Cabergoline reduces cell viability in non functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion

Abstract

Dopamine (DA) therapy of non-functioning pituitary adenomas (NFA) can result in tumor stabilization and shrinkage. However, the mechanism of action is still unknown. Previous evidence showed that DA can inhibit pituitary vascular endothelial growth factor expression (VEGF), that may be involved in pituitary tumor growth. The aim of our study was to clarify whether VEGF secretion modulation might mediate the effects of DA agonists on cell proliferation in human NFA. We assessed DA receptor subtype 2 (DR2) expression in 20 NFA primary cultures, where we also investigated the effects of a selective DR2 agonist, cabergoline (Cab), on VEGF secretion and on cell viability. All NFA samples expressed α-subunit and DR2 was expressed in 11 samples. In DR2 expressing tumors, Cab significantly reduced cell viability (-25%; P < 0.05) and VEGF secretion (-20%; P < 0.05). These effects were counteracted by treatment with the DA antagonist sulpiride. Cab antiproliferative effects were blocked by VEGF. Our data demonstrate that Cab, via DR2, inhibits cell viability also by reducing VEGF secretion in a selected group of NFA, supporting that DA agonists can be useful in the medical therapy of DR2 expressing NFA.

The expression profile of Dopamine D2 receptor, MGMT and VEGF in different histological subtypes of pituitary adenomas: a study of 197 cases and indications for the medical therapy

“…Octreotide was reported to down-regulate VEGF expression to achieve antiangiogenic effects on PAs [28]. Gagliano et al demonstrated that cabergoline reduces cell viability in non-functioning pituitary adenomas by inhibiting VEGF secretion, of which the modulation might mediate the effects of DA agonists on cell proliferation in nonfunctioning adenoma [29]. Interestingly, in present study, we did spearman's rank correlation analysis and found that D2R expression did not show a correlation with VEGF expression.…”

Differential Expression of Stem Cell Markers in Human Adamantinomatous Craniopharyngioma and Pituitary Adenoma

“…Cabergoline has been reported to decrease cell viability [44]. Ketoconazole has been demonstrated to decrease cell viability and also to promote the increased expression of apoptosis-related genes and cell cycle inhibitors in immortalized cell lines [45].…”

Alterations in plasma vascular endothelial growth factor levels in patients with schizophrenia before and after treatment

“…Animal studies show that dopamine stimulation inhibits angiogenesis via decreased functions of VEGF and VEGF receptors in tumor tissues (Basu et al, 2001;Teunis et al, 2002;Asada et al, 2008). An in vitro study with non-functioning pituitary adenomas demonstrated that cabergoline, a dopamine D2 receptor (DR2) agonist, reduces VEGF secretion and cell viability, and that this inhibitory effect of cabergoline is blocked by sulpiride, a selective DR2 antagonist in DR2-expressing pituitary adenomas (Gagliano et al, 2013). Moreover, other animal studies with antipsychotics have suggested that risperidone and olanzapine increase the phosphorylation of the cAMP response element binding protein (CREB) in the hippocampus (Keilhoff et al, 2010;Réus et al, 2012), and that these antipsychotics enhance VEGF expression therein (Pillai and Mahadik, 2006;Keilhoff et al, 2010).…”