Effect of everolimus on cell viability in nonfunctioning pituitary adenomas.
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.
Zatelli
Maria Chiara
MC
Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Via Savonarola 9, 44100 Ferrara, Italy.
Minoia
Mariella
M
Filieri
Carlo
C
Tagliati
Federico
F
Buratto
Mattia
M
Ambrosio
Maria Rosaria
MR
Lapparelli
Marcello
M
Scanarini
Massimo
M
Degli Uberti
Ettore C
EC
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
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