期刊
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
卷 297, 期 5, 页码 E1078-E1088出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00292.2009
关键词
somatostatin; somatostatin receptor; glioblastoma; antiproliferative activity; in vivo; extracellular signal-regulated kinase 1/2
资金
- Ricerca Corrente 2007 Istituto Zooprofilattico Sperimentale del Piemonte Liguria e Valle D'Aosta-Code IZSPLV [26/07 RC]
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.
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