Differential efficacy of SSTR1, -2, and -5 agonists in the inhibition of C6 glioma growth in nude mice.
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.
Barbieri
Federica
F
Laboratory of Pharmacology, Dept. of Oncology, Biology, and Genetics, Univ. of Genoa, Viale Benedetto XV, 2, 16132 Genoa, Italy.
Pattarozzi
Alessandra
A
Gatti
Monica
M
Aiello
Cinzia
C
Quintero
Ana
A
Lunardi
Gianluigi
G
Bajetto
Adriana
A
Ferrari
Angelo
A
Culler
Michael D
MD
Florio
Tullio
T
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control; D009842:Oligopeptides / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D017481:Receptors, Somatostatin / Q000819:agonists*; D012039:Regional Blood Flow / Q000187:drug effects; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C519495:BIM 23120; C111783:BIM 23190; C519496:BIM 23206; D009842:Oligopeptides; D010879:Piperazines; D017481:Receptors, Somatostatin; C492049:Sstr2 protein, mouse; C101130:somatostatin receptor type 1; D013004:Somatostatin; C094573:somatostatin receptor 5; D053148:Caspase 3