The Somatostatin Analogue Octreotide Confers Sensitivity to Rapamycin Treatment on Pituitary Tumor Cells

Abstract

Rapamycin and its analogues have significant antiproliferative action against a variety of tumors. However, sensitivity to rapamycin is reduced by Akt activation that results from the ablative effects of rapamycin on a p70 S6K-induced negative feedback loop that blunts phosphoinositide 3-kinase (PI3K)-mediated support for Akt activity. Thus, sensitivity to rapamycin might be increased by imposing an upstream blockade to the PI3K/Akt pathway. Here, we investigated this model using the somatostatin analogue octreotide as a tool to decrease levels of activated

The PI3K/AKT/mTOR pathway in the pathophysiology and treatment of pituitary adenomas

“…Administration of RAD001 to MENX PA cells in primary culture also resulted in a dose-dependent reduction in cellular viability that reached significance at a dose of 100 nM in 45% of their sample (five out of 11 cultures; Lee et al 2011). Finally, Cerovac et al (2010) exposed 28 human NFPAs in primary culture to rapamycin and reported a small (!20%) reduction in cellular proliferation in 29% (eight of 28 tumors) of their samples.…”

“…These findings were attributed to decreased levels of mTOR phosphorylation at the serine-2448 residue, which is a key determinant of mTOR activity. A third study noted a small Greater antiproliferative effect than RAD001; triggers apoptosis Lee et al (2011) but statistically significant antiproliferative effect of 1 nM rapamycin on mouse AtT20 cells and no effect at lower doses (Cerovac et al 2010). Musat et al (2005) have reported that NFPAs have the highest levels of AKT mRNA expression of all PA subtypes.…”

“…SST analogs, such as octreotide, are frequently used for the treatment of neuroendocrine tumors (Lamberts et al 2002). Cerovac et al (2010) demonstrated that the addition of octreotide to rapamycin increased serine-phosphorylated IRS1 levels, but notably decreased rapamycin-induced pAkt-Ser levels. In AtT20 cells, the addition of octreotide to rapamycin resulted in a 50% decrease in cell viability, an effect that was significantly greater than the actions of octreotide or rapamycin alone (Cerovac et al 2010).…”

“…Already implicated in other human cancers, including breast, endometrial, ovarian, prostate, and glioblastoma, recent studies have investigated the activation of this pathway in Pas (Faivre et al 2006). Furthermore, preclinical studies have investigated the therapeutic effects of targeting the PI3K/AKT/mTOR pathway in PAs (Cerovac et al 2010). The focus of this paper is to review the role of PI3K/AKT/mTOR signaling pathway, with particular attention to novel findings in its activation and potential therapeutic targeting in PAs.…”

Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies

“…The anti-proliferative effect of an mTOR inhibitor on different pituitary cell lines or primary cultures has been demonstrated in vitro (Cerovac et al 2010). In vitro data have also shown an effect of everolimus on cell viability in cell cultures from non-functioning pituitary adenomas (Zatelli et al 2010).…”