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

2017; Nature Portfolio; Volume: 7; Issue: 1 Linguagem: Inglês

10.1038/srep42002

2045-2322

Alejandro Ibáñez‐Costa, Laura M. López‐Sánchez, Manuel D. Gahete, Esther Rivero‐Cortés, Mari C. Vázquez‐Borrego, María A. Gálvez, Andrés de la Riva, Eva Venegas‐Moreno, Luis Jiménez‐Reina, Alberto Moreno-Carazo, Francisco J. Tinahones, Silvia Maraver-Selfa, Miguel Á. Japón, Juan Antonio García-Arnés, Alfonso Soto‐Moreno, Susan M. Webb, Rhonda D. Kineman, Michael D. Culler, Justo P. Castaño, Raúl M. Luque,

Neuroendocrine Tumor Research Advances

Abstract Chimeric somatostatin/dopamine compounds such as BIM-23A760, an sst2/sst5/D 2 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 (Ca 2+ 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 Ca 2+ concentration in human cells. In tumoral pituitaries, BIM-23A760 also inhibited Ca 2+ concentration, hormone secretion/expression and proliferation. However, BIM-23A760 elicited stimulatory effects in a subset of GHomas, ACTHomas and NFPAs in terms of Ca 2+ signaling and/or hormone secretion, which was associated with the relative somatostatin/dopamine-receptors levels, especially sst5 and sst5TMD4. The chimeric sst2/sst5/D 2 compound BIM-23A760 affects multiple, clinically relevant parameters on pituitary adenomas and may represent a valuable therapeutic tool. The relative ssts/D 2 expression profile, particularly sst5 and/or sst5TMD4 levels, might represent useful molecular markers to predict the ultimate response of pituitary adenomas to BIM-23A760.