Subtype selective interactions of somatostatin and somatostatin analogs with sst₁, sst₂, and sst₅ in BON-1 cells

Authors: Ludvigsen, Eva¹; Stridsberg, Mats¹; Taylor, John²; Culler, Michael²; Öberg, Kjell¹; Janson, Eva³

Source: Medical Oncology, Volume 21, Number 3, September 2004 , pp. 285-295(11)

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Abstract:

Somatostatin is a polypeptide hormone acting as an inhibitor of pituitary, pancreatic, and gastrointestinal secretion through specific membrane receptors of which five subtypes have been cloned (sst_1-5). Somatostatin analogs are used in the clinic to treat patients with excessive hormone production due to a neuroendocrine tumor. The aim of this study was to investigate the biological activity of three new somatostatin receptor subtype selective analogs (BIM-23926, sst₁-selective; BIM-23120, sst₂-selective; and BIM-23206, sst₅-selective) in the human neuroendocrine tumor cell line, BON-1, which expresses sst₁, sst₂, and sst₅ natively. Somatostatin-14 and octreotide were used as reference substances. Forskolin-induced cAMP accumulation and chromogranin A (CgA) secretion were inhibited by BIM-23120, BIM-23206, and somatostatin-14 in a dose-dependent manner. Cholecystokinin (CCK-8) stimulated activation of mitogen-activated protein (MAP) kinase was inhibited by BIM-23120 and BIM-23206, while BIM-23926 stimulated the activity. Selective BIM analogs showed a more efficient inhibitory effect on cAMP accumulation, CgA secretion, and MAP kinase activity than octreotide in BON-1 cells. This may be explained by the differences in affinity of the ligand to the receptor or by interaction between different sst subtypes. We conclude that increasing knowledge about sst physiology and expression in malignant disease indicates a need for new analogs that can be incorporated into the therapeutic arsenal.

Keywords: Somatostatin; somatostatin receptors; BON-1 cells; cAMP; chromogranin A; MAP kinase

Document Type: Research article

DOI: http://dx.doi.org/10.1385/MO:21:3:285

Affiliations: 1: Department of Medical Sciences, University Hospital, 751 85, Uppsala, Sweden, 2: Biomeasure, Inc./Beaufour-IPSEN Group, Milford, PA, USA, 3: Department of Medical Sciences, University Hospital, 751 85, Uppsala, Sweden, Email: Eva.Tiensuu_Janson@medsci.uu.se

Publication date: 2004-09-01