Effect of the Tryptophan Hydroxylase Inhibitor Telotristat on Growth and Serotonin Secretion in 2D and 3D Cultured Pancreatic Neuroendocrine Tumor Cells.


:Serotonin, a biologically active amine, is related to carcinoid syndrome in functioning neuroendocrine tumors (NETs). Telotristat ethyl is a novel inhibitor of the tryptophan hydroxylase (TPH), a key enzyme in the production of serotonin. While its use in patients with carcinoid syndrome and uncontrolled diarrhea under somatostatin analogs (SSAs) has been recently approved, in vitro data evaluating its effectiveness are lacking. For this reason, we aimed to evaluate the effect of telotristat as monotherapy, and in combination with SSAs, on proliferation and secretion in a NET cell line model. The human pancreatic NET cell lines BON-1/QGP-1 were used as 2D and 3D cultured models; somatostatin receptor and TPH mRNA expression, as well as the potential autocrine effect of serotonin on tumor cell proliferation using a 3D culture system were evaluated. Telotristat decreased serotonin production in a dose-dependent manner at a clinically feasible concentration, without affecting cell proliferation. Its combination with pasireotide, but not with octreotide, had an additive inhibitory effect on serotonin secretion. The effect of telotristat was slightly less potent, when BON-1 cells were co-treated with octreotide. Octreotide and pasireotide had no effect on the expression of TPH. Telotristat did not have an effect on mRNA expression of somatostatin receptor subtypes. Finally, we showed that serotonin did not have an autocrine effect on NET cell proliferation on the 3D cell model. These results suggest that telotristat is an effective drug for serotonin inhibition, but the effectiveness of its combination with SST2 (somatostatin receptor subtype 2)-preferring SSA should be evaluated in more detail.






Herrera-Martínez AD,Feelders RA,Van den Dungen R,Dogan-Oruc F,van Koetsveld PM,Castaño JP,de Herder WW,Hofland LJ




Has Abstract


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  • Corticotrophin-releasing factor and arginine vasopressin fibre projections to the median eminence of fetal sheep.

    abstract::Using specific antibodies to corticotrophin-releasing factor (CRF) and arginine vasopressin (AVP) we have immunocytochemically located cells and fibres containing these peptides in sheep fetuses. CRF neurones were first detected, in low frequency, in the paraventricular nuclei of fetuses of 90 days of gestation (term ...


    pub_type: 杂志文章


    authors: Levidiotis M,Oldfield B,Wintour EM

    更新日期:1987-11-01 00:00:00

  • Effect of steroids on vasoactive intestinal peptide in discrete brain regions and peripheral tissues.

    abstract::The effect of castration and adrenalectomy was studied on vasoactive intestinal peptide (VIP) concentrations in various brain and peripheral structures of male rats. Castration has no effect on any of the structures studied, whereas 4 weeks adrenalectomy (ADX) decreases VIP concentrations in the hippocampus and increa...


    pub_type: 杂志文章


    authors: Rotsztejn WH,Besson J,Briaud B,Gagnant L,Rosselin G,Kordon C

    更新日期:1980-10-01 00:00:00

  • Corticotropin-releasing hormone inhibits melatonin secretion in healthy volunteers--a potential link to low-melatonin syndrome in depression?

    abstract::Interactions between the hypothalamic-pituitary-adrenocortical (HPA) system and melatonin secretion have been demonstrated, but only the effects of melatonin on the activity of the HPA system have been studied in man. Alterations of melatonin secretion described as low-melatonin syndrome have been demonstrated in pati...


    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Kellner M,Yassouridis A,Manz B,Steiger A,Holsboer F,Wiedemann K

    更新日期:1997-04-01 00:00:00

  • Acetyl salmon endorphin-like and interrenal stress response in male gilthead sea bream, Sparus aurata.

    abstract::The present study investigates the role of melanotrope proopiomelanocortin-derived peptide in the interrenal stress response to different stressors in male gilthead sea bream, Sparus aurata. Plasma cortisol and acetyl salmon endorphin (acetyl s-EP), as well as pituitary acetyl s-EP contents, were measured during two s...


    pub_type: 杂志文章


    authors: Mosconi G,Gallinelli A,Polzonetti-Magni AM,Facchinetti F

    更新日期:1998-08-01 00:00:00

  • Subfornical organ efferents influence the excitability of neurohypophyseal and tuberoinfundibular paraventricular nucleus neurons in the rat.

    abstract::Electrical stimulation in the subfornical organ (SFO) alters the excitability of antidromically identified paraventricular nucleus neurons. Extracellular recordings demonstrate that the dominant effect of single stimuli delivered to the SFO on neurohypophyseal oxytocin and vasopressin containing neurons is an increase...


    pub_type: 杂志文章


    authors: Ferguson AV,Day TA,Renaud LP

    更新日期:1984-11-01 00:00:00

  • Site of gamma-aminobutyric acid (GABA)-mediated inhibition of growth hormone secretion in the rat.

    abstract::The effect of altering gamma-aminobutyric acid (GABA) activity on growth hormone (GH) secretion of freely moving chronically cannulated male rats was studied. Systemic injection of the GABA agonist muscimol (2 mg/kg i.v.) inhibited the anticipated secretory episode. Increasing brain GABA levels by gamma-acetylenic-GAB...


    pub_type: 杂志文章


    authors: Fiók J,Acs Z,Makara GB,Erdö SL

    更新日期:1984-12-01 00:00:00

  • Preoptic LH-RH and somatostatin in the rat median eminence. An experimental light and electron microscopic immunocytochemical study.

    abstract::Glass microknife lesions and immunocytochemistry were used to evaluate luteinizing hormone-releasing hormone (LH-RH)- and somatostatin (SS)-immunoreactive pathways from the preoptic region to the rat median eminence. Cuts were so placed that axons of more caudally located neurons in the periventricular hypothalamic ar...


    pub_type: 杂志文章


    authors: Jew JY,Léránth C,Arimura A,Palkovits M

    更新日期:1984-03-01 00:00:00

  • Epidemiology of Cushing's syndrome.

    abstract::Overt Cushing's syndrome is a rare disorder with an annual incidence of 2-3/million of which benign adrenal adenomas account for 0.6/million. The female:male ratio is 3:1. Preliminary data indicate a high proportion of subclinical Cushing's syndrome in certain risk populations such as patients with type 2 diabetes or ...


    pub_type: 杂志文章,评审


    authors: Steffensen C,Bak AM,Rubeck KZ,Jørgensen JO

    更新日期:2010-01-01 00:00:00

  • Progesterone reverses the estradiol-induced decrease in tyrosine hydroxylase mRNA levels in the arcuate nucleus.

    abstract::Estradiol (E2) and progesterone (P4) interact to influence tuberoinfundibular dopaminergic neuronal activity and contribute to the control of prolactin (PRL) release. This study examined tyrosine hydroxylase mRNA signal levels in the arcuate nucleus of the hypothalamus and tyrosine hydroxylase activity in the stalk-me...


    pub_type: 杂志文章


    authors: Arbogast LA,Voogt JL

    更新日期:1993-11-01 00:00:00

  • Classification and Prognostic Stratification of Bronchopulmonary Neuroendocrine Neoplasms.

    abstract::The accuracy and reproducibility of the World Health Organization (WHO) 2015 classification of bronchopulmonary neuroendocrine neoplasms (BP-NENs) is disputed. The aim of this study is to classify and grade BP-NENs using the WHO 2019 classification of digestive system NENs (DiS-NEN-WHO 2019), and to analyze its accura...


    pub_type: 杂志文章


    authors: Oka N,Kasajima A,Konukiewitz B,Sakurada A,Okada Y,Kameya T,Weichert W,Ishikawa Y,Suzuki H,Sasano H,Klöppel G

    更新日期:2020-01-01 00:00:00

  • D2 dopamine-receptor-mediated inhibition of proliferation of rat lactotropes in culture is accompanied by changes in cell shape.

    abstract::Dopaminergic agonists are effective in vivo in inhibiting lactotrope proliferation and prolactin (PRL)-secreting pituitary tumors. The purpose of the present study was to demonstrate in vitro actions of dopaminergic agents on proliferation and cell shape of rat lactotropes. Anterior pituitary cells cultured with serum...


    pub_type: 杂志文章


    authors: Arita J,Hashi A,Hoshi K,Mazawa S,Suzuki S

    更新日期:1998-09-01 00:00:00

  • Statins Directly Regulate Pituitary Cell Function and Exert Antitumor Effects in Pituitary Tumors.

    abstract:INTRODUCTION:Pituitary neuroendocrine tumors (PitNETs), the most abundant of all intracranial tumors, entail severe comorbidities. First-line therapy is transsphenoidal surgery, but subsequent pharmacological therapy is often required. Unfortunately, many patients are/become unresponsive to available drugs (somatostati...


    pub_type: 杂志文章


    authors: Vázquez-Borrego MC,Fuentes-Fayos AC,Herrera-Martínez AD,Venegas-Moreno E,L-López F,Fanciulli A,Moreno-Moreno P,Alhambra-Expósito MR,Barrera-Martín A,Dios E,Blanco-Acevedo C,Solivera J,Granata R,Kineman RD,Gahete MD,Soto-Mor

    更新日期:2020-01-01 00:00:00

  • Gaseous transmitters and neuroendocrine regulation.

    abstract::Recent work has demonstrated that the brain has the capacity to synthesize impressive amounts of the gases nitric oxide (NO) and carbon monoxide (CO). There is growing evidence that these gaseous molecules function as novel neural messengers in the brain. This article reviews the pertinent literature concerning the pu...


    pub_type: 杂志文章,评审


    authors: Brann DW,Bhat GK,Lamar CA,Mahesh VB

    更新日期:1997-06-01 00:00:00

  • Effects of stimulation of the preoptic area on hypothalamic paraventricular nucleus unit activity and corticosterone secretion in freely moving rats.

    abstract::Recordings were made of single unit activity through chronically implanted electrodes within the hypothalamic paraventricular nucleus of freely moving male rats also bearing chronically implanted stimulating electrodes in the preoptic area (POA) and indwelling jugular cannulae. High frequency electrical stimulation of...


    pub_type: 杂志文章


    authors: Saphier D,Feldman S

    更新日期:1986-01-01 00:00:00

  • Diurnal rhythmicity of gonadotropin-releasing hormone gene expression in the rat.

    abstract::The release of the decapeptide gonadotropin-releasing hormone (GnRH) from neuroterminals in the median eminence varies depending upon the stage of development, time of day, reproductive season, and day of the ovarian cycle. With respect to the biosynthetic events responsible for such alterations in GnRH release, we ha...


    pub_type: 杂志文章


    authors: Gore AC

    更新日期:1998-10-01 00:00:00

  • Elevated brain glucose and glycogen concentrations in an animal model of depression.

    abstract:INTRODUCTION:Recent data indicate that there is a link between depression and diabetes and that excess glucocorticoids may play an underlying role in the pathogenesis of both of these diseases. The aim of the present study was to determine whether there are any alterations in glucose, glycogen, glucose transporters, in...


    pub_type: 杂志文章


    authors: Detka J,Kurek A,Basta-Kaim A,Kubera M,Lasoń W,Budziszewska B

    更新日期:2014-01-01 00:00:00

  • Quantitative histochemical studies of the hypothalamus. Control point enzymes following androgen sterilization.

    abstract::Three control point enzymes of the Embden-Meyerhof pathway, hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK) were measured by quantitative histochemical methods in individual hypothalamic nuclei of adult neonatally androgenized female rats. HK activity was significantly increased in anterior hypotha...


    pub_type: 杂志文章


    authors: Packman PM,Bragdon MJ,Boshans RL

    更新日期:1977-01-01 00:00:00

  • An ultrastructural and radioimmunoassay study of anterior pituitary somatotrophs following pituitary portal vessel infusion of growth hormone releasing factor.

    abstract::The hypophysial portal vessels and anterior pituitary glands of adult male rats were surgically exposed, cannulated and infused for 1 min with saline, growth hormone-releasing factor (GH-RF), and dbcAMP. After cessation of infusion, anterior pituitary glands were collected at 1, 5, 15, 30 or 60 min for electron micros...


    pub_type: 杂志文章


    authors: Wilbur DL,Worthington WC Jr,Markwald RR

    更新日期:1975-01-01 00:00:00

  • Vasopressin has a direct effect on prolactin release in male rats.

    abstract::Prolactin-releasing (PRF) activity was found in Pitressin (a commercial extract from posterior pituitary for vasopressin). Injection of Pitressin into conscious free-moving rats implanted with a permanent atrial indwelling cannula, produced a transient increase in prolactin concentration in the circulation. In order t...


    pub_type: 杂志文章


    authors: Shin SH

    更新日期:1982-01-01 00:00:00

  • Estradiol Rapidly Attenuates ORL-1 Receptor-Mediated Inhibition of Proopiomelanocortin Neurons via Gq-Coupled, Membrane-Initiated Signaling.

    abstract::Estradiol rapidly regulates the activity of arcuate nucleus (ARH) proopiomelanocortin (POMC) neurons that project to the medial preoptic nucleus (MPN) to regulate lordosis. Orphanin FQ/nociceptin (OFQ/N) acts via opioid receptor-like (ORL)-1 receptors to inhibit these POMC neurons. Therefore, we tested the hypothesis ...


    pub_type: 杂志文章


    authors: Conde K,Meza C,Kelly MJ,Sinchak K,Wagner EJ

    更新日期:2016-01-01 00:00:00

  • Correlation of World Health Organization 2010 classification for gastroenteropancreatic neuroendocrine neoplasms with the prognosis of ovarian neuroendocrine neoplasms: Kansai Clinical Oncology Group-Protocol Review Committee/Intergroup Study.

    abstract:BACKGROUND:In 2014, the World Health Organization (WHO) released a classification system introducing neuroendocrine neoplasms (NENs) of the female reproductive tract, excluding the ovaries. This study aimed to evaluate whether retrospective adaption of the gastroenteropancreatic (GEP)-NEN classification is feasible for...


    pub_type: 杂志文章


    authors: Kai K,Nasu K,Nishida H,Daa T,Shikama A,Shiozaki T,Kurakazu M,Yano M,Imamura Y,Tokunaga H,Tasaki K,Iida Y,Yamada Y,Morisawa H,Nakagawa S,Fujimoto E,Tsuruta T,Matsumoto H,Arakawa A,Nonaka M,Takano H,Ushiwaka T,M

    更新日期:2020-02-25 00:00:00

  • Suckling-induced changes of vasoactive intestinal peptide concentrations in hypothalamic areas implicated in the control of prolactin release.

    abstract::The present study was designed to investigate whether the vasoactive intestinal peptide (VIP) concentration in hypothalamic nuclei, dorsal raphe nucleus (DR) and pituitary lobes of lactating rats changes in physiological situations when prolactin (PRL) secretion is stimulated (suckling) or inhibited (pup separation). ...


    pub_type: 杂志文章


    authors: Chiocchio SR,de las Nieves Parisi M,Vitale ML,Tramezzani JH

    更新日期:1991-07-01 00:00:00

  • Age- and sex-related changes in Tyr-MIF-1-like immunoreactivity in rat plasma.

    abstract::The concentrations in plasma of the biologically active endogenous peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) have not been measured during development or in female rats. By radioimmunoassay, we found that Tyr-MIF-1-like immunoreactivity (Tyr-MIF-1-LI) was first consistently detectable in plasma when the rat was 5 days o...


    pub_type: 杂志文章


    authors: Kastin AJ,Fabre L,Brown MM,Olson RD

    更新日期:1992-12-01 00:00:00

  • Stress-induced changes in cholecystokinin and substance P concentrations in discrete regions of the rat hypothalamus.

    abstract::The effects of acute stress exposure upon cholecystokinin (CCK) and substance P (SP) concentrations in discrete hypothalamic regions of the adult male rat brain were studied. Animals were exposed to foot shock stress for periods of 2, 4, 10, 30 or 60 min duration; immediately afterwards they were decapitated; brains w...


    pub_type: 杂志文章


    authors: Siegel RA,Düker EM,Pahnke U,Wuttke W

    更新日期:1987-06-01 00:00:00

  • Estrogen modulation of mu-opioid receptor-stimulated [35S]-GTP-gamma-S binding in female rat brain visualized by in vitro autoradiography.

    abstract::The mu-opioid receptor (OR) is involved in several aspects of female reproductive neuroendocrinology, such as the control of gonadotropin release and the display of lordosis behavior. Even though the neuroendocrine events modulated by mu-ORs are steroid hormone-dependent, few studies have shown how steroid hormones su...


    pub_type: 杂志文章


    authors: Acosta-Martinez M,Etgen AM

    更新日期:2002-10-01 00:00:00

  • Concomitant changes in the in vitro and in vivo release of opioid peptides and luteinizing hormone-releasing hormone from the hypothalamus following blockade of receptors for corticotropin-releasing factor.

    abstract::In vitro and in vivo perfusion techniques were used to examine the changes in the release of beta-endorphin, methionine-enkephalin (met-enkephalin), dynorphin and luteinizing hormone releasing hormone (LHRH) in response to the corticotropin releasing factor (CRF) receptor antagonist, alpha-helical CRF9-41. All four pe...


    pub_type: 杂志文章


    authors: Nikolarakis KE,Almeida OF,Sirinathsinghji DJ,Herz A

    更新日期:1988-06-01 00:00:00

  • Effects of leptin on intracellular calcium concentrations in isolated porcine somatotropes.

    abstract::Leptin, the product of the obese gene, is a protein that is secreted primarily from adipocytes. Leptin can influence the function of the pituitary gland through its action on the hypothalamus, but it can also directly act at the level of the pituitary gland. The ability of leptin to induce an increase in intracellular...


    pub_type: 杂志文章


    authors: Glavaski-Joksimovic A,Rowe EW,Jeftinija K,Scanes CG,Anderson LL,Jeftinija S

    更新日期:2004-01-01 00:00:00

  • The corticotropin-releasing hormone network and the hypothalamic-pituitary-adrenal axis: molecular and cellular mechanisms involved.

    abstract::Corticotropin-releasing hormone (CRH) plays a key role in adjusting the basal and stress-activated hypothalamic-pituitary-adrenal axis (HPA). CRH is also widely distributed in extrahypothalamic circuits, where it acts as a neuroregulator to integrate the complex neuroendocrine, autonomic, and behavioral adaptive respo...


    pub_type: 杂志文章,评审


    authors: Bonfiglio JJ,Inda C,Refojo D,Holsboer F,Arzt E,Silberstein S

    更新日期:2011-01-01 00:00:00

  • The compartmentalized hypothalamo-neurohypophysial system: evidence for a neurohypophysial action of acetylcholine on vasopressin release.

    abstract::A portion of medial basal hypothalamus containing the supraoptic nuclei with the neurohypophysis attached was organ cultured. Hypothalamus and neurohypophysis were maintained in separate compartments, and the intact infundibular stalk passed through a hole in a fluid-tight barrier which separated the two compartments....


    pub_type: 杂志文章


    authors: Gregg CM

    更新日期:1985-05-01 00:00:00

  • Prolactin suppression by serotonin antagonists in man: further evidence for serotoninergic control of prolactin secretion.

    abstract::To further investigate the role of serotonin in human prolactin (Prl) secretion, serotonin antagonists have been administered to healthy volunteers in basal conditions and after pretreatment with the selective blocker of dopamine receptors, pimozide (Pim). Highly significant falls (p less than 0.001) in serum Prl were...


    pub_type: 临床试验,杂志文章


    authors: Ferrari C,Caldara R,Romussi M,Rampini P,Telloli P,Zaatar S,Curtarelli G

    更新日期:1978-01-01 00:00:00