 play important function at this stage, opening up an opportunity to further understand the regulation of early neural commitment.
Asunto(s)
Diferenciación Celular , Células Madre Embrionarias/citología , Factor Inhibidor de Leucemia/metabolismo , Células-Madre Neurales/citología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Células Cultivadas , Regulación hacia Abajo , Fosfatasas de Especificidad Dual/genética , Fosfatasas de Especificidad Dual/metabolismo , Cuerpos Embrioides/citología , Cuerpos Embrioides/metabolismo , Células Madre Embrionarias/metabolismo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Perfilación de la Expresión Génica , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Factor Inhibidor de Leucemia/farmacología , Ratones , Proteína Homeótica Nanog , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factor de Transcripción HES-1 , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Regulación hacia ArribaRESUMEN
AIM: To investigate the feasibility of compression anastomosis clip (CAC) for gastrointestinal anastomosis proximal to the ileocecal junction. METHODS: Sixty-six patients undergoing gastrointestinal anastomosis proximal to the ileocecal junction were randomized into two groups according to the anastomotic method, CAC or stapler. RESULTS: The postoperative recovery of patients in CAC and stapled anastomosis groups was similar. No postoperative complication related to the anastomotic method was found in either group. Both upper gastrointestinal contrast radiography at the early postoperative course and endoscopic examination after a 6-mo follow-up showed a better healing at the compression anastomosis. CONCLUSION: CAC can be used not only in colonic surgery but also in gastrointestinal anastomosis. Our result strongly suggests that CAC anastomosis is safe in various complication circumstances. However, it should be further confirmed with a larger patient sample.