RESUMO
OBJECT: Trichostatin A (TSA) is a histone deacetylase inhibitor that causes growth inhibition of malignant cells. The authors' goal was to evaluate its effect on cell growth and cell cycle regulation in a large panel of glioma cell lines, as well as in human astrocytes, fibroblasts, and endothelial cells. METHODS: Cell growth in response to TSA was evaluated using a tetrazolium colorimetric assay and a clonogenic assay. Cell cycle effects were examined using flow cytometry. A DNA fragmentation assay was used to evaluate induction of apoptosis. Histone acetylation status and the expression of p21WAF1, phosphorylated retinoblastoma protein (Rb), poly(adenosine diphosphate-ribose) polymerase (PARP), and caspase-3 were studied using Western blot analysis. In the glioma cell lines, there was significant inhibition of cell growth and detection of increased levels of acetylated histones after TSA treatment. The mechanisms underlying the growth inhibition include cell cycle arrest at the G2/M phase and apoptosis induction. The expression of p21WAF1 was activated, with a temporally related decrease in levels of phosphorylated Rb. Apoptosis was preceded by detection of cleaved PARP and activated caspase-3. The effects of TSA were less pronounced or absent in human astrocytes, fibroblasts, and endothelial cells. CONCLUSIONS: The TSA caused inhibition of glioma cell growth by both cell cycle arrest and apoptosis. Cell cycle arrest was associated with an increase in p21WAF1 expression and a decrease in phosphorylated Rb. Apoptosis was mediated at least partly through the activation of caspase-3. Because of the differential effects in glioma cells compared with nonneoplastic cells, TSA may provide a novel strategy for achieving tumor growth inhibition and cytotoxicity. Further investigation is warranted.
Assuntos
Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glioma/patologia , Glioma/fisiopatologia , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/farmacologia , Acetilação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Glioma/metabolismo , Histonas/metabolismo , HumanosRESUMO
The effect of sodium taurocholate instillation on the stimulated stomachs of patients with duodenal ulceration has been investigated. Instillation into the stomach of sodium taurocholate significantly reduced pentagastrin stimulated volume and outputs of both acid and sodium, with no change in the calculated volume of duodenogastric reflux. These observations are not consistent with the back-diffusion theory, but suggest direct parietal cell inhibition of gastric secretion by sodium taurocholate.