Pasireotide, a multiple somatostatin receptor subtypes ligand, reduces cell viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion.
Somatostatin (SRIF) analogs have been employed in medical therapy of non-functioning pituitary adenomas (NFA), with contrasting results. Previous evidence showed that SRIF can exert its antiproliferative effects by reducing vascular endothelial growth factor (VEGF) secretion and action, and that VEGF expression may be related to pituitary tumor growth. The aim of our study was to clarify the possible effects of a multireceptor SRIF ligand on VEGF secretion and cell proliferation in human NFA primary cultures. We assessed the expression of SRIF receptors (SSTR1-5), the in vitro effects on VEGF secretion, and on cell viability of SRIF and of the stable SRIF analog pasireotide (SOM230), which activates SSTR1, 2, 3, and 5. Twenty-five NFA were examined by RT-PCR for expression of alpha-subunit, SSTR, VEGF, and VEGF receptors 1 (VEGF-R1) and 2 (VEGF-R2). Primary cultures were tested with SRIF and with pasireotide. All NFA samples expressed alpha-sub, VEGF and VEGFR-1 and 2, while SSTR expression pattern was highly variable. Two different groups were identified according to VEGF secretion inhibition by SRIF. VEGF secretion and cell viability were reduced by SRIF and pasireotide in the 'responder' group, but not in the 'non-responder' group, including NFA expressing SSTR5. SRIF and pasireotide completely blocked forskolin-induced VEGF secretion. In addition, SRIF and pasireotide completely abrogated the promoting effects of VEGF on NFA cell viability. Our data demonstrate that pasireotide can inhibit NFA cell viability by inhibiting VEGF secretion, and suggest that the multireceptor-SSTR agonist pasireotide might be useful in medical therapy of selected NFA.
Zatelli
Maria Chiara
MC
Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Via Savonarola 9, 44100 Ferrara, Italy.
Piccin
Daniela
D
Vignali
Cristina
C
Tagliati
Federico
F
Ambrosio
Maria Rosaria
MR
Bondanelli
Marta
M
Cimino
Vincenzo
V
Bianchi
Antonio
A
Schmid
Herbert A
HA
Scanarini
Massimo
M
Pontecorvi
Alfredo
A
De Marinis
Laura
L
Maira
Giulio
G
degli Uberti
Ettore C
EC
D000236:Adenoma / Q000378:metabolism*; D000328:Adult; D000368:Aged; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D010911:Pituitary Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism; D013004:Somatostatin / Q000494:pharmacology* / Q000031:analogs & derivatives; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D006728:Hormones; D008024:Ligands; D009842:Oligopeptides; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; D042461:Vascular Endothelial Growth Factor A; D013004:Somatostatin; C517782:pasireotide