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 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 Evaluation of a New 177Lu-Labeled Somatostatin Analog for the Treatment of Tumors Expressing Somatostatin Receptor Subtypes 2 and 5

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4155
Author(s):  
Rosalba Mansi ◽  
Guillaume Pierre Nicolas ◽  
Luigi Del Pozzo ◽  
Karim Alexandre Abid ◽  
Eric Grouzmann ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Somatostatin Analog ◽  
Receptor Subtypes ◽  
In Vivo Evaluation ◽  
Somatostatin Receptor Subtypes ◽  
Lower Extent ◽  
Lower Background

Targeted radionuclide therapy of somatostatin receptor (SST)-expressing tumors is only partially addressed by the established somatostatin analogs having an affinity for the SST subtype 2 (SST2). Aiming to target a broader spectrum of tumors, we evaluated the bis-iodo-substituted somatostatin analog ST8950 ((4-amino-3-iodo)-d-Phe-c[Cys-(3-iodo)-Tyr-d-Trp-Lys-Val-Cys]-Thr-NH2), having subnanomolar affinity for SST2 and SST5, labeled with [177Lu]Lu3+ via the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). Human Embryonic Kidney (HEK) cells stably transfected with the human SST2 (HEK-SST2) and SST5 (HEK-SST5) were used for in vitro and in vivo evaluation on a dual SST2- and SST5-expressing xenografted mouse model. natLu-DOTA-ST8950 showed nanomolar affinity for both subtypes (IC50 (95% confidence interval): 0.37 (0.22–0.65) nM for SST2 and 3.4 (2.3–5.2) for SST5). The biodistribution of [177Lu]Lu-DOTA-ST8950 was influenced by the injected mass, with 100 pmol demonstrating lower background activity than 10 pmol. [177Lu]Lu-DOTA-ST8950 reached its maximal uptake on SST2- and SST5-tumors at 1 h p.i. (14.17 ± 1.78 and 1.78 ± 0.35%IA/g, respectively), remaining unchanged 4 h p.i., with a mean residence time of 8.6 and 0.79 h, respectively. Overall, [177Lu]Lu-DOTA-ST8950 targets SST2-, SST5-expressing tumors in vivo to a lower extent, and has an effective dose similar to clinically used radiolabeled somatostatin analogs. Its main drawbacks are the low uptake in SST5-tumors and the persistent kidney uptake.

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 MNGI-08. PHARMACOKINETIC ANALYSIS OF 68GA-DOTATOC IN MENINGIOMAS USING PET/CT FOR ASSESSMENT OF SOMATOSTATIN RECEPTORS AND CORRELATION WITH ANGIOGENESIS, INFLAMMATION AND PROLIFERATION

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi140-vi141
Author(s):  
Asma Bashir ◽  
Mark Bitsch Vestergaard ◽  
Tina Binderup ◽  
Helle Broholm ◽  
Lisbeth Marner ◽  
...  
Keyword(s):  
Quantitative Polymerase Chain Reaction ◽  
Somatostatin Receptor ◽  
Linear Regression Analysis ◽  
World Health ◽  
Pharmacokinetic Analysis ◽  
Receptor Subtype ◽  
Neck Muscle ◽  
Specific Marker ◽  
Who Grade ◽  
Pet Ct

Abstract BACKGROUND A quantitative correlative analysis between 68Ga-DOTATOC accumulation using PET/CT and somatostatin receptor subtype 2 (SSTR2) in meningiomas was conducted. The possible contributions of angiogenesis and inflammation were investigated as well. METHODS Fifteen patients with newly (n = 12) and recurrent (n = 3) meningiomas were prospectively assigned to a 60-minute dynamic 68Ga-DOTATOC PET/CT scan prior to surgery. PET data included measurements of maximum and mean standardized uptake value (SUVmax, SUVmean) with/without normalisation to different reference tissues, and quantitative measures derived from kinetic modeling using a reversible two-tissue compartment model with the fractional blood volume (VB) included in the model. The SSTR2-expression was determined by immunohistochemistry and quantitative polymerase chain reaction (qPCR), while biomarkers of inflammation (macrophage-specific marker CD68, interleukin-18 [IL18]) and angiogenesis (endothelial marker CD34, vascular endothelial growth factor-A [VEGF-A]), were assessed by qPCR only. RESULTS Twelve patients (80%) were diagnosed with World Health Organization (WHO) grade I meningioma and three with WHO grade II (20%). No significant differences in SSTR2-expression was seen between WHO grades or subtypes (P ≥ 0.05; Mann-Whitney, Kruskal-Wallis). Upon stratification of patients based on the median SUVs (SUVmax, 20.9; SUVmean, 9.9), SSTR2-expression was seven-fold increased in patients with SUVs above the medians compared to patients with SUVs below the medians. Spearman’s rank correlation coefficient revealed significant correlations between SSTR2-expression, and SUVmean (r = 0.532, P = .041) and mean tumor-to-neck muscle ratio (TNMRmean) (r = 0.593, P = .020). 68Ga-DOTATOC uptake was additionally associated with VB and VEGF-A (P < 0.01), while no association with inflammatory biomarkers were found. In univariate linear regression analysis, SUVmean and TNMRmean remained the optimal surrogate biomarkers for SSTR2-expression (P < .0001). CONCLUSIONS 68Ga-DOTATOC accumulation in meningiomas is more complex than previously reported, and may not be limited to the SSTR2-density but also be associated with the vascular component.

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.

scholarly journals Mir-139-5p inhibits glioma cell proliferation and progression by targeting GABRA1

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lei Wang ◽  
Yan Liu ◽  
Zhengtao Yu ◽  
Jianwu Gong ◽  
Zhiyong Deng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Target Genes ◽  
Differentially Expressed ◽  
World Health ◽  
Biological Behavior ◽  
Migration And Invasion ◽  
Overlapping Genes ◽  
Who Grade ◽  
The Impact

AbstractGlioma is an extremely aggressive malignant neoplasm of the central nervous system. MicroRNA (miRNA) are known to bind to specific target mRNA to regulate post-transcriptional gene expression and are, therefore, currently regarded as promising biomarkers for glioma diagnosis and prognosis. The aim of the present study was to examine the pathogenesis and potential molecular markers of glioma by comparing the differential expression of miRNA and mRNA between glioma tissue and peritumor brain tissue. We explored the impact of screened core miRNA and mRNA on cell proliferation, invasion, and migration of glioma. An miRNA expression profile dataset (GSE90603) and a transcriptome profile dataset (GSE90598) were downloaded from combined miRNA-mRNA microarray chips in the Gene Expression Omnibus (GEO) database. Overall, 59 differentially expressed miRNAs (DEMs) and 419 differentially expressed genes (DEGs) were identified using the R limma software package. FunRich software was used to predict DEM target genes and miRNA-gene pairs, and Perl software was used to find overlapping genes between DEGs and DEM target genes. There were 129 overlapping genes regulated by nine miRNAs between target genes of the DEMs and DEGs. The Chinese Glioma Genome Atlas(CGGA) was analyzed in order to identify miRNAs with diagnostic and prognostic significance. MiR-139-5p, miR-137, and miR-338-3p were validated to be significantly linked to prognosis in glioma patients. Finally, we validated that miR-139-5p affected glioma malignant biological behavior via targeting gamma-aminobutyric acid A receptor alpha 1(GABRA1) through rescue experiments. Low miR-139-5p expression was correlated with survival probability and World Health Organization (WHO) grade. MiR-139-5p overexpression inhibited cell proliferation, migration, and invasion of glioma in vitro. GABRA1 was identified as a functional downstream target of miR-139-5p. Decreased GABRA1 expression was related to similar biological roles as miR-139-5p overexpression while upregulation of GABRA1 effectively reversed the inhibition effects of miR-139-5p. These results demonstrate a novel axis for miR-139-5p/GABRA1 in glioma progression and provide potential prognostic predictors and therapeutic target for glioma patients.

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 (&gt;50% stained cells), 1 (10–50% stained cells), and 0 (&lt;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 Octreotide and Pasireotide Combination Treatment in Somatotroph Tumor Cells: Predominant Role of SST2 in Mediating Ligand Effects

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1816
Author(s):  
Jessica Amarù ◽  
Federica Barbieri ◽  
Marica Arvigo ◽  
Agnese Solari ◽  
Adriana Bajetto ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Cells ◽  
Intracellular Signaling ◽  
Somatostatin Receptor ◽  
Combined Treatment ◽  
Primary Cultures ◽  
Receptor Subtype ◽  
Camp Accumulation ◽  
Gh Secretion ◽  
Somatostatin Receptor Ligands

First-generation somatostatin receptor ligands (fg-SRLs), such as octreotide (OCT), represent the first-line medical therapy in acromegaly. Fg-SRLs show a preferential binding affinity for somatostatin receptor subtype-2 (SST2), while the second-generation ligand, pasireotide (PAS), has high affinity for multiple SSTs (SST5 > SST2 > SST3 > SST1). Whether PAS acts via SST2 in somatotroph tumors, or through other SSTs (e.g., SST5), is a matter of debate. In this light, the combined treatment OCT+PAS could result in additive/synergistic effects. We evaluated the efficacy of OCT and PAS (alone and in combination) on growth hormone (GH) secretion in primary cultures from human somatotroph tumors, as well as on cell proliferation, intracellular signaling and receptor trafficking in the rat GH4C1 cell line. The results confirmed the superimposable efficacy of OCT and PAS in reducing GH secretion (primary cultures), cell proliferation, cAMP accumulation and intracellular [Ca2+] increase (GH4C1 cells), without any additive effect observed for OCT+PAS. In GH4C1 cells, co-incubation with a SST2-selective antagonist reversed the inhibitory effect of OCT and PAS on cell proliferation and cAMP accumulation, while both compounds resulted in a robust internalization of SST2 (but not SST5). In conclusion, OCT and PAS seem to act mainly through SST2 in somatotroph tumor cells in vitro, without inducing any additive/synergistic effect when tested in combination.

scholarly journals A new 68Ga-labeled somatostatin analog containing two iodo-amino acids for dual somatostatin receptor subtype 2 and 5 targeting

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Rosalba Mansi ◽  
Karim Abid ◽  
Guillaume P. Nicolas ◽  
Luigi Del Pozzo ◽  
Eric Grouzmann ◽  
...  
Keyword(s):  
Amino Acids ◽  
Somatostatin Receptor ◽  
Somatostatin Analog ◽  
Receptor Subtype ◽  
Somatostatin Receptor Subtype 2

scholarly journals Keratinocytes Regulate the Threshold of Inflammation by Inhibiting T Cell Effector Functions

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1606
Author(s):  
Peter Seiringer ◽  
Stefanie Eyerich ◽  
Kilian Eyerich ◽  
Daniela Dittlein ◽  
Anna Caroline Pilz ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Cytokine Production ◽  
Nickel Sulfate ◽  
Human Keratinocytes ◽  
T Cell Proliferation ◽  
Effector Functions ◽  
The Impact ◽  
Cell Effector

Whilst the importance of keratinocytes as a first-line defense has been widely investigated, little is known about their interactions with non-resident immune cells. In this study, the impact of human keratinocytes on T cell effector functions was analyzed in an antigen-specific in vitro model of allergic contact dermatitis (ACD) to nickel sulfate. Keratinocytes partially inhibited T cell proliferation and cytokine production. This effect was dependent on the keratinocyte/T cell ratio and was partially reversible by increasing the number of autologous dendritic cells. The inhibition of T cell proliferation by keratinocytes was independent of the T cell subtype and antigen presentation by different professional antigen-presenting cells. Autologous and heterologous keratinocytes showed comparable effects, while the fixation of keratinocytes with paraformaldehyde abrogated the immunosuppressive effect. The separation of keratinocytes and T cells by a transwell chamber, as well as a cell-free keratinocyte supernatant, inhibited T cell effector functions to the same amount as directly co-cultured keratinocytes, thus proving that soluble factor/s account for the observed suppressive effects. In conclusion, keratinocytes critically control the threshold of inflammatory processes in the skin by inhibiting T cell proliferation and cytokine production.

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