Differential inhibition of growth hormone secretion by analogs selective for somatostatin receptor subtypes 2 and 5 in human growth-hormone-secreting adenoma cells in vitro

Giovanni Tulipano, Carlo Bonfanti, Gabriella Milani, Bruno Billeci, Angelo Bollati, Renato Cozzi, Giulio Maira, William A. Murphy, Claudio Poiesi, Sergio Turazzi, Andrea Giustina

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Somatostatin (SRIH), a cyclic tetradecapeptide hormone originally isolated from mammalian hypothalamus, is a potent suppressor of pituitary growth hormone (GH) secretion. SRIH acts through a family of G-protein-coupled membrane receptors containing seven transmembrane domains. Five genes encoding distinct SRIH receptor (SSTR) subtypes have so far been cloned in human and other species and termed SSTR1-5. In human somatotrophe pituitary adenomas GH secretion is controlled by both SSTR2 and SSTR5. However, in clinical practice only somatostatin analogs selective for SSTR2 (octreotide and lanreotide) are available. This may explain why clinical and in vitro responses to these analogs in acromegaly are only partial. In this study, we investigated the inhibitory effect of two new SRIH analogs with high selectivity for SSTR2 (NC-4-28B) and SSTR5 (BIM-23268) and compared it to that of native somatostatin (SRIH-14) on a large number of GH-secreting adenomas obtained by transphenoidal neurosurgery. Tissues from 16 adenomas were enzymatically dispersed and plated in 24-well dishes at 50,000 cells/well. After 3 days, groups of three wells were incubated for 4 h with medium alone, SRIH-14 or analogs NC-4-28B or BIM-23268, at the concentrations of 0.01, 0.1 and 1 μM. Our results show that 9 out of 16 adenomas were responsive (GH suppression: 20-40% vs. control, p <0.05) to SRIH. In this group only 4 adenomas showed similar responses to both selective analogs, with 2 nonresponders (expression of other SRIH receptor subtypes) and 2 responders (concomitant expression of SSTR2 and SSTR5) to both analogs. GH release was selectively inhibited by NC-4-28B in 3 adenomas and by BIM-23268 in the remaining 2 adenomas, suggesting predominant expression of SSTR2 and SSTR5, respectively. SRIH failed to inhibit GH release in 7 adenomas (43%). Interestingly, in that group a better inhibitory effect was obtained with BIM-23268 (5 out of 7 adenomas) than with NC-4-28B, suggesting expression of a few SSTR5 receptors only, or of both SSTR2 and SSTR5, respectively. We conclude that the availability of somatostatin analogs selective for SSTR5 will enhance the treatment potency and spectrum in acromegaly.

Original languageEnglish
Pages (from-to)344-351
Number of pages8
JournalNeuroendocrinology
Volume73
Issue number5
DOIs
Publication statusPublished - 2001

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Human Growth Hormone
Adenoma
Growth Hormone
Somatostatin
Somatostatin Receptors
Acromegaly
Octreotide
In Vitro Techniques
somatostatin receptor 5
somatostatin receptor 2
Neurosurgery
Pituitary Neoplasms
G-Protein-Coupled Receptors
Hypothalamus
Hormones
Membranes
BIM 23268

Keywords

  • Adenomas
  • Clinical neuroendocrinology
  • Growth hormone
  • Somatostatin
  • Somatostatin analogs
  • Somatostatin receptors

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)

Cite this

Differential inhibition of growth hormone secretion by analogs selective for somatostatin receptor subtypes 2 and 5 in human growth-hormone-secreting adenoma cells in vitro. / Tulipano, Giovanni; Bonfanti, Carlo; Milani, Gabriella; Billeci, Bruno; Bollati, Angelo; Cozzi, Renato; Maira, Giulio; Murphy, William A.; Poiesi, Claudio; Turazzi, Sergio; Giustina, Andrea.

In: Neuroendocrinology, Vol. 73, No. 5, 2001, p. 344-351.

Research output: Contribution to journalArticle

Tulipano, G, Bonfanti, C, Milani, G, Billeci, B, Bollati, A, Cozzi, R, Maira, G, Murphy, WA, Poiesi, C, Turazzi, S & Giustina, A 2001, 'Differential inhibition of growth hormone secretion by analogs selective for somatostatin receptor subtypes 2 and 5 in human growth-hormone-secreting adenoma cells in vitro', Neuroendocrinology, vol. 73, no. 5, pp. 344-351. https://doi.org/10.1159/000054651
Tulipano, Giovanni ; Bonfanti, Carlo ; Milani, Gabriella ; Billeci, Bruno ; Bollati, Angelo ; Cozzi, Renato ; Maira, Giulio ; Murphy, William A. ; Poiesi, Claudio ; Turazzi, Sergio ; Giustina, Andrea. / Differential inhibition of growth hormone secretion by analogs selective for somatostatin receptor subtypes 2 and 5 in human growth-hormone-secreting adenoma cells in vitro. In: Neuroendocrinology. 2001 ; Vol. 73, No. 5. pp. 344-351.
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AU - Bonfanti, Carlo

AU - Milani, Gabriella

AU - Billeci, Bruno

AU - Bollati, Angelo

AU - Cozzi, Renato

AU - Maira, Giulio

AU - Murphy, William A.

AU - Poiesi, Claudio

AU - Turazzi, Sergio

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N2 - Somatostatin (SRIH), a cyclic tetradecapeptide hormone originally isolated from mammalian hypothalamus, is a potent suppressor of pituitary growth hormone (GH) secretion. SRIH acts through a family of G-protein-coupled membrane receptors containing seven transmembrane domains. Five genes encoding distinct SRIH receptor (SSTR) subtypes have so far been cloned in human and other species and termed SSTR1-5. In human somatotrophe pituitary adenomas GH secretion is controlled by both SSTR2 and SSTR5. However, in clinical practice only somatostatin analogs selective for SSTR2 (octreotide and lanreotide) are available. This may explain why clinical and in vitro responses to these analogs in acromegaly are only partial. In this study, we investigated the inhibitory effect of two new SRIH analogs with high selectivity for SSTR2 (NC-4-28B) and SSTR5 (BIM-23268) and compared it to that of native somatostatin (SRIH-14) on a large number of GH-secreting adenomas obtained by transphenoidal neurosurgery. Tissues from 16 adenomas were enzymatically dispersed and plated in 24-well dishes at 50,000 cells/well. After 3 days, groups of three wells were incubated for 4 h with medium alone, SRIH-14 or analogs NC-4-28B or BIM-23268, at the concentrations of 0.01, 0.1 and 1 μM. Our results show that 9 out of 16 adenomas were responsive (GH suppression: 20-40% vs. control, p <0.05) to SRIH. In this group only 4 adenomas showed similar responses to both selective analogs, with 2 nonresponders (expression of other SRIH receptor subtypes) and 2 responders (concomitant expression of SSTR2 and SSTR5) to both analogs. GH release was selectively inhibited by NC-4-28B in 3 adenomas and by BIM-23268 in the remaining 2 adenomas, suggesting predominant expression of SSTR2 and SSTR5, respectively. SRIH failed to inhibit GH release in 7 adenomas (43%). Interestingly, in that group a better inhibitory effect was obtained with BIM-23268 (5 out of 7 adenomas) than with NC-4-28B, suggesting expression of a few SSTR5 receptors only, or of both SSTR2 and SSTR5, respectively. We conclude that the availability of somatostatin analogs selective for SSTR5 will enhance the treatment potency and spectrum in acromegaly.

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