Regulation of Growth Hormone and Prolactin Gene Expression and Secretion by Chimeric Somatostatin-Dopamine Molecules

Gruszka, Anna; Ren, Shaolei; Dong, Jesse Z.; Culler, Michael D.; Melmed, Shlomo

doi:10.1210/en.2007-0378

Cited by 44 publications

(46 citation statements)

References 22 publications

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“…These findings in prolactinomas are far away from the synergistic cooperation of these two receptors in cAMP suppression demonstrated in experimentally transfected cells (36). Recently, BIM-23A760 was found to suppress PRL in a similar manner to D2DR agonists in primary rat pituitary cell cultures and MMQ prolactin-secreting rat cell line (37). These results seem roughly similar to our prolactinoma data and confirm the crucial role of D2DR affinity for the PRL suppression by BIM-23A760.…”

Section: Discussionsupporting

confidence: 88%

Somatostatinergic ligands in dopamine-sensitive and -resistant prolactinomas

Fusco

Gunz²,

Jaquet³

et al. 2008

European Journal of Endocrinology

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Objective: Ten percent of patients with prolactinoma fail to respond with normalization of prolactin (PRL) and tumor shrinkage under dopamine agonist (DA) therapy. The resistance to treatment is linked to a loss of dopamine receptor 2 (D2DR). Prolactinomas express somatostatin (SST) receptor subtypes, SSTR1, 2, and 5. The aim of this study was to determine whether different SST compounds could overcome the resistance to DA in prolactinomas. Design and methods: The efficacy of SSTR1, SSTR2, and SSTR5 ligands; the universal SST ligand, SOM230; and the chimeric SST-DA compound, BIM-23A760, was compared with cabergoline in suppressing PRL secretion from primary cultures of ten prolactinomas (six DA responders and four DA resistant). Receptor mRNAs were assessed by quantitative PCR. Results: The mean mRNA levels for D2DR, SSTR1, SSTR2, and SSTR5 were 92.3G47.3, 2.2G1.4, 1.1G0.7, and 1.6G0.6 copy/copy b-glucuronidase (b-Gus) respectively. The SSTR1 agonist, BIM-23926, did not suppress PRL in prolactinomas. In a DA-resistant prolactinoma, it did not inhibit [ 3 H]thymidine incorporation. The SSTR5 compound, BIM-23206, produced a dose-dependent inhibition of PRL release similar to that of cabergoline in three DA-sensitive prolactinomas. BIM-23A760 produced a maximal PRL inhibition superimposable to that obtained with cabergoline with a lower EC 50 (0.5G0.1 vs 2.5G1.5 pmol/l). In DA-resistant prolactinomas, BIM-23206 and SOM230 were ineffective. Cabergoline and BIM-23A760 produced a partial inhibition of PRL secretion (19G6 and 21G3% respectively). Conclusion: Although the SSTRs are expressed in prolactinomas, the somatostatinergic ligands analyzed do not appear to be highly effective in suppressing PRL. D2DR remains the primary target for effective treatment of prolactinomas.European Journal of Endocrinology 158 595-603

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Section: Discussionsupporting

confidence: 88%

Somatostatinergic ligands in dopamine-sensitive and -resistant prolactinomas

Fusco

Gunz²,

Jaquet³

et al. 2008

European Journal of Endocrinology

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“…Again, such an absence of synergistic effects seems to be an event related to individual characteristics of the NFPAs analyzed. Indeed, while no synergism was recently observed in GH and prolactin-secreting rat pituitary cell lines (Gruszka et al 2007), a different response was observed in human GH-secreting adenomas in which the simultaneous activation of sstr and D2R significantly enhanced their antisecretory and antiproliferative responses . Interestingly, a different sstr expression pattern was observed in tumors from acromegalic patients that show significantly higher sstr5 mRNA levels than NFPAs, which, instead, display higher levels of sstr3.…”

Section: Discussionmentioning

confidence: 94%

Efficacy of a dopamine-somatostatin chimeric molecule, BIM-23A760, in the control of cell growth from primary cultures of human non-functioning pituitary adenomas: a multi-center study

Florio¹,

Barbieri²,

Spaziante³

et al. 2008

Endocrine Related Cancer

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Dopamine D2 and somatostatin receptors (sstrs) were reported to affect non-functioning pituitary adenoma (NFPA) proliferation in vitro. However, the reported results differ according to the experimental conditions used. We established an experimental protocol allowing reproducible evaluation of NFPA cell proliferation in vitro, to test and compare the antiproliferative effects of dopamine and somatostatin analogs (alone or in combination) with the activity of the dopamine-somatostatin chimeric molecule BIM-23A760. The protocol was utilized by four independent laboratories, studying 38 fibroblast-deprived NFPA cell cultures. Cells were characterized for GH, POMC, sstr1-sstr5, total dopamine D2 receptor (D2R) (in all cases), and D2 receptor long and short isoforms (in 15 out of 38 cases) mRNA expression and for a-subunit, LH, and FSH release. D2R, sstr3, and sstr2 mRNAs were consistently observed, with the dominant expression of D2R (2.9G2.6 copy/copy b-glucuronidase; meanGS.E.M.), when compared with sstr3 and sstr2 (0.6G1.0 and 0.3G0.6 respectively). BIM-23A760, a molecule with high affinity for D2R and sstr2, significantly inhibited [ 3 H]thymidine incorporation in 23 out of 38 (60%) NFPA cultures (EC 50 Z1.2 pM and E max ZK33.6G3.7%). BIM-23A760 effects were similar to those induced by the selective D2R agonist cabergoline that showed a statistically significant inhibition in 18 out of 27 tumors (compared with a significant inhibition obtained in 17 out of 27 tumors using BIM-23A760, in the same subgroup of adenomas analyzed), while octreotide was effective in 13 out of 27 cases. In conclusion, superimposable data generated in four independent laboratories using a standardized protocol demonstrate that, in vitro, chimeric dopamine/sstr agonists are effective in inhibiting cell proliferation in two-thirds of NFPAs.

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“…In these studies, inhibition or interference of dopaminergic signaling pathway(s) was initially investigated in GH3 cells, where endogenous D2R expression had been "unmasked," and then in the MMQ cell line that expresses endogenous functional D2R (42). In D2R-expressing GH3 cells the augmented apoptotic response to either DA or BC challenges was attenuated through preincubation with the D2R antagonists, haloperidol, or eticlopride.…”

Section: Discussionmentioning

confidence: 99%

Reversal of Endogenous Dopamine Receptor Silencing in Pituitary Cells Augments Receptor-Mediated Apoptosis

et al. 2010

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Dopamine (DA)-agonist targeting of the DA D 2 receptor (D2R) in prolactinomas is the first-line treatment choice for suppression of prolactin and induction of tumor shrinkage. Resistance to DA agonists seems to be related to receptor number. Using the MMQ and GH3 pituitary cell lines, that either do or do not express D2R, respectively, we explored the epigenetic profile associated with the presence or absence of D2R in these cells lines. These studies led us to explore pharmacological strategies designed to restore receptor expression and thereby potentially augment DA agonistmediated apoptosis. We show in GH3 cells that the D2R harbors increased CpG island-associated methylation and enrichment for histone H3K27me3. Conversely, MMQ cells and normal pituitaries show enrichment for H3K9Ac and barely detectable H3K27me3. Coculture of GH3 cells with the demethylating agent zebularine and the histone deacetylase inhibitor trichostatin A was responsible for a decrease in CpG island methylation and enrichment for the histone H3K9Ac mark. In addition, challenge of GH3 cells with zebularine alone or coculture with both agents led to expression of endogenous D2R in these cells. Induced expression D2R in GH3 cells was associated with a significant increase in apoptosis indices to challenge with either DA or bromocriptine. Specificity of a receptor-mediated response was established in coincubations with specific D2R antagonist and siRNA approaches in GH3 cell and D2R expressing MMQ cell lines. These studies point to the potential efficacy of combined treatment with epigenetic drugs and DA agonists for the medical management of different pituitary tumor subtypes, resistant to conventional therapies. (Endocrinology 152: 364 -373, 2011) D opamine (DA) agonists are considered a first-line treatment choice for patients with pituitary prolactinomas where they not only effectively suppress prolactin (PRL) but also reduce tumor size (1, 2). Despite their success, a small proportion of patients are intolerant to DA agonist therapy (3, 4), and in cases where resistance is apparent this seems to be related to the number of DA D2 receptors (D2R) expressed by the adenoma (5). Activation of the D2R by DA and DA agonists leads to reduced cAMP production through interaction with Gi/Go proteins (6).The reduction in cAMP levels in normal and tumoral lactotrophs is considered integral to the inhibition of PRL synthesis and release (1, 6 -9).In contrast to our understanding of pathways regulating PRL release within the lactotroph our understanding of receptor(s) and their intracellular pathways responsible for tumor shrinkage and or apoptosis are less clear. Early studies suggested that resistance to DA but not bromocriptine (BC)-mediated apoptosis was a consequence of these cells not expressing a D2R (10). However, more recent

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Regulation of Growth Hormone and Prolactin Gene Expression and Secretion by Chimeric Somatostatin-Dopamine Molecules

Cited by 44 publications

References 22 publications

Somatostatinergic ligands in dopamine-sensitive and -resistant prolactinomas

Somatostatinergic ligands in dopamine-sensitive and -resistant prolactinomas

Efficacy of a dopamine-somatostatin chimeric molecule, BIM-23A760, in the control of cell growth from primary cultures of human non-functioning pituitary adenomas: a multi-center study

Reversal of Endogenous Dopamine Receptor Silencing in Pituitary Cells Augments Receptor-Mediated Apoptosis

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