Somatostatin (SST) modulates exocrine and endocrine secretion, proliferation and apoptosis, via 5 transmembrane receptors (SSTRs 1 to 5), which predominantly signal through inhibitory G proteins. Stable analogs such as Lanreotide and Octreotide have been developed for use in clinical practice. Both have high affinity for SSTR 2, and moderate affinity for SSTR 5. Octreotide has been shown to inhibit endothelial proliferation, probably via SSTR 2, which is expressed by proliferating endothelial cells. Recently we have shown that proliferating human umbilical vein endothelial cells (HUVECs) not only express SSTR 2, but also express SSTR 5. The antiproliferative effects of SSTR 5 activation have been well characterized in several cell types. Our aim was to determine the antiproliferative potential of endothelial SSTR 5, and to identify if the new SSTR 2 and 5 selective analog, BIM-23244, effectively inhibited HUVEC proliferation in vitro.
Proliferating HUVECs were screened for SSTR 2 and 5 mRNA using Taqman qRT PCR. SSTR 2 and 5 positive HUVECs were treated with the SSTR 5 selective analog, BIM-23206, the SSTR 2 selective analog BIM-23120, and BIM-23244 (10-6 to 10-11 M) for 18hrs (5 replicates). WST-1 was added to measure proliferation and the absorbance measured hourly for 4hrs. The data were analysed with ANOVA, using SPSS.
BIM-23244 significantly inhibited HUVEC proliferation by up to 72.9 plus/minus 8.7% (concentration range: 10-7 to 10-10 M: P<0.05). BIM-23206 and BIM-23120 significantly inhibited proliferation by 19.0 plus/minus 2.8% and 25.1 plus/minus 13.1%, respectively (both 10-7 only: P<0.05).
SSTR 2 selective and SSTR 5 selective analogs moderately inhibit HUVEC proliferation. BIM-23244, which simultaneously activates SSTRs 2 and 5, potently inhibits endothelial proliferation, and may therefore have therapeutic utility as an antiangiogenic agent.
22 - 24 Mar 2004
British Endocrine Societies