Direct effects of first-generation somatostatin analogues
The anti-proliferative effects of somatostatin analogues in pituitary adenomas may be mediated by somatostatin receptors, activation of which can induce apoptosis, cell cycle inhibition, and inhibition of growth factor effects [
15,
16]. In cancer models, for example, it has been demonstrated that somatostatin analogues targeting sst
1 and/or sst
2 inhibit platelet-derived growth factor (PDGF)-stimulated ERK activity, with associated anti-proliferative effects [
17]. Elsewhere, it was shown that sst
2 receptors may also be involved in restoration of functional gap junctions (critical for maintenance of the differentiated state) by inducing expression of connexin [
18]. The sst
2 receptor has also been shown to exert anti-oncogenic properties. Buscail and colleagues demonstrated the loss of sst
2 receptor expression in human pancreatic carcinoma and showed that restoration of the sst
2 gene defect resulted in a significant reduction in cell growth and tumorigenicity [
19]. Animal models have also shown that re-expression of sst
2 resulted in decreased tumor growth [
20,
21].
The underlying mechanism for these direct effects has not been fully elucidated, although certain pathways activated by binding to the sst
2 receptor have a known role in mediating cell growth. Ligand interaction with sst
2 initiates upregulation of protein tyrosine phosphatase (PTP), a key modulator of mitogenic effects that include cell differentiation and development. SHP-1, a negative regulator of hematopoietic cell signal transduction and negative regulator of cell signaling, is dissociated after treatment with somatostatin or octreotide, thereby dephosphorylating tyrosine kinase receptors [
16,
22]. Additionally, sst
2 activation has a role in modulating another central regulator of cell growth, the MAPK pathway, including phosphatidylinositol triphosphate kinases (PI3K) and Akt phosphorylation [
23].
In a recent study using a pituitary tumor model including GH-secreting pituitary cells, through upregulation of the PI3K/Akt pathway, as well as mitogen-activated protein kinase pathways, octreotide increased both transcription of the mixed lineage leukemia (
MLL) gene and levels of p27(Kip1), a protein that controls G1 cell cycle progression [
24]. The authors concluded that the
MLL–p27(Kip1) pathway may be a novel therapeutic target in pituitary tumors [
24]. Additionally, a recent study evaluated the anti-proliferative effect of octreotide in combination with an mTOR inhibitor in pituitary tumor cells, as Akt activation reduces sensitivity to rapamycin and its analogues and octreotide acts as an upstream inhibitor of the PI3K/Akt pathway [
25]. The study found that octreotide decreased levels of activated Ser(473)-phosphorylated Akt via modulating SHP-1, which, in combination with rapamycin, led to increased levels of p27(Kip1), as well as to macroscopic effects such as G1 cell cycle arrest [
25].
In a pituitary cell model, it was shown that octreotide exerts its anti-proliferative action by increasing expression of the tumor suppressor gene
Zac1 [
26]. Zac1 is a recently discovered novel zinc finger protein expressed in the pituitary gland and brain that induces cell cycle arrest and apoptosis [
27,
28]. Octreotide was found to increase Zac1 levels by inhibiting the PI3K/Akt protein survival pathway, thereby preventing phosphorylation of Zac1 [
26]. The same investigators subsequently demonstrated an association between pituitary tumor Zac1 expression and response to somatostatin analogue therapy in patients with acromegaly [
29].
Indirect effects of first-generation somatostatin analogues
Somatostatin analogues may also act indirectly by inhibiting the release of growth factors and trophic hormones (such as IGF-1 and insulin), or through inhibition of angiogenesis, which limits tumor growth [
15]. There is also evidence that downregulation of vascular endothelial growth factor (VEGF) may be how octreotide inhibits angiogenesis in pituitary tumors [
30]. In neuroendocrine tumors, administration of octreotide significantly reduces VEGF secretion (likely via the PI3K/Akt pathway) [
31]. Clinically, the anti-angiogenic effect of octreotide has been demonstrated in a small study of five patients with acromegaly, who showed a significant reduction in the functional vascularity of their pituitary tumors after 24 weeks of octreotide as first-line therapy [
32].
Antiproliferative effects of pasireotide
Somatostatin analogues with different receptor binding profiles may also exert varying effects on cell growth. For example, pasireotide, the multireceptor-targeted somatostatin analogue, has approximately 30-, 11-, and 158-fold higher functional activity than octreotide on sst
1, sst
3, and sst
5, respectively, and seven-fold lower activity on sst
2 [
33,
34]. Recent studies have shown that octreotide and pasireotide stimulate distinct patterns of sst
2A phosphorylation, with both compounds internalizing the receptor upon binding, but with pasireotide forming less stable beta-arrestin–sst
2A complexes compared with octreotide, leading to earlier recycling of sst
2A on the cell membrane [
35]. Additionally, although an adenylyl cyclase inhibitor like somatostatin, pasireotide has an antagonistic effect on intracellular calcium stimulation and ERK phosphorylation [
36]. A previous study of pituitary tumors had suggested that downregulation of phospho-ERK (and upregulation of p27) is associated with sst-mediated growth inhibition and that broader-spectrum somatostatin analogues are likely to play an increasing role in tumor types in which the MAPK pathway is over-expressed [
37]. As a recent immunohistochemical study showed that different types of pituitary adenomas express a variety of sst, and that in tumors isolated from patients with acromegaly, sst
5 and sst
1 were more prevalent than sst
2A, the authors concluded that multireceptor somatostatin analogues may be a useful approach, especially in somatotroph adenomas [
38].