Somatostatin (SRIF) and its analogs exert potent inhibitory effects on hormonal hypersecretion. In addition, they have been demonstrated to inhibit the proliferation of various cell lines as well as the growth of some endocrine
tumors in vivo. To evaluate the action of SRIF and its analog
octreotide on the proliferation and cell cycle kinetics of endocrine cells, we investigated their effect on GH3 rat
pituitary tumor cells, a GH-producing cell line. Using flow cytometric
DNA analysis with
propidium iodide staining, we found that
octreotide inhibits the proliferation of synchronized GH3 cells, achieving a maximal reduction, compared to controls, of 19.4 +/- 5.3% and 22.4 +/- 5.1% with 100 ng/ml and 1000 ng/ml
octreotide, respectively (P < 0.05). This effect was demonstrated to be due to a block in progression from the G0/G1 phase to the S phase of the cell cycle. This was most evident after 24 h of exposure to 100 ng/ml
octreotide, at which time there was a 7.1 +/- 1.4% increase in cells in G0/G1 (P < 0.01) and a 6.6 +/- 1.3% decrease in cells in S phase (P < 0.01). However, unless
octreotide was replenished, this effect was transient and overcome by 36-48 h. No apoptosis was seen, and
trypan blue studies confirmed that cell death by
necrosis did not occur. A single exposure to native SRIF-14 had little effect, but a G0/G1 cell cycle block and inhibition of proliferation were seen if SRIF was regularly replenished. We conclude that SRIF and
octreotide exert a
cytostatic effect on GH3 cells by causing a partial G0/G1 cell cycle block. These findings suggest that the actions of SRIF and
octreotide occur through signal transduction pathways that act predominantly on downstream regulators.