BIM-23A760 influences key functional endpoints in pituitary adenomas and normal pituitaries: molecular mechanisms underlying the differential response in adenomas.
BIM-23A760 influences key functional endpoints in pituitary adenomas and normal pituitaries: molecular mechanisms underlying the differential response in adenomas.
复制标题
DOI：
10.1038/srep42002
复制
发表时间：
2017-02-09
影响因子：
4.6
通讯作者：
Luque RM
中科院分区：
文献类型：
--
作者：
Ibáñez-Costa A;López-Sánchez LM;Gahete MD;Rivero-Cortés E;Vázquez-Borrego MC;Gálvez MA;de la Riva A;Venegas-Moreno E;Jiménez-Reina L;Moreno-Carazo A;Tinahones FJ;Maraver-Selfa S;Japón MA;García-Arnés JA;Soto-Moreno A;Webb SM;Kineman RD;Culler MD;Castaño JP;Luque RM
嵌合生长抑素/多巴胺化合物，如BIM-23 A760，一种Sst 2/Sst 5/D2受体激动剂，已成为治疗垂体腺瘤的有前途的新方法。然而，关于BIM-23 A760在正常和肿瘤垂体中的直接体外作用的信息仍然不完整。本研究的目的是分析BIM-23 A760对垂体腺瘤（n = 74）中的功能参数（Ca 2+信号传导、激素表达/分泌、细胞活力和凋亡）的影响，并与正常灵长类动物和人垂体（n = 3-5）的反应进行比较。灵长类动物和人类正常垂体表现出相似的sst 2/sst 5/D2表达模式，其中BIM-23 A760抑制几种垂体激素（特别是GH/PRL）的表达/分泌，这伴随着灵长类动物中sst 2/sst 5/D2表达增加和人类细胞中Ca 2+浓度降低。在肿瘤垂体中，BIM-23 A760还抑制Ca 2+浓度、激素分泌/表达和增殖。然而，BIM-23 A760在GHoma、ACTHoma和NFPA的子集中引起Ca 2+信号传导和/或激素分泌方面的刺激作用，这与相对生长抑素/多巴胺受体水平相关，尤其是sst 5和sst 5 TMD 4。嵌合sst 2/sst 5/D2化合物BIM-23 A760影响垂体腺瘤的多种临床相关参数，可能是一种有价值的治疗工具。相对ssts/D2表达谱，特别是sst 5和/或sst 5 TMD 4水平，可能代表有用的分子标志物，以预测垂体腺瘤对BIM-23 A760的最终反应。
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.