O6-methylguanine-DNA methyltransferase (MGMT) activity is responsible for temozolomide (TMZ) resistance in patients harboring aggressive pituitary adenomas. Recently, disulfiram (DSF) has been shown to induce the loss of MGMT protein and increase TMZ efficacy in glioblastoma cells,
while CD133+ nestin+ cells isolated from the cell population have been implicated as pituitary adenoma stemlike cells. However, whether DSF is able to potentiate the cytotoxic effects of TMZ on human pituitary adenoma cells has not been investigated to date. In the present study,
CD133+ nestin+ phenotype cells were isolated from primary cultured human pituitary adenoma cells using microbeads. It was found that DSF reduced MGMT protein expression and sensitized human pituitary adenoma cells and stem-like cells to TMZ in vitro, while the proteasome inhibitor
PS-341 abrogated the inhibitory effect of DSF on MGMT in vitro. The sensitizing effect of DSF was also verified in primary cultured human pituitary adenoma cells in vivo. The results of the present study suggested that DSF can increase the efficacy of the anti-tumor effect of TMZ
on human pituitary adenoma cells and CD133+ nestin+ stem like cells via the ubiquitinproteasomal MGMT protein elimination route. DSF combined with TMZ may be an effective therapeutic strategy against aggressive pituitary adenomas.
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Document Type: Research Article
Department of Neurosurgery, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
Department of Neurology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
Publication date: August 1, 2015
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Molecular Medicine Reports is a monthly, peer-reviewed journal available in print and online, that includes studies devoted to molecular medicine, underscoring aspects including pharmacology, pathology, genetics, neurosciences, infectious diseases, molecular cardiology and molecular surgery. In vitro and in vivo studies of experimental model systems pertaining to the mechanisms of a variety of diseases offer researchers the necessary tools and knowledge with which to aid the diagnosis and treatment of human diseases.
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