Differential efficacy of SSTR1,-2, and-5 agonists in the inhibition of C6 glioma growth in nude mice

作者：Barbieri Federica; Pattarozzi Alessandra; Gatti Monica; Aiello Cinzia; Quintero Ana; Lunardi Gianluigi; Bajetto Adriana; Ferrari Angelo; Culler Michael D; Florio Tullio^*

来源：American Journal of Physiology - Endocrinology And Metabolism, 2009, 297(5): E1078-E1088.

DOI：10.1152/ajpendo.00292.2009

• somatostatin
• somatostatin receptor
• glioblastoma
• antiproliferative activity
• in vivo
• extracellular signal-regulated kinase 1/2

Barbieri F, Pattarozzi A, Gatti M, Aiello C, Quintero A, Lunardi G, Bajetto A, Ferrari A, Culler MD, Florio T. Differential efficacy of SSTR1, -2, and -5 agonists in the inhibition of C6 glioma growth in nude mice. Am J Physiol Endocrinol Metab 297: E1078-E1088, 2009. First published August 25, 2009; doi: 10.1152/ajpendo.00292.2009.-Somatostatin receptors (SSTR1-5) mediate antiproliferative effects. In C6 rat glioma cells, somatostatin is cytostatic in vitro via phosphotyrosine phosphatase-dependent inhibition of ERK1/2 activity mediated by SSTR1, -2, and -5. Here we analyzed the effects of SSTR activation on C6 glioma growth in vivo and the intracellular mechanisms involved, comparing somatostatin effects with selective agonists for SSTR1, -2, and -5 (BIM-23745, BIM-23120, BIM-23206) or receptor biselective compounds (SSTR1 and -2, BIM-23704; and SSTR2 and -5, BIM-23190). Nude mice subcutaneously xenografted with C6 cells were treated with somatostatin, SSTR agonists (50 mu g, twice/day), or vehicle. Tumor growth was evaluated every 3 days for 19 days. The intracellular pathways responsible of SSTR effects in vivo were evaluated measuring Ki-67, phospho-ERK1/2, and p27(kip1) expression by immunohistochemistry in sections from explanted tumors. Somatostatin and SSTR1, -2, and -5 agonists strongly inhibited in vivo C6 tumor growth, intratumoral neovessel formation, Ki-67 expression, and ERK1/2 phosphorylation and induced upregulation of p27(Kip1), whereas only a modest activation of caspase-3 was observed. Somatostatin (acting on SSTR1, -2, and -5) displayed the highest efficacy; SSTR5 selective agonist showed a stronger effect than SSTR1 agonist, and SSTR2 agonist was less effective. On the other hand, SSTR1 and -2 agonists maximally reduced tumor neovascularization. The combined activation of SSTR1 and -2 showed a synergistic activity, reaching a higher efficacy than BIM-23206, whereas the simultaneous activation of SSTR2 and -5 resulted in a response resembling SSTR5 effects. Thus the simultaneous activation of different SSTRs inhibits glioma cell proliferation in vivo through both direct cytotostatic and antiangiogenic effects.

• 出版日期2009-11