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Differential effects of somatostatin and angiopeptin on cell proliferation
Author(s) -
Alderton Forbes,
Lauder Heather,
Feniuk Wasyl,
Fan TaiPing D,
Humphrey Patrick P A
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701843
Subject(s) - somatostatin , medicine , endocrinology , agonist , receptor , somatostatin receptor , somatostatin receptor 2 , transfection , biology , chemistry , cell culture , genetics
Somatostatin (SRIF) exerts antiproliferative effects, and angiopeptin (an sst 2 /sst 5 receptor‐selective analogue) has recently been evaluated in clinical trials for the prophylaxis of restenosis following coronary angioplasty. Using an in vitro model of cell growth we have examined the effects of SRIF and angiopeptin on cell proliferation in CHO‐K1 cells stably transfected with the human or rat recombinant sst 2 or sst 5 receptor and compared these with their effects on rat aortic vascular smooth muscle cells (VSMC) expressing endogenous somatostatin receptors. In CHO‐K1 cells, expressing either human or rat recombinant sst 2 or sst 5 receptors, or in rat aortic VSMC, SRIF and angiopeptin (0.1–1000 n M ) had no effect on basal re‐growth of cells into a denuded area of a previously confluent monolayer. In contrast, basic fibroblast growth factor (bFGF, 10 ng ml −1 ) stimulated re‐growth of these cells. SRIF (0.1–1000 n M ) caused a concentration‐dependent inhibition of the bFGF‐stimulated re‐growth in CHO‐K1 cells expressing human sst 2 (h sst 2 ) or sst 5 (h sst 5 ) receptors (pIC 50 =8.05±0.03 and 8.56±0.12, respectively). In contrast, angiopeptin (0.1–1000 n M ) acted as a partial agonist at the h sst 2 receptor (44.6±2.7% inhibition of the bFGF‐stimulated re‐growth at 100 n M ; pIC 50 =8.69±0.25) but was devoid of any agonist activity at the h sst 5 receptor. In CHO‐K1 cells stably expressing rat recombinant sst 2 (r sst 2 ) or sst 5 (r sst 5 ) receptors, SRIF (0.1–1000 n M ) was able to inhibit the bFGF‐stimulated re‐growth (pIC 50 =7.98±24 and 8.50±0.12, respectively). Angiopeptin (0.1–1000 n M ) caused a concentration‐dependent inhibition of bFGF‐stimulated re‐growth at the r sst 2 receptor (pIC 50 =8.08±0.24) but acted as a partial agonist at the r sst 5 receptor (maximum response=57.7±3.6% inhibition of bFGF‐stimulated re‐growth at 100 n M ; pIC 50 =8.60±0.16). Although angiopeptin was inactive as an agonist at the h sst 5 receptor, 100 n M angiopeptin potently antagonized the SRIF‐induced inhibition of proliferation in CHO h sst 5 (estimated pK B =10.4±0.3). 5‐Hydroxytryptamine (0.1 n M –10 μ M ) also inhibited bFGF‐stimulated re‐growth (pIC 50 =8.36±0.11) and angiopeptin had no effect on this response (pK B <7). SRIF (0.1–1000 n M ) caused a concentration‐dependent (pIC 50 =8.04±0.08) inhibition of bFGF‐stimulated re‐growth in VSMC, whereas angiopeptin displayed weak agonist activity, only inhibiting bFGF‐stimulated re‐growth at concentrations greater than 100 n M . Angiopeptin (100 n M ) caused a rightward displacement of the concentration‐effect curve to SRIF with an estimated pK B value of 7.70±0.12. These findings suggest that the low intrinsic activity of angiopeptin at the h sst 2 receptor, combined with its lack of agonist activity at the h sst 5 receptor, may explain the poor clinical efficacy of angiopeptin in trials for coronary artery restenosis, which contrasts with encouraging data found in equivalent in vivo animal studies.