title: Effect of everolimus on cell viability in nonfunctioning pituitary adenomas.
abstract: BACKGROUND
  Pituitary adenomas can cause specific syndromes due to hormone excess and/or determine sellar mass symptoms. Pituitary cell growth can sometimes be influenced by medical therapy, such as for somatotroph adenomas treated with somatostatin analogs or prolactinomas treated with dopaminergic drugs. However, nonfunctioning pituitary adenomas (NFAs) are still orphans of medical therapy. Everolimus (RAD001), a derivative of rapamycin, is a well-known immunosuppressant drug, which has been recently shown to have antineoplastic activity in several human cancers.
  
  
  OBJECTIVE
  The objective of the study was to investigate the possible antiproliferative effects of RAD001 in human NFAs.
  
  
  METHODS
  We collected 40 NFAs that were dispersed in primary cultures, treated without or with 1 nm to 1 microm RAD001, 10 nm cabergoline, 10 nm SOM230 (a somatostatin receptor multiligand), and/or 50 nm IGF-I. Cell viability and apoptosis were evaluated after 48 h, and vascular endothelial growth factor (VEGF) secretion was assessed after an 8-h incubation. Somatostatin and dopamine subtype 2 receptor expression was investigated by quantitative PCR.
  
  
  RESULTS
  In 28 cultures (70%), Everolimus significantly reduced cell viability (by approximately 40%; P < 0.05 vs. control), promoted apoptosis (+30%; P < 0.05 vs. control), inhibited p70S6K activity (-20%), and blocked IGF-I proliferative and antiapoptotic effects. In selected tissues cotreatment with SOM230, but not cabergoline, exerted an additive effect. Everolimus did not affect VEGF secretion but blocked the stimulatory effects of IGF-I on this parameter.
  
  
  CONCLUSIONS
  Everolimus reduced NFA cell viability by inducing apoptosis, with a mechanism likely involving IGF-I signaling but not VEGF secretion, suggesting that it might represent a possible medical treatment of invasive/recurrent NFAs.
authors: Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Via Savonarola 9, 44100 Ferrara, Italy.
authors: Maria Chiara
authors: MC
authors: Zatelli
authors: Mariella
authors: M
authors: Minoia
authors: Carlo
authors: C
authors: Filieri
authors: Federico
authors: F
authors: Tagliati
authors: Mattia
authors: M
authors: Buratto
authors: Maria Rosaria
authors: MR
authors: Ambrosio
authors: Marcello
authors: M
authors: Lapparelli
authors: Massimo
authors: M
authors: Scanarini
authors: Ettore C
authors: EC
authors: Degli Uberti
mesh_terms: D000236:Adenoma / Q000188:drug therapy* / Q000473:pathology; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D000077465:Cabergoline; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004873:Ergolines / Q000494:pharmacology; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017481:Receptors, Somatostatin / Q000502:physiology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D004873:Ergolines; D007166:Immunosuppressive Agents; D017481:Receptors, Somatostatin; D042461:Vascular Endothelial Growth Factor A; D013004:Somatostatin; C517782:pasireotide; D000068338:Everolimus; C093733:somatostatin receptor 2; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D000077465:Cabergoline; D020123:Sirolimus