AP102 对 hSSTR2 和 hSSTR5 受体具有平衡亲和力的生长抑素类似物的细胞效应。

Cellular effects of AP102, a somatostatin analog with balanced affinities for the hSSTR2 and hSSTR5 receptors.

机构信息

Service of Clinical Pharmacology, Catecholamine and Peptides Laboratory, Centre Hospitalier Universitaire Vaudois (CHUV), 1001 Lausanne, Switzerland.

Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium.

出版信息

Neuropeptides. 2018 Apr;68:84-89. doi: 10.1016/j.npep.2018.02.005. Epub 2018 Mar 2.

DOI:10.1016/j.npep.2018.02.005

PMID:29523357

Abstract

BACKGROUND

Somatostatin analogs (SSAs) are first-line medical therapy for the treatment of acromegaly and neuroendocrine tumors that express somatostatin receptors (SSTR). Somatostatin suppresses secretion of a large number of hormones through the stimulation of the five SSTR. However, unbalanced inhibition of secretion as observed with the highly potent SSAs pasireotide causes hyperglycaemia mainly by inhibiting insulin secretion. In contrast, AP102 a new SSAs has neutral effect on blood glucose while suppressing GH secretion. Our objective was to establish the cellular effects of AP102 on SSTR2 and SSTR5 that may explain the differences observed between AP102 and other SSAs.

METHODS

We compared the binding and agonist activity of AP102 with somatostatin-14, octreotide and pasireotide in HEK293 cells transfected with human SSTR2 and SSTR5 receptors. SSAs signal transduction effects (cAMP concentrations) were measured in forskolin-treated cells in the presence of SSAs. Proliferation and apoptotic effects were determined and binding assays were performed using I- somatostatin-14.

RESULTS

AP102 has comparable affinity and agonist effect to octreotide at SSTR2 (IC50's of 112 pM and 244 pM, respectively; EC50's of 230 pM and 210 pM, respectively) in contrast to pasireotide that exhibits a 12-27 fold higher IC50 (3110 pM) and about 5-fold higher EC50 (1097 pM). At SSTR5, AP102 has much higher affinity and stimulating effect than octreotide (IC50's of 773 pM and 16,737 pM, respectively; EC50's of 8526 pM and 26,800 pM), and an intermediate affinity and agonist effect between octreotide and pasireotide. AP102, octreotide and pasireotide have variable anti-proliferative effects on HEK cells transfected with SSTR2 and SSTR5.

CONCLUSION

AP102 is a new SSA that better reduces signaling at SSTR2 than SSTR5 and prevents cell proliferation at both receptors. The euglycaemic effect of AP102 observed in preclinical studies may be related to this intermediate agonistic potency between pasireotide and octreotide at SSTR2 and SSTR5.

摘要

背景

生长抑素类似物（SSAs）是治疗表达生长抑素受体（SSTR）的肢端肥大症和神经内分泌肿瘤的一线医学治疗方法。生长抑素通过刺激五个 SSTR 来抑制大量激素的分泌。然而，具有高活性的 SSAs 帕瑞肽观察到的分泌抑制不平衡会导致高血糖，主要是通过抑制胰岛素分泌。相比之下，新型 SSAs AP102 在抑制 GH 分泌的同时对血糖具有中性作用。我们的目标是确定 AP102 对 SSTR2 和 SSTR5 的细胞作用，这可以解释 AP102 与其他 SSAs 之间观察到的差异。

方法

我们比较了 AP102 与生长抑素-14、奥曲肽和帕瑞肽在转染人 SSTR2 和 SSTR5 受体的 HEK293 细胞中的结合和激动剂活性。在 SSAs 存在下，用 forskolin 处理细胞测量 SSAs 信号转导效应（cAMP 浓度）。使用 I-生长抑素-14 测定增殖和凋亡作用，并进行结合测定。

结果

AP102 在 SSTR2 上与奥曲肽具有相当的亲和力和激动剂作用（IC50 分别为 112 pM 和 244 pM；EC50 分别为 230 pM 和 210 pM），而帕瑞肽的 IC50 高 12-27 倍（3110 pM），EC50 高 5 倍（1097 pM）。在 SSTR5 上，AP102 的亲和力和刺激作用比奥曲肽高得多（IC50 分别为 773 pM 和 16737 pM；EC50 分别为 8526 pM 和 26800 pM），而与奥曲肽和帕瑞肽之间的亲和力和激动剂作用介于两者之间。AP102、奥曲肽和帕瑞肽对转染 SSTR2 和 SSTR5 的 HEK 细胞具有不同的抗增殖作用。