Dissociation of antiproliferative and antihormonal effects of the somatostatin analog octreotide on 7315b pituitary tumor cells.
The somatostatin (SS) analog octreotide has been successfully used in the treatment of (neuro)endocrine tumors. The mechanism of action of the tumor (growth) inhibitory action by octreotide is not fully understood. We have investigated the effect of octreotide on 7315b rat pituitary tumor cell growth, PRL release, and intracellular PRL concentrations in vitro. When cultured in medium with 10% fetal calf serum, the number of high affinity SS receptors increased with increasing culture time. On days 7, 14, and 21 of culture, the number of SS receptors amounted to 978 +/- 217, 3588 +/- 705, and 5865 +/- 3332 fmol/mg protein, respectively, whereas they were not measurable on day 0. From days 0-7, 7-14, and 14-21 of culture, octreotide (1 pM to 1 microM) inhibited PRL release and the intracellular PRL concentration, with IC50 values in the nanomolar range. However, no inhibition of cell growth was observed by these octreotide concentrations from day 0-7 of culture, while octreotide inhibited cell growth in a dose-dependent fashion from days 7-14 and 14-21 of culture (maximal inhibition by 25% and 26%, respectively). In a series of nine consecutive experiments we found a significant positive correlation between the percent inhibition of cell growth induced by 1 microM octreotide and the number of SS receptors on 7315b cells (r = 0.7865; P = 0.012). Inhibition of PRL release did not correlate with SS receptor numbers. Octreotide (1 microM) inhibited forskolin (0.5 microM)-stimulated cell growth and intracellular PRL concentrations, while in the presence of a high concentration of forskolin (10 microM), octreotide had no effect on forskolin-stimulated cell growth and intracellular PRL concentrations. In addition, its PRL release inhibitory effect was significantly lower in forskolin-stimulated cultures. Pretreatment of the cells with pertussis toxin (10 micrograms/liter) completely prevented the inhibition of cell growth by octreotide and diminished the inhibitory effect of octreotide on PRL release. Finally, 1 microM octreotide significantly inhibited forskolin-stimulated cAMP production (by 29% and 53% on days 7 and 14 of culture, respectively). We conclude that 1) octreotide inhibits 7315b rat pituitary tumor cell proliferation via a pertussis toxin-sensitive GTP-binding protein- and adenylate cyclase-dependent mechanism; and 2) the number of SS receptors on 7315b pituitary tumor cells may determine whether octreotide exerts a direct antiproliferative effect, whereas its antihormonal effect occurs in the presence of relatively low numbers of SS receptors. This suggests a dissociation of the antiproliferative and antihormonal effects induced by octreotide.
Hofland
L J
LJ
Department of Medicine III, Erasmus University, Rotterdam, The Netherlands.
van Koetsveld
P M
PM
Wouters
N
N
Waaijers
M
M
Reubi
J C
JC
Lamberts
S W
SW
D037361:Adenylate Cyclase Toxin; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D005260:Female; D007700:Kinetics; D015282:Octreotide / Q000494:pharmacology*; D037342:Pertussis Toxin; D010911:Pituitary Neoplasms / Q000378:metabolism* / Q000473:pathology; D011388:Prolactin / Q000378:metabolism; D051381:Rats; D011915:Rats, Inbred BUF; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D017481:Receptors, Somatostatin; D014407:Tumor Cells, Cultured; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D017981:Receptors, Neurotransmitter; D017481:Receptors, Somatostatin; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D011388:Prolactin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D015282:Octreotide