Cao Min, Xu Lun-Shan, Huang Ping, Fan Bin-Bin, Zhang Yi-Hua
Department of Neurosurgery, Daping Hospital, Army Medical University, Chongqing, China.
Mol Divers. 2025 Apr;29(2):1415-1425. doi: 10.1007/s11030-024-10923-8. Epub 2024 Jul 16.
Prolactinoma was the most common functional pituitary neuroendocrine tumor tissue type, which was caused by excessive proliferation of pituitary prolactin (PRL) cells. Drug therapy of dopamine receptor agonists was generally considered as the prior treatment for prolactinoma patients. However, there were still prolactinoma patients who were resistant to dopamine agonists. Studies have been reported that paeoniflorin can inhibit the secretion of PRL in prolactinoma cells lacking dopamine D receptor (DR) expression, and paeoniflorin can be metabolized into albiflorin by intestinal flora in rats. The effect of albiflorin on prolactinoma has not been reported yet. In this study, network pharmacology was used to analyze the mechanism of paeoniflorin and its metabolite albiflorin as multi-target therapy for prolactinoma, and the experimental verification was carried out. In order to clarify the complex relationship among paeoniflorin, albiflorin and prolactinoma, we constructed a component-target-disease network, and further constructed interaction network, MMP9, EGFR, FGF2, FGFR1 and LGALS3 were screened as the core targets. Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that paeoniflorin and albiflorin may be involved in various pathways in the treatment of prolactinoma, included relaxin signaling pathway and PI3K-Akt signaling pathway. Molecular docking analysis showed that paeoniflorin and albiflorin had good binding activity with MMP9. Western blotting results showed that paeoniflorin and albiflorin could significantly reduce the expression of MMP9, and ELISA results showed that paeoniflorin and albiflorin could significantly reduce the concentration of PRL in GH3 cells, and the reduce degree of albiflorin was stronger than paeoniflorin at 50 μM, which indicated that albiflorin might be a potential drug to treat prolactinoma, which can regulate prolactinoma through MMP9 and reduce the concentration of PRL. Our study provided a new therapeutic strategy for prolactinoma.
催乳素瘤是最常见的功能性垂体神经内分泌肿瘤组织类型，由垂体催乳素（PRL）细胞过度增殖引起。多巴胺受体激动剂的药物治疗通常被认为是催乳素瘤患者的首选治疗方法。然而，仍有一些催乳素瘤患者对多巴胺激动剂耐药。有研究报道，芍药苷可抑制缺乏多巴胺D受体（DR）表达的催乳素瘤细胞中PRL的分泌，且芍药苷在大鼠体内可被肠道菌群代谢为芍药内酯苷。目前尚未见芍药内酯苷对催乳素瘤作用的报道。本研究采用网络药理学方法分析芍药苷及其代谢产物芍药内酯苷对催乳素瘤多靶点治疗的作用机制，并进行实验验证。为阐明芍药苷、芍药内酯苷与催乳素瘤之间的复杂关系，构建了成分-靶点-疾病网络，并进一步构建相互作用网络，筛选出基质金属蛋白酶9（MMP9）、表皮生长因子受体（EGFR）、成纤维细胞生长因子2（FGF2）、成纤维细胞生长因子受体1（FGFR1）和半乳糖凝集素3（LGALS3）作为核心靶点。京都基因与基因组百科全书（KEGG）分析表明，芍药苷和芍药内酯苷在治疗催乳素瘤时可能参与多种信号通路，包括松弛素信号通路和磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-Akt）信号通路。分子对接分析表明，芍药苷和芍药内酯苷与MMP9具有良好的结合活性。蛋白质免疫印迹结果显示，芍药苷和芍药内酯苷可显著降低MMP9的表达，酶联免疫吸附测定（ELISA）结果显示，芍药苷和芍药内酯苷可显著降低GH3细胞中PRL的浓度，且在50 μM时芍药内酯苷的降低程度强于芍药苷，这表明芍药内酯苷可能是治疗催乳素瘤的潜在药物，其可通过MMP9调节催乳素瘤并降低PRL浓度。本研究为催乳素瘤提供了一种新的治疗策略。
