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

Sci Rep. 2017 Feb 9:7:42002. doi: 10.1038/srep42002.

Abstract

Chimeric 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenoma / metabolism*
  • Adolescent
  • Adult
  • Aged
  • Animals
  • Apoptosis
  • Calcium Signaling
  • Cell Survival
  • Cells, Cultured
  • Dopamine / analogs & derivatives*
  • Dopamine / pharmacology
  • Dopamine Agonists / pharmacology*
  • Exocytosis
  • Female
  • Humans
  • Male
  • Middle Aged
  • Papio
  • Pituitary Gland / cytology
  • Pituitary Gland / drug effects*
  • Pituitary Gland / metabolism
  • Pituitary Neoplasms / metabolism*
  • Receptors, Dopamine / genetics
  • Receptors, Dopamine / metabolism
  • Receptors, Somatostatin / genetics
  • Receptors, Somatostatin / metabolism
  • Somatostatin / analogs & derivatives*
  • Somatostatin / pharmacology

Substances

  • Dopamine Agonists
  • Receptors, Dopamine
  • Receptors, Somatostatin
  • Somatostatin
  • TBR-760
  • Dopamine