Somatostatin analogs that activate the
somatostatin subtype 2A (
sst2A) receptor are used to treat neuroendocrine
cancers because they inhibit
tumor secretion and growth. Recently, new analogs capable of activating multiple
somatostatin receptor subtypes have been developed to increase
tumor responsiveness. We tested two such multi-
somatostatin analogs for functional selectivity at the
sst2A receptor:
SOM230, which activates sst1, sst2, sst3, and sst5 receptors, and
KE108, which activates all sst receptor subtypes. Both compounds are reported to act as full agonists at their target sst receptors. In sst2A-expressing HEK293 cells,
somatostatin inhibited cAMP production, stimulated intracellular
calcium accumulation, and increased ERK phosphorylation.
SOM230 and
KE108 were also potent inhibitors of cAMP accumulation, as expected. However, they antagonized
somatostatin stimulation of intracellular
calcium and behaved as partial agonists/antagonists for ERK phosphorylation. In pancreatic AR42J cells, which express sst2A receptors endogenously,
SOM230 and
KE108 were both full agonists for cAMP inhibition. However, although
somatostatin increased intracellular
calcium and ERK phosphorylation,
SOM230 and
KE108 again antagonized these effects. Distinct mechanisms were involved in
sst2A receptor signaling in AR42J cells;
pertussis toxin pretreatment blocked
somatostatin inhibition of cAMP accumulation but not the stimulation of intracellular
calcium and ERK phosphorylation. Our results demonstrate that
SOM230 and
KE108 behave as agonists for inhibition of
adenylyl cyclase but antagonize
somatostatin's actions on intracellular
calcium and ERK phosphorylation. Thus,
SOM230 and
KE108 are not
somatostatin mimics, and their functional selectivity at sst2A receptors must be considered in clinical applications where it may have important consequences for
therapy.