Disulfiram sensitizes pituitary adenoma cells to temozolomide by regulating O6-methylguanine-DNA methyltransferase expression.
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 stem-like 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 ubiquitin-proteasomal MGMT protein elimination route. DSF combined with TMZ may be an effective therapeutic strategy against aggressive pituitary adenomas.
Department of Neurosurgery, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China.
Yachao
Y
Zhao
Department of Neurosurgery, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China.
Zheng
Z
Xiao
Department of Neurology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China.
Wenna
W
Chen
Department of Neurosurgery, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China.
Jinsheng
J
Yang
Department of Neurosurgery, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China.
Tao
T
Li
Department of Neurosurgery, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China.
Bo
B
Fan
D000071916:AC133 Antigen; D065086:Acetaldehyde Dehydrogenase Inhibitors / Q000494:pharmacology*; D000236:Adenoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D000069286:Bortezomib / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D061988:Proteasome Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D000077204:Temozolomide; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays
D000071916:AC133 Antigen; D065086:Acetaldehyde Dehydrogenase Inhibitors; D015703:Antigens, CD; D018906:Antineoplastic Agents, Alkylating; D006023:Glycoproteins; C577484:NES protein, human; D064231:Nestin; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D061988:Proteasome Inhibitors; D025521:Tumor Suppressor Proteins; D000069286:Bortezomib; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D004221:Disulfiram; D000077204:Temozolomide