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

Abstract

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.

• Authors: Federica Barbieri, Alessandra Pattarozzi, Monica Gatti, Cinzia Aiello, Ana Quintero, Gianluigi Lunardi, Adriana Bajetto, Angelo Ferrari, Michael D Culler, Tullio Florio
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 297 Issue 5 Pg. E1078-88 (Nov 2009) ISSN: 1522-1555 [Electronic] United States
• PMID: 19706788 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• BIM 23120
• BIM 23190
• BIM 23206
• Oligopeptides
• Piperazines
• Receptors, Somatostatin
• Sstr2 protein, mouse
• somatostatin receptor type 1
• Somatostatin
• somatostatin receptor 5
• Caspase 3

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Brain Neoplasms (blood supply, drug therapy, pathology)
• Caspase 3 (metabolism)
• Cell Proliferation (drug effects)
• Fluorescent Antibody Technique
• Glioma (blood supply, drug therapy, pathology)
• Immunohistochemistry
• Mice
• Mice, Nude
• Microcirculation (drug effects)
• Neovascularization, Pathologic (pathology, prevention & control)
• Oligopeptides (pharmacology)
• Piperazines (pharmacology)
• Receptors, Somatostatin (agonists)
• Regional Blood Flow (drug effects)
• Somatostatin (analogs & derivatives, pharmacology)