Abstract
Endogenous somatostatin shows anti-secretory effects in both physiological and pathological settings, as well as inhibitory activity on cell growth. Since somatostatin is not suitable for clinical practice, researchers developed synthetic somatostatin receptor ligands (SRLs) to overcome this limitation. Currently, SRLs represent pivotal tools in the treatment algorithm of neuroendocrine tumors (NETs). Octreotide and lanreotide are the first-generation SRLs developed and show a preferential binding affinity to somatostatin receptor (SST) subtype 2, while pasireotide, which is a second-generation SRL, has high affinity for multiple SSTs (SST5 > SST2 > SST3 > SST1). A number of studies demonstrated that first-generation and second-generation SRLs show distinct functional properties, besides the mere receptor affinity. Therefore, the aim of the present review is to critically review the current evidence on the biological effects of SRLs in pituitary adenomas and neuroendocrine tumors, by mainly focusing on the differences between first-generation and second-generation ligands.
Highlights
Somatostatin is an endogenous, and ubiquitous hormonal peptide [1] acting though a family of five G-protein-coupled receptors, named somatostatin receptors (SST) 1 to 5, and represents one of the main physiological inhibitors of endocrine and exocrine hormone secretion [2]
PAS treatment results in a specific activation of intracellular pathways, as well as in a peculiar target-receptor internalization and trafficking compared to both OCT and native SRIF, mainly when evaluating SST2
These observations mainly result from preclinical studies carried out on transfected cell models, which do not always represent reliable models for pituitary adenomas and neuroendocrine neoplasms (NENs)
Summary
Somatostatin (somatotropin release–inhibiting factor, SRIF) is an endogenous, and ubiquitous hormonal peptide [1] acting though a family of five G-protein-coupled receptors, named somatostatin receptors (SST) 1 to 5, and represents one of the main physiological inhibitors of endocrine and exocrine hormone secretion [2]. SRIF is able to modulate immune responses [5,6] and gastro-enteric-pancreatic cell activity [7] The interest in the potential use of SRIF as an anti-proliferative agent grew in recent years This novel potential pharmacological use, despite being preclinically tested with unique results in several human solid tumors, including breast and lung carcinomas and gliomas [3,4], acquired particular interest for neuroendocrine tumors, including both pituitary adenomas and gastro-entero-pancreatic (GEP), as well as thoracic neuroendocrine neoplasms (NENs). Notwithstanding the negative results reported for non-endocrine tumors, several studies thoroughly characterized the expression pattern of the five SST subtypes in human tumors and the molecular intracellular mechanisms by which each of these receptors activates anti-secretory and anti-proliferative signals in tumor cells
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