scholarly journals Dopamine receptor subtype 2 and somatostatin receptor subtype 5 expression influences somatostatin analogs effects on human somatotroph pituitary adenomas in vitro

2005 ◽  
Vol 35 (2) ◽  
pp. 333-341 ◽  
Author(s):  
M C Zatelli ◽  
D Piccin ◽  
F Tagliati ◽  
A Bottoni ◽  
M R Ambrosio ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Primary Culture ◽  
Pituitary Adenomas ◽  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Receptor Subtype ◽  
Inhibitory Effects ◽  
Gh Secretion ◽  
Secretion Inhibition

Dopamine (DA) and somatostatin (SRIF) receptor agonists inhibit growth hormone (GH) secretion by pituitary adenomas. We investigated DA subtype 2 receptor (DR2) and SRIF receptor (sst) subtypes 2 and 5 expression in 25 GH-secreting pituitary adenomas and tested in primary culture the effects on GH and prolactin (PRL) secretion of sst agonists selectively interacting with sst2 (BIM-23120), sst5 (BIM-23206), and sst2 and sst5 (BIM-23244). All adenomas expressed sst2; eight adenomas expressed both sst5 and DR2, eight sst5 but not DR2, and eight DR2 but not sst5. One tissue lacked expression of DR2 and sst5. GH secretion was inhibited by BIM-23120 in all samples, while it was reduced by BIM-23206 only in adenomas not expressing DR2. BIM-23120’s inhibitory effects correlated with sst2 and DR2 expression, whereas DR2 expression correlated inversely with BIM-23206 inhibitory effects on GH secretion. In seven mixed GH-/PRL-secreting pituitary adenomas, PRL secretion was inhibited in sst5-expressing tumors by BIM-23206, but not by BIM-23120. BIM-23244 reduced PRL secretion only in adenomas expressing sst2, sst5 and DR2. sst5 and DR2 expression correlated directly with BIM23206 inhibitory effects on PRL secretion. Our results suggest that adenomas expressing DR2 are less likely to respond to clinically available SRIF analogs in terms of GH secretion inhibition. Therefore, drugs interacting also with DR2 might better control secretion of pituitary adenomas.

scholarly journals Ghrelin Receptor (GHS-R1a) and Its Constitutive Activity in Somatotroph Adenomas: A New Co-targeting Therapy Using GHS-R1a Inverse Agonists and Somatostatin Analogs

2014 ◽  
Vol 99 (12) ◽  
pp. E2463-E2471 ◽  
Author(s):  
Yves Mear ◽  
Marie-Pierre Blanchard ◽  
Céline Defilles ◽  
Thierry Brue ◽  
Dominique Figarella-Branger ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Inverse Agonist ◽  
Receptor Subtype ◽  
Dependent Manner ◽  
Constitutive Activity ◽  
Targeting Therapy ◽  
Ghrelin Receptor ◽  
Gh Secretion

Context: The ghrelin receptor GHS-R1a is highly expressed in human somatotroph adenomas and exhibits unusually high basal signaling activity. In humans, the suppression of this constitutive activity by mutation induces a short stature. Objective: Using a GHS-R1a inverse agonist, modified substance P (MSP), we explored the role of GHS-R1a constitutive activity in GH hypersecretion from somatotroph adenomas and as a putative therapeutic target. Design: The effects of MSP were assessed on GH secretion from 19 human somatotroph tumors in vitro. Moreover, these effects were compared with those of octreotide (somatostatin receptor subtype 2 [sst2] agonist) and with the combination of both drugs. Expression and localization of GHS-R1a and sst2 were studied. Results: For all tumors, MSP inhibited GH secretion in a dose-dependent manner from 13 to 64%. Moreover, MSP enhanced octreotide-induced GH inhibition. For five tumors, the effects of combined MSP plus octreotide treatment were significantly higher than the sum of effects of each drug alone. MSP increased the membrane localization of GHS-R1a and of microdomains colocalizing sst2-GHS-R1a, highlighting the cooperation between the two drugs. Conclusions: The GHS-R1a inverse agonist could open new therapeutic options for acromegalic patients, particularly patients partially sensitive to octreotide whose GH secretion is not completely controlled by the sst2 agonist.

scholarly journals Correlation of in Vitro and in Vivo Somatotropic Adenoma Responsiveness to Somatostatin Analogs and Dopamine Agonists with Immunohistochemical Evaluation of Somatostatin and Dopamine Receptors and Electron Microscopy

2008 ◽  
Vol 93 (4) ◽  
pp. 1412-1417 ◽  
Author(s):  
Diego Ferone ◽  
Wouter W. de Herder ◽  
Rosario Pivonello ◽  
Johan M. Kros ◽  
Peter M. van Koetsveld ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Pituitary Adenomas ◽  
Dopamine D2 Receptor ◽  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Receptor Expression ◽  
Receptor Subtype ◽  
Mixed Cell

Abstract Objective and Patients: Twenty-four pituitary adenomas from acromegalic patients (13 females, 11 males; age range 19–65 yr) were characterized for somatostatin receptor subtype 2A (sst2A), dopamine D2 receptor (D2R), GH, and prolactin (PRL) expression by immunohistochemistry, and results correlated with the in vitro and in vivo hormone responses to octreotide and quinagolide. In nine cases, GH and PRL content was further studied by immunoelectron microscopy. Results: Immunoreactivity was semiquantitatively scored as 2 (>50% stained cells), 1 (10–50% stained cells), and 0 (<10% stained cells). Sst2A was scored as 2 in 13 cases, 1 in 10, and 0 in one; D2R was scored as 2 in 13 cases, 1 in nine, and 0 in 2; GH was 2 in 15 cases and 1 in nine; PRL was 2 in six cases, 1 in 13, and 0 in 5. Sst2A was positively correlated with in vitro (P = 0.003) and in vivo (P = 0.006) percent GH suppression by octreotide and with the chronic suppression of IGF-I by somatostatin analogs (P =0.008). D2R was positively correlated with in vitro percent GH (P =0.000) and PRL (P =0.005) suppression by quinagolide. Electron microscopy revealed two pure somatotroph adenomas, five somatomammotrophs with a variable coexpression of GH and PRL in the same cells, and two tumors consisting of mixed cell types, which were less sensitive to quinagolide and octreotide. Conclusion: Sst2A and D2R are frequently coexpressed in adenomas from acromegalic patients, and immunohistochemistry may be helpful in characterizing receptor expression in pituitary adenomas to select patients responsive to different treatments.

scholarly journals Selective Loss of Somatostatin Receptor 2 in Octreotide-Resistant Growth Hormone-Secreting Adenomas

2008 ◽  
Vol 93 (4) ◽  
pp. 1203-1210 ◽  
Author(s):  
Ursula Plöckinger ◽  
Susann Albrecht ◽  
Christian Mawrin ◽  
Wolfgang Saeger ◽  
Michael Buchfelder ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Maximum Dose ◽  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Gh Secretion ◽  
Selective Loss ◽  
Octreotide Treatment ◽  
Group A ◽  
Group B ◽  
Growth Hormone Secreting Adenomas

Abstract Objective: The somatostatin analog octreotide preferentially binds to somatostatin receptor (sst) 2A and to a lesser extent to sst5. Although sst2A and sst5 mRNAs are consistently expressed in GH-secreting adenomas, octreotide controls GH secretion only in 65% of acromegalic patients. Hence, we investigated the immunocytochemical expression of sst in a large group of somatotroph tumors. Methods: Acromegalic patients, cared for in a university referral center, were either operated on without pretreatment (group A, n = 14) or pretreated with octreotide [median (minimum-maximum): dose 1250 (300–1500) μg/d for 5.6 (3–9) months] before surgery (group B, n = 20). In group B octreotide reduced GH secretion by more than 50% in 14 patients (70%) (GH responders). Six patients with less than 50% GH suppression were considered GH nonresponders. We used a panel of extensively characterized antibodies to determine the immunocytochemical sst status in somatotroph adenomas and compared their expression between the groups. Results: All group A tumors demonstrated immunoreactive sst2A, and all but one had sst5. A similar pattern was found in the GH responders of group B. In contrast, none of the GH nonresponders exhibited detectable sst2A (sst2A: GH responders vs. GH nonresponders, P < 0.0001), whereas sst5 was found in 70%. sst1 and sst3 were detected in 85 and 24% of all cases, independent of previous octreotide treatment. Conclusions: Our findings suggest that octreotide resistance in GH-secreting adenomas occurs due to a selective loss of sst2A. The persistent expression of sst1 and sst5 receptors suggests that these tumors are potential targets for pan-somatostatin analogs.

scholarly journals Octreotide and pasireotide (dis)similarly inhibit pituitary tumor cells in vitro

2016 ◽  
Vol 231 (2) ◽  
pp. 135-145 ◽  
Author(s):  
Alejandro Ibáñez-Costa ◽  
Esther Rivero-Cortés ◽  
Mari C Vázquez-Borrego ◽  
Manuel D Gahete ◽  
Luis Jiménez-Reina ◽  
...  
Keyword(s):  
Cell Viability ◽  
Pituitary Adenomas ◽  
Somatostatin Receptor ◽  
Hormone Secretion ◽  
Somatostatin Analogs ◽  
Hormone Release ◽  
Growth Hormone Release ◽  
Molecular Features ◽  
Intracellular Ca

Somatostatin analogs (SSA) are the mainstay of pharmacological treatment for pituitary adenomas. However, some patients escape from therapy with octreotide, a somatostatin receptor 2 (sst2)-preferring SSA, and pasireotide, a novel multi-sst-preferring SSA, may help to overcome this problem. It has been proposed that correspondence between sst1-sst5 expression pattern and SSA-binding profile could predict patient’s response. To explore the cellular/molecular features associated with octreotide/pasireotide response, we performed a parallel comparison of their in vitro effects, evaluating sst1-sst5 expression, intracellular Ca2+ signaling ([Ca2+]i), hormone secretion and cell viability, in a series of 85 pituitary samples. Somatotropinomas expressed sst5>sst2, yet octreotide reduced [Ca2+]i more efficiently than pasireotide, while both SSA similarly decreased growth hormone release/expression and viability. Corticotropinomas predominantly expressed sst5, but displayed limited response to pasireotide, while octreotide reduced functional endpoints. Non-functioning adenomas preferentially expressed sst3 but, surprisingly, both SSA increased cell viability. Prolactinomas mainly expressed sst1 but were virtually unresponsive to SSA. Finally, both SSA decreased [Ca2+]i in normal pituitaries. In conclusion, both SSA act in vitro on pituitary adenomas exerting both similar and distinct effects; however, no evident correspondence was found with the sst1-sst5 profile. Thus, it seems plausible that additional factors, besides the simple abundance of a given sst, critically influence the SSA response.

scholarly journals Octreotide therapy in meningiomas: in vitro study, clinical correlation, and literature review

2017 ◽  
Vol 127 (3) ◽  
pp. 660-669 ◽  
Author(s):  
Thomas Graillon ◽  
David Romano ◽  
Céline Defilles ◽  
Alexandru Saveanu ◽  
Amira Mohamed ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Somatostatin Analog ◽  
World Health ◽  
Receptor Subtype ◽  
Who Grade ◽  
Average Cell ◽  
The Impact

OBJECTIVEMeningiomas express somatostatin receptor subtype 2 (SST2), which is targeted by the somatostatin analog octreotide. However, to date, using somatostatin analog therapy for the treatment of these tumors in clinical practice has been debated. This study aims to clarify the in vitro effects of octreotide on meningiomas for precise clinical applications.METHODSThe effects of octreotide were analyzed in a large series of 80 meningiomas, including 31 World Health Organization (WHO) Grade II and 4 WHO Grade III tumors, using fresh primary cell cultures to study the impact on cell viability, apoptosis, and signal transduction pathways.RESULTSSST2 mRNA was detected in 100% of the tested meningiomas at levels similar to those observed in other SST2-expressing tumors, neuroendocrine tumors, or pituitary adenomas. Octreotide significantly decreased cell proliferation in 88% of meningiomas but did not induce cell death. On average, cell proliferation was more inhibited in the meningioma group expressing a high level of SST2 than in the low-SST2 group. Moreover, octreotide response was positively correlated to the level of merlin protein and inversely correlated to the level of phosphorylated p70-S6 kinase, a downstream effector of the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway. Octreotide inhibited Akt phosphorylation and activated tyrosine phosphatase without impacting the extracellular regulated kinase (ERK) pathway.CONCLUSIONSOctreotide acts exclusively as an antiproliferative agent and does not promote apoptosis in meningioma in vitro. Therefore, in vivo, octreotide is likely to limit tumor growth rather than induce tumor shrinkage. A meta-analysis of the literature reveals an interest in octreotide for the treatment of WHO Grade I tumors, particularly those in the skull base for which the 6-month progression-free survival level reached 92%. Moreover, somatostatin analogs, which are well-tolerated drugs, could be of interest for use as co-targeting therapies for aggressive meningiomas.

scholarly journals Somatostatin and its analog lanreotide inhibit the proliferation of dispersed human non-functioning pituitary adenoma cells in vitro

1999 ◽  
pp. 396-408 ◽  
Author(s):  
T Florio ◽  
S Thellung ◽  
S Arena ◽  
A Corsaro ◽  
R Spaziante ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pituitary Adenomas ◽  
Intracellular Signaling ◽  
Tyrosine Phosphatase ◽  
Somatostatin Receptor ◽  
Hormone Secretion ◽  
Somatostatin Analogs ◽  
Thymidine Uptake ◽  
Endocrine Tumors

OBJECTIVE: Somatostatin is a powerful inhibitor of hormone secretion and cell proliferation. Treatment with somatostatin analogs in humans causes a reduction in size and secretory activity of some endocrine tumors, including somatotropic pituitary adenomas. Less studied are the effects of somatostatin agonists on non-functioning pituitary adenomas (NFPAs). In this study we characterized the effects of somatostatin and its analog lanreotide on the proliferation of NFPAs in vitro and the intracellular mechanisms involved. DESIGN: Twenty-three NFPA post-surgical specimens were analyzed for somatostatin receptor (SSTR) expression and 12 of them were cultured in vitro to study somatostatin's effects on cell proliferation, assessed by means of [(3)H]thymidine uptake, and the intracellular signaling. RESULTS: One or more SSTR subtypes were expressed in 90% of the adenomas tested. Somatostatin and lanreotide treatment inhibited phorbol myristate acetate (PMA)-induced cell proliferation. Vanadate pretreatment reversed somatostatin and lanreotide inhibition of PMA-induced DNA synthesis suggesting an involvement of tyrosine phosphatase in this effect. In the only adenoma tested, somatostatin directly induced a tyrosine phosphatase activity. Somatostatin and lanreotide caused also a significant inhibition of voltage-sensitive calcium channel activity induced by 40mmol/l K(+) depolarization in microfluorimetric analysis. CONCLUSIONS: These data show that somatostatin and lanreotide inhibit human NFPA cell proliferation in vitro, and suggest that activation of tyrosine phosphatases and inhibition of the activity of voltage-dependent calcium channels may represent intracellular signals mediating this effect.

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