BIM-23A760 influences key functional endpoints in pituitary adenomas and normal pituitaries: molecular mechanisms underlying the differential response in adenomas

• DOI: 10.1038/srep42002
• Publication Date: 2017-02-09T10:26:57Z
• Authors: Alejandro Ibáñez-...; Laura M. López-Sá...; Manuel D. Gahete; Esther Rivero-Cortés; Mari C. Vázquez-B...; María A. Gálvez; Andrés de la Riva; Eva Venegas-Moreno; Luis Jiménez-Reina; Alberto Moreno-Ca...; Francisco J. Tina...; Silvia Maraver-Selfa; Miguel A. Japón; Juan A. García-Arnés; Alfonso Soto-Moreno; Susan M. Webb; Rhonda D. Kineman; Michael D. Culler; Justo P. Castaño; Raúl M. Luque
• Keywords: Adenoma; Adult; Male; Adolescent; Cell Survival; Medical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Survival; Dopamine; 610; Apoptosis; Article; Exocytosis; Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans; Receptors, Dopamine; 03 medical and health sciences; Medical Subject Headings::Diseases::Endocrine System Diseases::Pituitary Diseases::Pituitary Neoplasms; Animals; Humans; Pituitary Neoplasms; Calcium Signaling; Cells, Cultured; Aged; Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Amines::Catecholamines::Dopamine; Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Neurotransmitter::Receptors, Biogenic Amine::Receptors, Catecholamine::Receptors, Dopamine; 0303 health sciences; Medical Subject Headings::Diseases::Endocrine System Diseases::Endocrine Gland Neoplasms::Pituitary Neoplasms::ACTH-Secreting Pituitary Adenoma; Medical Subject Headings::Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Peptide Hormones::Hypothalamic Hormones::Pituitary Hormone Release Inhibiting Hormones::Somatostatin; Middle Aged; Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Neurotransmitter::Receptors, Neuropeptide::Receptors, Somatostatin; Pituitary Gland; Dopamine Agonists; Medical Subject Headings::Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Peptide Hormones::Pituitary Hormones; Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates; Female; BIM 23A760; Medical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::Apoptosis; Somatostatin; Medical Subject Headings::Diseases::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Glandular and Epithelial::Adenoma; Papio

AbstractChimeric somatostatin/dopamine compounds such as BIM-23A760, an sst2/sst5/D2 receptors-agonist, have emerged as promising new approaches to treat pituitary adenomas. However, information on direct in vitro effects of BIM-23A760 in normal and tumoral pituitaries remains incomplete. The objective of this study was to analyze BIM-23A760 effects on functional parameters (Ca2+ signaling, hormone expression/secretion, cell viability and apoptosis) in pituitary adenomas (n = 74), and to compare with the responses of normal primate and human pituitaries (n = 3–5). Primate and human normal pituitaries exhibited similar sst2/sst5/D2 expression patterns, wherein BIM-23A760 inhibited the expression/secretion of several pituitary hormones (specially GH/PRL), which was accompanied by increased sst2/sst5/D2 expression in primates and decreased Ca2+ concentration in human cells. In tumoral pituitaries, BIM-23A760 also inhibited Ca2+ concentration, hormone secretion/expression and proliferation. However, BIM-23A760 elicited stimulatory effects in a subset of GHomas, ACTHomas and NFPAs in terms of Ca2+ signaling and/or hormone secretion, which was associated with the relative somatostatin/dopamine-receptors levels, especially sst5 and sst5TMD4. The chimeric sst2/sst5/D2 compound BIM-23A760 affects multiple, clinically relevant parameters on pituitary adenomas and may represent a valuable therapeutic tool. The relative ssts/D2 expression profile, particularly sst5 and/or sst5TMD4 levels, might represent useful molecular markers to predict the ultimate response of pituitary adenomas to BIM-23A760.