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Abstract：
Somatostatin receptor ligands (SRLs) with high affinity for somatostatin receptors 2 and 5 (SSTR2 and SSTR5) are poorly efficacious in NF-PitNETs, expressing high levels of SSTR3. ITF2984 is a pan-SSTR ligand with high affinity for SSTR3, able to induce SSTR3 activation and to exert antitumoral activity in the MENX rat model. The aim of this study was to test ITF2984\'s antiproliferative and proapoptotic effects in NF-PitNET primary cultured cells derived from surgically removed human tumors and to characterize their SSTR expression profile. We treated cells derived from 23 NF-PitNETs with ITF2984, and a subset of them with octreotide, pasireotide (SRLs with high affinity for SSTR2 or 5, respectively), or cabergoline (DRD2 agonist) and we measured cell proliferation and apoptosis. SSTR3, SSTR2, and SSTR5 expression in tumor tissues was analyzed by qRT-PCR and Western blot. We demonstrated that ITF2984 reduced cell proliferation (-40.8 (17.08)%, p < 0.001 vs. basal, n = 19 NF-PitNETs) and increased cell apoptosis (+41.4 (22.1)%, p < 0.001 vs. basal, n = 17 NF-PitNETs) in all tumors tested, whereas the other drugs were only effective in some tumors. In our model, SSTR3 expression levels did not correlate with ITF2984 antiproliferative nor proapoptotic effects. In conclusion, our data support a possible use of ITF2984 in the pharmacological treatment of NF-PitNET.
摘要：
对生长抑素受体2和5（SSTR2和SSTR5）具有高亲和力的生长抑素受体配体（SRL）在NF-PitNET中效果较差，表达高水平的SSTR3。ITF2984是对SSTR3具有高亲和力的泛SSTR配体,能够在MENX大鼠模型中诱导SSTR3活化并发挥抗肿瘤活性。这项研究的目的是测试ITF2984在源自手术切除的人肿瘤的NF-PitNET原代培养细胞中的抗增殖和促凋亡作用，并表征其SSTR表达谱。我们用ITF2984处理来自23个NF-PitNETs的细胞，并用奥曲肽处理其中的一个子集，pasireotide（分别对SSTR2或5具有高亲和力的SRL），或卡麦角林（DRD2激动剂），我们测量了细胞增殖和凋亡。通过qRT-PCR和Western印迹分析肿瘤组织中的SSTR3、SSTR2和SSTR5表达。我们证明ITF2984降低了细胞增殖（-40.8（17.08）％，p<0.001vs.基底,n=19NF-PitNETs）和增加的细胞凋亡（+41.4（22.1）％，p<0.001vs.基底,n=17NF-PitNET）在所有测试的肿瘤中，而其他药物仅对某些肿瘤有效。在我们的模型中,SSTR3表达水平与ITF2984抗增殖或促凋亡作用无关。总之,我们的数据支持ITF2984可能用于NF-PitNET的药物治疗.
