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This Article Full Text Full Text (PDF) All Versions of this Article: 297/5/E1078    most recent 00292.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Barbieri, F. Articles by Florio, T. PubMed PubMed Citation Articles by Barbieri, F. Articles by Florio, T.

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

¹Laboratory of Pharmacology, Department of Oncology, Biology, and Genetics, University of Genoa; ²Istituto Nazionale per la Ricerca sul Cancro, S. C. Terapia Immunologica, Genoa, Italy; ³Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain; ⁴Istituto Zooprofilattico Sperimentale del Piemonte Liguria e Valle D'Aosta, National Reference Center of Veterinary and Comparative Oncology, Genoa, Italy; and ⁵Biomeasure/IPSEN, Milford, Massachusetts

Submitted 6 May 2009 ; accepted in final form 23 August 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 µg, 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.

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