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Somatostatin–dopamine ligands in the treatment of pituitary adenomas

Article

Abstract

Somatostatin receptors (sst1–5) and dopamine receptor 2 (D2DR) are well expressed and co-localized in several human pituitary adenomas, suggesting possible functional interactions in the control of hormonal hypersecretion and tumor cell growth. The present review describes the expression and functionality of these receptors in the different classes of human pituitary adenomas. The sst2 agonists, octreotide and lanreotide, control GH hypersecretion and tumor growth in about 65% of somatotropinomas. The D2DR agonists, bromocriptine and cabergoline, control about 90% of prolactinomas. Such drugs are much less effective in the control of the others pituitary adenomas also expressing ssts and D2DR receptors. The second part summarizes the current knowledge on new chimeric compounds with sst2, sst5, and D2DR affinity. Such ligands bearing distinct ssts and DRD2 pharmacophores may synergistically produce an increased control of secretion and/or of proliferation in the different types of pituitary adenomas. The mechanisms of action of such chimeric molecules through increased binding affinities, prolonged bioavailability, ligand-induced modulation of receptors heterodimerization, are discussed.

Keywords

Pituitary adenomas Somatostatin receptors Dopamine receptors Chimeric ligands BIM-23A387 BIM-23A760 

References

  1. 1.
    Reubi JC, Waser B, Schaer JC, Laissue JA. Somatostatin receptor sst1–sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur J Nucl Med. 2001;28:836–46.PubMedCrossRefGoogle Scholar
  2. 2.
    Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol. 1999;20:157–98.PubMedCrossRefGoogle Scholar
  3. 3.
    Stefaneanu L, Kovacs K, Horvath E, Buchfelder M, Fahlbusch R, Lancranjan L. Dopamine D2 receptor gene expression in human adenohypophysial adenomas. Endocrine. 2001;14:329–36.PubMedCrossRefGoogle Scholar
  4. 4.
    Bevan JS, Webster J, Burke CW, Scanlon MF. Dopamine agonists and pituitary tumor shrinkage. Endocr Rev. 1992;13:220–40.PubMedGoogle Scholar
  5. 5.
    Freda PU. Somatostatin analogs in acromegaly. J Clin Endocrinol Metab. 2002;87:3013–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Reubi JC. Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev. 2003;24:389–427.PubMedCrossRefGoogle Scholar
  7. 7.
    Taboada GF, Luque RM, Bastos W, Guimaraes RF, Marcondes JB, Chimelli LM, et al. Quantitative analysis of somatostatin receptor subtype (SSTR1–5) gene expression levels in somatotropinomas and non-functioning pituitary adenomas. Eur J Endocrinol. 2007;156:65–74.PubMedCrossRefGoogle Scholar
  8. 8.
    Jaquet P, Saveanu A, Gunz G, Fina F, Zamora AJ, Grino M, et al. Human somatostatin receptor subtypes in acromegaly: distinct patterns of messenger ribonucleic acid expression and hormone suppression identify different tumoral phenotypes. J Clin Endocrinol Metab. 2000;85:781–92.PubMedCrossRefGoogle Scholar
  9. 9.
    Shimon I, Yan X, Taylor JE, Weiss MH, Culler MD, Melmed S. Somatostatin receptor (SSTR) subtype-selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas. Novel potential therapy for functional pituitary tumors. J Clin Invest. 1997;100:2386–92.PubMedCrossRefGoogle Scholar
  10. 10.
    Zatelli MC, Piccin D, Tagliati F, Ambrosio MR, Margutti A, Padovani R, et al. Somatostatin receptor subtype 1 selective activation in human growth hormone (GH)- and prolactin (PRL)-secreting pituitary adenomas: effects on cell viability, GH, and PRL secretion. J Clin Endocrinol Metab. 2003;88:2797–802.PubMedCrossRefGoogle Scholar
  11. 11.
    Jaquet P, Ouafik L, Saveanu A, Gunz G, Fina F, Dufour H, et al. Quantitative and functional expression of somatostatin receptor subtypes in human prolactinomas. J Clin Endocrinol Metab. 1999;84:3268–76.PubMedCrossRefGoogle Scholar
  12. 12.
    Saveanu A, Morange-Ramos I, Gunz G, Dufour H, Enjalbert A, Jaquet P. A luteinizing hormone-, alpha-subunit- and prolactin-secreting pituitary adenoma responsive to somatostatin analogs: in vivo and in vitro studies. Eur J Endocrinol. 2001;145:35–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Hofland LJ, van der Hoek J, Feelders R, van Aken MO, van Koetsveld PM, Waaijers M, et al. The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5. Eur J Endocrinol. 2005;152:645–54.PubMedCrossRefGoogle Scholar
  14. 14.
    van der Hoek J, Waaijers M, van Koetsveld PM, Sprij-Mooij D, Feelders RA, Schmid HA, et al. Distinct functional properties of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH release by corticotroph tumor cells. Am J Physiol Endocrinol Metab. 2005;289:E278–87.PubMedCrossRefGoogle Scholar
  15. 15.
    Batista DL, Zhang X, Gejman R, Ansell PJ, Zhou Y, Johnson SA, et al. The effects of SOM230 on cell proliferation and adrenocorticotropin secretion in human corticotroph pituitary adenomas. J Clin Endocrinol Metab. 2006;91:4482–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Bertherat J, Brue T, Enjalbert A, Gunz G, Rasolonjanahary R, Warnet A, et al. Somatostatin receptors on thyrotropin-secreting pituitary adenomas: comparison with the inhibitory effects of octreotide upon in vivo and in vitro hormonal secretions. J Clin Endocrinol Metab. 1992;75:540–6.PubMedCrossRefGoogle Scholar
  17. 17.
    van der Hoek J, de Herder WW, Feelders RA, van der Lely AJ, Uitterlinden P, Boerlin V, et al. A single-dose comparison of the acute effects between the new somatostatin analog SOM230 and octreotide in acromegalic patients. J Clin Endocrinol Metab. 2004;89:638–45.PubMedCrossRefGoogle Scholar
  18. 18.
    Ferone D, de Herder W, Pivonello R, Kros J, van Koetsfeld P, de Jong T, et al. 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. J Clin Endocrinol Metab. 2008;93:1412–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Fusco A, Gunz G, Jaquet P, Germanetti A-L, Dufour H, Culler MD, et al. Somatostatinergic ligands in dopamine-sensitive and -resistant prolactinomas. Eur J Endocrinol. 2008;158:595–603.PubMedCrossRefGoogle Scholar
  20. 20.
    Saveanu A, Gunz G, Dufour H, Caron P, Fina F, Ouafik L, et al. Bim-23244, a somatostatin receptor subtype 2- and 5-selective analog with enhanced efficacy in suppressing growth hormone (GH) from octreotide-resistant human GH-secreting adenomas. J Clin Endocrinol Metab. 2001;86:140–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Florio T, Thellung S, Arena S, Corsaro A, Spaziante R, Gussoni G, et al. Somatostatin and its analog lanreotide inhibit the proliferation of dispersed human non-functioning pituitary adenoma cells in vitro. Eur J Endocrinol. 1999;141:396–408.PubMedCrossRefGoogle Scholar
  22. 22.
    Renner U, Mojto J, Lange M, Muller OA, von Werder K, Stalla GK. Effect of bromocriptine and SMS 201-995 on growth of human somatotrophic and non-functioning pituitary adenoma cells in vitro. Eur J Endocrinol. 1994;130:80–91.PubMedCrossRefGoogle Scholar
  23. 23.
    Zatelli MC, Piccin D, Bottoni A, Ambrosio MR, Margutti A, Padovani R, et al. Evidence for differential effects of selective somatostatin receptor subtype agonists on alpha-subunit and chromogranin a secretion and on cell viability in human nonfunctioning pituitary adenomas in vitro. J Clin Endocrinol Metab. 2004;89:5181–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Greenman Y, Melmed S. Heterogeneous expression of two somatostatin receptor subtypes in pituitary tumors. J Clin Endocrinol Metab. 1994;78:398–403.PubMedCrossRefGoogle Scholar
  25. 25.
    de Bruin TW, Kwekkeboom DJ, Van’t Verlaat JW, Reubi JC, Krenning EP, Lamberts SW, et al. Clinically nonfunctioning pituitary adenoma and octreotide response to long term high dose treatment, and studies in vitro. J Clin Endocrinol Metab. 1992;75:1310–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Katznelson L, Oppenheim DS, Coughlin JF, Kliman B, Schoenfeld DA, Klibanski A. Chronic somatostatin analog administration in patients with alpha-subunit-secreting pituitary tumors. J Clin Endocrinol Metab. 1992;75:1318–25.PubMedCrossRefGoogle Scholar
  27. 27.
    Strowski MZ, Kohler M, Chen HY, Trumbauer ME, Li Z, Szalkowski D, et al. Somatostatin receptor subtype 5 regulates insulin secretion and glucose homeostasis. Mol Endocrinol. 2003;17:93–106.PubMedCrossRefGoogle Scholar
  28. 28.
    Socin HV, Chanson P, Delemer B, Tabarin A, Rohmer V, Mockel J, et al. The changing spectrum of TSH-secreting pituitary adenomas: diagnosis and management in 43 patients. Eur J Endocrinol. 2003;148:433–42.PubMedCrossRefGoogle Scholar
  29. 29.
    Liuzzi A, Chiodini PG, Botalla L, Cremascoli G, Silvestrini F. Inhibitory effect of l-Dopa on GH release in acromegalic patients. J Clin Endocrinol Metab. 1972;35:941–3.PubMedGoogle Scholar
  30. 30.
    Abs R, Verhelst J, Maiter D, Van Acker K, Nobels F, Coolens JL, et al. Cabergoline in the treatment of acromegaly: a study in 64 patients. J Clin Endocrinol Metab. 1998;83:374–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Cozzi R, Attanasio R, Barausse M, Dallabonzana D, Orlandi P, Da Re N, et al. Cabergoline in acromegaly: a renewed role for dopamine agonist treatment? Eur J Endocrinol. 1998;139:516–21.PubMedCrossRefGoogle Scholar
  32. 32.
    Marzullo P, Ferone D, Di Somma C, Pivonello R, Filippella M, Lombardi G, et al. Efficacy of combined treatment with lanreotide and cabergoline in selected therapy-resistant acromegalic patients. Pituitary. 1999;1:115–20.PubMedCrossRefGoogle Scholar
  33. 33.
    Pivonello R, Ferone D, de Herder WW, Kros JM, De Caro ML, Arvigo M, et al. Dopamine receptor expression and function in corticotroph pituitary tumors. J Clin Endocrinol Metab. 2004;89:2452–62.PubMedCrossRefGoogle Scholar
  34. 34.
    Greenman Y, Tordjman K, Osher E, Veshchev I, Shenkerman G, Reider G II, et al. Postoperative treatment of clinically nonfunctioning pituitary adenomas with dopamine agonists decreases tumour remnant growth. Clin Endocrinol (Oxf). 2005;63:39–44.CrossRefGoogle Scholar
  35. 35.
    Colao A, Ferone D, Lastoria S, Cerbone G, Di Sarno A, Di Somma C, et al. Hormone levels and tumour size response to quinagolide and cabergoline in patients with prolactin-secreting and clinically non-functioning pituitary adenomas: predictive value of pituitary scintigraphy with 123I-methoxybenzamide. Clin Endocrinol (Oxf). 2000;52:437–45.CrossRefGoogle Scholar
  36. 36.
    Lohmann T, Trantakis C, Biesold M, Prothmann S, Guenzel S, Schober R, et al. Minor tumour shrinkage in nonfunctioning pituitary adenomas by long-term treatment with the dopamine agonist cabergoline. Pituitary. 2001;4:173–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Pivonello R, Matrone C, Filippella M, Cavallo LM, Di Somma C, Cappabianca P, et al. Dopamine receptor expression and function in clinically nonfunctioning pituitary tumors: comparison with the effectiveness of cabergoline treatment. J Clin Endocrinol Metab. 2004;89:1674–83.PubMedCrossRefGoogle Scholar
  38. 38.
    Pellegrini I, Rasolonjanahary R, Gunz G, Bertrand P, Delivet S, Jedynak CP, et al. Resistance to bromocriptine in prolactinomas. J Clin Endocrinol Metab. 1989;69:500–9.PubMedGoogle Scholar
  39. 39.
    Ren SG, Taylor J, Dong J, Yu R, Culler MD, Melmed S. Functional association of somatostatin receptor subtypes 2 and 5 in inhibiting human growth hormone secretion. J Clin Endocrinol Metab. 2003;88:4239–45.PubMedCrossRefGoogle Scholar
  40. 40.
    Saveanu A, Lavaque E, Gunz G, Barlier A, Kim S, Taylor JE, et al. Demonstration of enhanced potency of a chimeric somatostatin–dopamine molecule, BIM-23A387, in suppressing growth hormone and prolactin secretion from human pituitary somatotroph adenoma cells. J Clin Endocrinol Metab. 2002;87:5545–52.PubMedCrossRefGoogle Scholar
  41. 41.
    Ren SG, Kim S, Taylor J, Dong J, Moreau JP, Culler MD, et al. Suppression of rat and human growth hormone and prolactin secretion by a novel somatostatin/dopaminergic chimeric ligand. J Clin Endocrinol Metab. 2003;88:5414–21.PubMedCrossRefGoogle Scholar
  42. 42.
    Jaquet P, Gunz G, Saveanu A, Dufour H, Taylor J, Dong J, et al. Efficacy of chimeric molecules directed towards multiple somatostatin and dopamine receptors on inhibition of GH and prolactin secretion from GH-secreting pituitary adenomas classified as partially responsive to somatostatin analog therapy. Eur J Endocrinol. 2005;153:135–41.PubMedCrossRefGoogle Scholar
  43. 43.
    Yang L, Guo L, Pasternak A, Mosley R, Rohrer S, Birzin E, et al. Spiro[1H-indene-1,4′-piperidine] derivatives as potent and selective non-peptide human somatostatin receptor subtype 2 (sst2) agonists. J Med Chem. 1998;41:2175–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Saveanu A, Gunz G, Guillen S, Dufour H, Culler MD, Jaquet P. Somatostatin and dopamine–somatostatin multiple ligands directed towards somatostatin and dopamine receptors in pituitary adenomas. Neuroendocrinology. 2006;83:258–63.PubMedCrossRefGoogle Scholar
  45. 45.
    Rocheville M, Lange DC, Kumar U, Patel SC, Patel RC, Patel YC. Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science. 2000;288:154–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Gruszka A, Kunert-Radek J, Radek A, Pisarek H, Taylor J, Dong JZ, et al. The effect of selective sst1, sst2, sst5 somatostatin receptors agonists, a somatostatin/dopamine (SST/DA) chimera and bromocriptine on the “clinically non-functioning” pituitary adenomas in vitro. Life Sci. 2006;78:689–93.PubMedCrossRefGoogle Scholar
  47. 47.
    Ferone D, Arvigo M, Semino C, Jaquet P, Saveanu A, Taylor JE, et al. Somatostatin and dopamine receptor expression in lung carcinoma cells and effects of chimeric somatostatin–dopamine molecules on cell proliferation. Am J Physiol Endocrinol Metab. 2005;289:E1044–50.PubMedCrossRefGoogle Scholar
  48. 48.
    Kidd M, Modlin IM, Black JW, Boyce M, Culler M. A comparison of the effects of gastrin, somatostatin and dopamine receptor ligands on rat gastric enterochromaffin-like cell secretion and proliferation. Regul Pept. 2007;143:109–17.PubMedCrossRefGoogle Scholar
  49. 49.
    Plockinger U, Albrecht S, Mawrin C, Saeger W, Buchfelder M, Petersenn S, et al. Selective loss of somatostatin receptor 2 in octreotide-resistant growth hormone-secreting adenomas. J Clin Endocrinol Metab. 2008;93:1203–10.PubMedCrossRefGoogle Scholar
  50. 50.
    Schaer JC, Waser B, Mengod G, Reubi JC. Somatostatin receptor subtypes sst1, sst2, sst3 and sst5 expression in human pituitary, gastroentero-pancreatic and mammary tumors: comparison of mRNA analysis with receptor autoradiography. Int J Cancer. 1997;70:530–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Hofland LJ, Lamberts SW, van Hagen PM, Reubi JC, Schaeffer J, Waaijers M, et al. Crucial role for somatostatin receptor subtype 2 in determining the uptake of [111In-DTPA-D-Phe1]octreotide in somatostatin receptor-positive organs. J Nucl Med. 2003;44:1315–21.PubMedGoogle Scholar
  52. 52.
    Barlier A, Pellegrini-Bouiller I, Caccavelli L, Gunz G, Morange-Ramos I, Jaquet P, et al. Abnormal transduction mechanisms in pituitary adenomas. Horm Res. 1997;47:227–34.PubMedCrossRefGoogle Scholar
  53. 53.
    Patel RC, Kumar U, Lamb DC, Eid JS, Rocheville M, Grant M, et al. Ligand binding to somatostatin receptors induces receptor-specific oligomer formation in live cells. Proc Natl Acad Sci USA. 2002;99:3294–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Grant M, Patel RC, Kumar U. The role of subtype-specific ligand binding and the C-tail domain in dimer formation of human somatostatin receptors. J Biol Chem. 2004;279:38636–43.PubMedCrossRefGoogle Scholar
  55. 55.
    Armstrong D, Strange PG. Dopamine D2 receptor dimer formation: evidence from ligand binding. J Biol Chem. 2001;276:22621–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Ng GY, O’Dowd BF, Lee SP, Chung HT, Brann MR, Seeman P, et al. Dopamine D2 receptor dimers and receptor-blocking peptides. Biochem Biophys Res Commun. 1996;227:200–4.PubMedCrossRefGoogle Scholar
  57. 57.
    Baragli A, Alturaihi H, Watt HL, Abdallah A, Kumar U. Heterooligomerization of human dopamine receptor 2 and somatostatin receptor 2 Co-immunoprecipitation and fluorescence resonance energy transfer analysis. Cell Signal. 2007;19:2304–16.PubMedCrossRefGoogle Scholar
  58. 58.
    Bulenger S, Marullo S, Bouvier M. Emerging role of homo- and heterodimerization in G-protein-coupled receptor biosynthesis and maturation. Trends Pharmacol Sci. 2005;26:131–7.PubMedCrossRefGoogle Scholar
  59. 59.
    George SR, O’Dowd BF, Lee SP. G-protein-coupled receptor oligomerization and its potential for drug discovery. Nat Rev Drug Discov. 2002;1:808–20.PubMedCrossRefGoogle Scholar
  60. 60.
    Terrillon S, Bouvier M. Roles of G-protein-coupled receptor dimerization. EMBO Rep. 2004;5:30–4.PubMedCrossRefGoogle Scholar
  61. 61.
    Brink CB, Harvey BH, Bodenstein J, Venter DP, Oliver DW. Recent advances in drug action and therapeutics: relevance of novel concepts in G-protein-coupled receptor and signal transduction pharmacology. Br J Clin Pharmacol. 2004;57:373–87.PubMedCrossRefGoogle Scholar
  62. 62.
    Maudsley S, Martin B, Luttrell LM. The origins of diversity and specificity in G protein-coupled receptor signaling. J Pharmacol Exp Ther. 2005;314:485–94.PubMedCrossRefGoogle Scholar
  63. 63.
    Ostrom RS, Post SR, Insel PA. Stoichiometry and compartmentation in G protein-coupled receptor signaling: implications for therapeutic interventions involving G(s). J Pharmacol Exp Ther. 2000;294:407–12.PubMedGoogle Scholar
  64. 64.
    Hofland LJ, Lamberts SW. The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocr Rev. 2003;24:28–47.PubMedCrossRefGoogle Scholar
  65. 65.
    Tulipano G, Stumm R, Pfeiffer M, Kreienkamp HJ, Hollt V, Schulz S. Differential beta-arrestin trafficking and endosomal sorting of somatostatin receptor subtypes. J Biol Chem. 2004;279:21374–82.PubMedCrossRefGoogle Scholar
  66. 66.
    Hakak Y, Shrestha D, Goegel MC, Behan DP, Chalmers DT. Global analysis of G-protein-coupled receptor signaling in human tissues. FEBS Lett. 2003;550:11–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Pfeiffer M, Koch T, Schroder H, Laugsch M, Hollt V, et al. Heterodimerization of somatostatin and opioid receptors cross-modulates phosphorylation, internalization, and desensitization. J Biol Chem. 2002;277:19762–72.PubMedCrossRefGoogle Scholar
  68. 68.
    Canals M, Marcellino D, Fanelli F, Ciruela F, de Benedetti P, Goldberg SR, et al. Adenosine A2A-dopamine D2 receptor–receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Biol Chem. 2003;278:46741–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Rocheville M, Lange DC, Kumar U, Sasi R, Patel RC, Patel YC. Subtypes of the somatostatin receptor assemble as functional homo- and heterodimers. J Biol Chem. 2000;275:7862–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Pfeiffer M, Koch T, Schroder H, Klutzny M, Kirscht S, Kreienkamp HJ, et al. Homo- and heterodimerization of somatostatin receptor subtypes. Inactivation of sst (3) receptor function by heterodimerization with sst (2A). J Biol Chem. 2001;276:14027–36.PubMedGoogle Scholar
  71. 71.
    Ben-Shlomo A, Pichurin O, Barshop NJ, Wawrowsky KA, Taylor J, Culler MD, et al. Selective regulation of somatostatin receptor subtype signaling: evidence for constitutive receptor activation. Mol Endocrinol. 2007;21:2565–78.PubMedCrossRefGoogle Scholar
  72. 72.
    Watt HL, Kumar U. Colocalization of somatostatin receptors and epidermal growth factor receptors in breast cancer cells. Cancer Cell Int. 2006;6:5.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.CRN2M UMR 6231, Centre National de la Recherche ScientifiqueUniversite de la Mediterranee, Faculté de Médecine NordMarseilleFrance

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