Inhibition of gastrin-stimulated cell proliferation by the CCK-B/gastrin receptor ligand CI-988.
The gastrointestinal hormone gastrin functions as a trophic factor for oxyntic mucosa as well as a secretagogue for gastric acid. In preclinical toxicology studies CI-988, a peptoid cholecystokinin (CCK) ligand with nanomolar affinity for the CCK-B/gastrin receptor, caused gastric gland degeneration and mucosal atrophy in cynomolgus monkeys, perhaps consistent with an expected pharmacological outcome of inhibition of the trophic effect of gastrin on stomach mucosa. Because of the expense and difficulty associated with experimental use of non-human primates, we investigated the effects of CI-988 on signal transduction pathways associated with gastrin-stimulated cell proliferation using the AR42J rat pancreatic tumour cell line as a model. The AR42J cell line was selected because it is known to express the CCK-B/gastrin receptor and because it is responsive to the growth promoting effects of gastrin in vitro. Gastrin-17 at 1 nM stimulated proliferation of AR42J cells 26% and 104% above control after 24 and 96 hours, respectively. CI-988 at 1 nM had no apparent effect on basal cell proliferation rates, but decreased gastrin-17 stimulated cell proliferation 13% and 47%, respectively, after 24 and 96 hours of treatment, consistent with competitive antagonism at the gastrin receptor. Because the trophic effect of gastrin towards AR42J cells has been linked to intracellular calcium ([Ca2+]i) mobilization and/or cyclic AMP, the effect of CI-988 on these second messengers were also investigated. Gastrin-17 at 10 nM stimulated both ([Ca2+]i) and cAMP, while CI-988 alone at 100 nM had no effect, but blocked the gastrin-stimulated increases in both mediators. Therefore, using the AR42J pancreatic tumour cell line as a model, the dipeptoid CCK-B/gastrin receptor ligand CI-988 behaves as an antagonist towards gastrin receptor-stimulated signal transduction pathways and cell proliferation in vitro.
Dethloff
L A
LA
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Barr
B M
BM
Bestervelt
L L
LL
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D007211:Indoles / Q000633:toxicity*; D008024:Ligands; D008536:Meglumine / Q000031:analogs & derivatives* / Q000633:toxicity; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D034444:Peptoids; D051381:Rats; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects
D000970:Antineoplastic Agents; D007211:Indoles; D008024:Ligands; D034444:Peptoids; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C065599:PD 134308; D008536:Meglumine; D000242:Cyclic AMP; D002118:Calcium