Octreotide and Pasireotide Combination Treatment in Somatotroph Tumor Cells: Predominant Role of SST(2) in Mediating Ligand Effects

SIMPLE SUMMARY: First-generation somatostatin receptor ligands, such as octreotide, are the first-line medical therapy in acromegaly. Octreotide shows preferential binding for somatostatin receptor subtype 2 (SST(2)), while the second-generation ligand, pasireotide, has high affinity for multiple SSTs. We aimed to elucidate whether pasireotide acts via other receptors than SST(2) in somatotroph tumors, and to investigate the potential role of the combination therapy octreotide plus pasireotide. We found that octreotide and pasireotide are superimposable in reducing GH secretion in cultured somatotroph tumor cells, as well as in inhibiting cell proliferation and intracellular pathway activity in rat GH4C1 cells (a model of somatotroph tumors). We did not find any additive/synergistic effect for the combination treatment. Furthermore, we observed that co-incubation with a SST(2)-selective antagonist reversed the inhibitory effect of both compounds. Therefore, the two drugs act mainly via SST(2) in somatotroph tumor cells, and their combination is not superior to single agent treatment. ABSTRACT: First-generation somatostatin receptor ligands (fg-SRLs), such as octreotide (OCT), represent the first-line medical therapy in acromegaly. Fg-SRLs show a preferential binding affinity for somatostatin receptor subtype-2 (SST(2)), while the second-generation ligand, pasireotide (PAS), has high affinity for multiple SSTs (SST(5) > SST(2) > SST(3) > SST(1)). Whether PAS acts via SST(2) in somatotroph tumors, or through other SSTs (e.g., SST(5)), is a matter of debate. In this light, the combined treatment OCT+PAS could result in additive/synergistic effects. We evaluated the efficacy of OCT and PAS (alone and in combination) on growth hormone (GH) secretion in primary cultures from human somatotroph tumors, as well as on cell proliferation, intracellular signaling and receptor trafficking in the rat GH4C1 cell line. The results confirmed the superimposable efficacy of OCT and PAS in reducing GH secretion (primary cultures), cell proliferation, cAMP accumulation and intracellular [Ca(2+)] increase (GH4C1 cells), without any additive effect observed for OCT+PAS. In GH4C1 cells, co-incubation with a SST(2)-selective antagonist reversed the inhibitory effect of OCT and PAS on cell proliferation and cAMP accumulation, while both compounds resulted in a robust internalization of SST(2) (but not SST(5)). In conclusion, OCT and PAS seem to act mainly through SST(2) in somatotroph tumor cells in vitro, without inducing any additive/synergistic effect when tested in combination.