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Somatostatin Analogs in Clinical Practice: a Review

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International Journal of Molecular Sciences Review Somatostatin Analogs in Clinical Practice: A Review Mariana Gomes-Porras 1, Jersy Cárdenas-Salas 2 and Cristina Álvarez-Escolá 1,* 1 Department of Endocrinology, “La Paz” University Hospital. Paseo de la Castellana, 261, 28046 Madrid, Spain; [email protected] 2 Department of Endocrinology, “Fundación Jiménez-Diaz” University Hospital. Av. de los Reyes Católicos, 2, 28040 Madrid, Spain; [email protected] * Correspondence: [email protected]; Tel.: +34-917-277-209 Received: 31 December 2019; Accepted: 25 February 2020; Published: 29 February 2020 Abstract: Somatostatin analogs are an invaluable therapeutic option in the diagnosis and treatment of somatotropinomas, thyrotropinomas, and functioning and non-functioning gastroenteropancreatic neuroendocrine tumors. They should also be considered an effective and safe therapeutic alternative to corticotropinomas, gonadotropinomas, and prolactinomas resistant to dopamine agonists. Somatostatin analogs have also shown to be useful in the treatment of other endocrine diseases (congenital hyperinsulinism, Graves’ orbitopathy, diabetic retinopathy, diabetic macular edema), non-endocrine tumors (breast, colon, prostate, lung, and hepatocellular), and digestive diseases (chronic refractory diarrhea, hepatorenal polycystosis, gastrointestinal hemorrhage, dumping syndrome, and intestinal fistula). Keywords: Somatostatin analog; pituitary adenoma; neuroendocrine tumor; cancer; carcinoid; lanreotide; octreotide; pasireotide 1. Introduction Somastostatin (SST) is a cyclic polypeptide derived from an SST precursor protein that is processed into several peptide hormones, including SST-14, SST-28, and neuronostatin. SST-14 is the isoform that was originally characterized [1]. STT is one of the main inhibitors of endocrine and exocrine hormone secretion in humans [2]. Native SST is not useful in clinical practice because it has an extremely short half life of 1–3 min, rapidly degradated by ubiquitously distributed peptidases in plasma and tissues [3]. After the characterization of SST, several SST synthetic analogs (SSAs) with longer half-life were developed. To date, three of them have been approved in clinical practice: lanreotide and octretide are considered first-generation SSAs, and pasireotide is considered a second-generation SSA. Their main clinical use has been evaluated in Phase III clinical Trials, and some other uses have been evaluated in prospective studies. 2. Physiological Actions of Somatostatin STT inhibits the secretion of growth hormone (GH), prolactin (PRL), thyrotropin (TSH), cholecystokinin (CCK), gastric inhibitory peptide (GIP), gastrin, motilin, neurotensin, secretin, glucagon, insulin, and pancreatic polypeptide (PP). It also inhibits the exocrine secretion of amylase of salivary glands; hydrochloric acid, pepsinogen, and intrinsic factor of gastrointestinal mucosa; and enzymes and bicarbonate of pancreas and bile in the liver. Furthermore, glucose, fat, and amino acid absorption is inhibited by STT. STT also modulates gastrointestinal motility, delaying the late phase of gastric emptying, weakening gallbladder contraction, and prolonging small-intestinal transit time, but it also accelerates early gastric emptying and shortens the interval between migrating motor complexes. SST decreases portal (and varicose) pressure, inhibits retinal secretion and has an antidiuretic effect in Int. J. Mol. Sci. 2020, 21, 1682; doi:10.3390/ijms21051682 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 1682 2 of 27 Int. J. Mol. Int.Sci. J.2020, Mol. 21, Sci. 1682 2020 , 21, x FOR PEER REVIEW 2 of 26 2 of 26 system thatsystemhumans. underlie that It isunderlie cognition also believed cognition and thatlocomotion and SST locomotion modulates [4]. An inhibition activities[4]. An inhibition ofof theimmunoglobulin central of immunoglo nervous synthesis systembulin synthesis thatand underlie and lymphocytelymphocytecognition proliferation and proliferation locomotion in lymphoid [in4]. lymphoid An tissues inhibition has tissues al ofso immunoglobulin hasbeen also observed. been observed. synthesisAn antiproliferative An and antiproliferative lymphocyte potential proliferation potential was alsowasin demonstrated lymphoid also demonstrated tissues by reversing has by also reversing the been impact observed. the of impact mitogenic An of antiproliferative mitogenic signals delivered signals potential delivered by substances was by also substances demonstrated such as such byas epidermalepidermalreversing growth thefactorgrowth impact (EGF) factor of mitogenicand (EGF) insulin-like and signals insulin growth delivered-like factorgrowth by substances1 factor(IGF-1) 1 [5,6].(IGF such- 1)The as [5,6]. epidermalmechanisms The mechanisms growth of factor of action ofaction(EGF) SSAs andareof SSAs described insulin-like are described in growth Figure in factor1. Figure 1 (IGF-1)1. [5,6]. The mechanisms of action of SSAs are described in Figure1. Figure 1. Mechanisms of action of Somatostatin synthetic Analogs (SSAs). (A). The antisecretory Figure 1. MechanismsMechanisms of of action of Somatostatin synthetic Analogs (SSAs). ( (AA).). The The antisecretory effects occur through the inhibition of the enzyme adenylyl cyclase (AC), the inhibition of voltage- effectseffects occur occur through through the the inhibition inhibition of the of enzyme the enzyme adenyl adenylylyl cyclase cyclase (AC), the (AC), inhibition the inhibition of voltage of- dependentdependentvoltage-dependent calcium channels calcium channels calciumand the stimulation channelsand the stimulation and of thevoltage-dependent stimulation of voltage of-dependent voltage-dependent potassium potassium channels. potassium channels. (B). The channels. (B). The antiproliferativeantiproliferative(B). The effects. antiproliferative (B.1 effects.) Direct (B.1 e ffantiproliferative)ects. Direct (B.1 antiproliferative) Direct effects antiproliferative occu effectsr through occur eff ectsthethrough activation occur the through activation of the the Src activationof the Src HomologyHomologyof 2 the Domain Src Homology 2 Phosphatase-1Domain 2Phosphatase Domain (SHP-1) Phosphatase-1-1 and(SHP Sr-1)c Homologyand (SHP-1) Src Homologyand 2 Domain Src Homology 2 Phosphatase-2Domain 2 Phosphatase Domain (SHP-2). Phosphatase-2-2 (SHP-2). SHP-1 triggersSHP(SHP-2).-1 intracellulartriggers SHP-1 triggersintracellular pro- intracellularapoptotic pro-apoptotic signals pro-apoptotic by signals the signalsinductio by the by ninduction theof inductionp53 and of p53Bax, of p53 andwhile and Bax, Bax,SHP-2 while while SHP SHP-2-2 activates activatesthe tyrosine the the kinasetyrosine Src kinase that inducesSrc that thinduces e phosphorylation the phosphorylation of protein of tyrosine protein phosphatasetyr tyrosineosine phosphatase receptor typereceptorreceptor J (PTPRJ), type J which,(PTPRJ), in which, turn, dephosphorylates in turn, dephosphorylates phosphat phosphatidylinositol idylinositol 3-kinase (PI3K/Akt)3 3-kinase-kinase (PI3K/Akt) (PI3K /Akt) and extracellularand extracellular signal-regulated signal signal-regulated-regulated protein kinase protein s 1 kinases and 2 (ERK1/2), 1 and 2 (ERK1/2), (ERK1 impairing/2), impairing cell proliferation cell proliferation proliferation.. (B.2 . ( B.2 and B.3). andIndirect B.3).) . antiproliferative Indirect antiproliferativeantiproliferativ effects occure e effectsffects throug occur occurh through thethrough inhibition the the inhibition inhibition of circulating of circulatingof circulating growth growth factors growth factors factors like like vascularlikevascular vascularendothelial endothelial endothelial growth growth factorgrowth factor (VEGF), factor (VEGF), in(VEGF),sulin-like insulin-like insulin growth growth-like factorgrowth factor 1 1(IGF-1),factor (IGF-1), 1 insulin-like(IGF insulin-like-1), insulin growth-like growth factorgrowthfactor 2 2(IGF-2) factor (IGF-2) 2(B.2 ((IGFB.2) and)- and2) (throughB.2 through) and the through the inhibition inhibition the inhibition of of tumor tumor ofangiogenesis angiogenesis tumor angiogenesis by by al alteringtering by the alteri the release releaseng the ofrelease nitric of nitric oxideofoxide nitric (NO) (NO) oxide (B.3 (B.3 (NO)).). (Red (Red (B.3 “X “).X”: ”:(Red Inhibition; Inhibition; “X”: Inhibition; Green Green “ “ ✚Green ”:”: Stimulation).Stimulation) “✚”: Stimulation) . 3. Somatostatin Receptors (SSTRs) 3. Somatostatin3. Somatostatin Receptors Receptors (SSTRs) (SSTRs) SST induces its biological effects by interacting with specific receptors that belong to the superfamily SST inducesSST inducesits biological its biological effects byeffects interactin by interactingg with specific with specificreceptors receptors that belong that tobelong the to the of G protein-coupled receptors. Five receptor subtypes have been identified (SSTR1–SSTR5), and superfamilysuperfamily of G protein-coupled of G protein- coupledreceptors. recept Fiveors. receptor Five receptor subtypes subtypes have been have identified been identified (SSTR1– (SSTR1– the SSTR2 subtype has two splice variants (SSTR2A and SSTR2B). While all five subtypes are SSTR5), andSSTR5), the SSTR2and the subtype SSTR2 subtypehas two splicehas two variants splice variants(SSTR2A (SSTR2A and SSTR2B). and SSTR2B). While all While five subtypes all five subtypes expressed in normal human tissues, the predominant subtypes in endocrine tissues are SSTR2 and are expressedare expressed in normal in humannormal tissues,human thetissues, pred
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