Disulfiram Sensitizes Pituitary Adenoma Cells To Temozolomide

Background and Objectives: Although surgery,radiotherapy and pharmaceutical therapy are routinely employed, tumor recurrence of these aggressive adenomas still remains very high, resulting high morbidity and mortality. Recently, being used as the last line treatment in aggressive pituitary adenomas, temozolomide(TMZ) has been shown to display promising antitumor effect in pituitary adenoma. Because TMZ is only used as the last line therapy for aggressive pituitary adenomas resistant to conventional therapies, it is necessary to develop novel therapeutic approaches to improve the TMZ efficiency in pituitary adenomas. Recent studies have recealed that Disulfiram(DSF) can inhibit the MGMT expression and increase the TMZ effecicacy in glioma. Whether DSF can display similar effect in pituitary ademonas has not been clarified. In our study, we tried to clarify this issue.Methods: A series of 6 surgically removed pituitary adenomas were obtained from patients undergoing transsphenoidal surgery. Among these tissues, there were 3 pituitary apoplexy adenomas resistant to TMZ treatment and 3 pituitary adenomas being effective to TMZ treatment. The MGMT protein expression levels were examined in these pituitary adenoma tissues via Western blot. The MMQ pituitary adenoma cells were treated by Con, TMZ, DSF or TMZ/DSF. The proferation rate and the MGMT expression was examined by CCK8 and western blot. The MMQ cells were injected subcutaneously into nude mice and the MMQ cell xenograft were treated by Con, TMZ, DSF or TMZ/DSF. The proliferation rate and the apoptosis rate was examined via Brdu and Tunel staining.Results: Western blot showed that expression levels of MGMT proteins in higher in pituitary adenomas resistant to TMZ treatment. Compared to TMZ or DSF treatment alone, the TMZ plus DSF treatment can significantly inhibit the cell proferation rate and the MGMT preotein expression. In vivo experiment, Compared to TMZ or DSF treatment alone, the TMZ plus DSF treatment can significantly inhibit the cell proferation rate and increase the apoptosis rate.Conclusions: DSF can reduce MGMT protein expression and sensitize TMZ antitumor effect in MMQ pituitary adenoma cells in vitro. The DSF sensitizing effect was also verified in vivo. Overall, the effect DSF can potentiate the cytotoxic effects of TMZ on pituitary adenoma cells.