RESUMEN
Basic fibroblast growth factor (bFGF) has been demonstrated to correlate with glioma grade and clinical outcome and has established its possible usefulness as a target for glioma therapy. Vpr has been described as an antitumor agent and displays a potent antitumor nature. Here, we try to investigate whether a combined treatment with bFGF-siRNA and Vpr gene would have a enhanced effectiveness on glioma in vitro and in vivo.After treatments with only Ad-bFGF-siRNA, only Ad-Vpr, and a combination of both, we assessed the changes in cell proliferation, cell cycle, and apoptosis in vitro by the methods of MTT, PI and FITC-AnnexinV double staining, respectively. In addition, we also evaluated the combined effect of bFGF-siRNA and Vpr gene therapy on glioma in vivo using xenograft glioma models in nude mice. Combined Ad-bFGF-siRNA and Ad-Vpr treatment was more better successful in inhibiting cell proliferation in comparison with treatments of either Ad-bFGF-siRNA or Ad-Vpr alone. Treatment of Ad-Vpr alone or a treatment of a combination of Ad-bFGF-siRNA and Ad-Vpr induced the G2/M cell cycle arrest and apoptosis; however, combined treatment was more effective than the Ad-Vpr treatment alone. Although each single treatment can slow the growth of xenograft glioma, the combined treatment with Ad-bFGF-siRNA and Ad-Vpr was better than either the Ad-bFGF-siRNA or Ad-Vpr treatment alone. Our results suggest that the combination therapy with bFGF-siRNA and Vpr gene can achieve a enhanced activity of anti-glioma, supporting the idea that the combination of these two antitumor agents could open new perspectives in glioma therapy.
Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Factor 2 de Crecimiento de Fibroblastos/antagonistas & inhibidores , Productos del Gen vpr/uso terapéutico , Terapia Genética/métodos , Glioma/tratamiento farmacológico , ARN Interferente Pequeño/uso terapéutico , Adenoviridae , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Factor 2 de Crecimiento de Fibroblastos/genética , Vectores Genéticos , Ratones , Ratones Desnudos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
New and effective approaches for inflammatory diseases based on novel mechanisms of action are needed. One potential source of anti-inflammatory drugs exists among viruses. Viruses have evolved to infect, replicate within, and kill human cells through diverse mechanisms. They accomplish this fact by finding ways to out with the host's complex immune machinery. It is possible that the viral proteins and pathways involved in the downregulation of host immune function during infection can be exploited as a therapeutic in diseases that result in the overactivity of the immune system. Indeed, the human immunodeficiency virus type 1 (HIV-1) protein, Vpr, affects cells in a number of ways that may prove useful for exploitation for the treatment of inflammatory diseases. Vpr has effects on T-cell proliferation, cytokine production, chemokine production, and Nuclear Factor kappa B (NF-kappaB)-mediated transcription. Importantly, it has been observed that Vpr downregulates NF-kappaB and the production of pro-inflammatory cytokines such as TNF-alpha, and IL-12. These activities are worthy of further examination for control of hyperinflammatory and hyperproliferative conditions.