Pei Xiangdong, Peng Yuyang, Yin Huachun, Zang Zhenle, Shen Kaifeng, Li Song, Zhang Chunqing
Department of Neurosurgery, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
Sci Rep. 2025 Apr 5;15(1):11703. doi: 10.1038/s41598-025-95509-6.
Leflunomide's anti-tumor effects have been investigated in various types of tumors; however, its impact on pituitary adenoma, particularly prolactinoma, is unclear. Hence, the current study evaluates the effects of leflunomide on prolactinoma cells in vitro and in vivo and elucidates the potential underlying mechanism(s). Cell Counting Kit-8 results revealed that leflunomide inhibits the proliferation of rat pituitary tumor cell lines (GH3 and MMQ) in a concentration-dependent manner in vitro. However, combination therapy of cabergoline and leflunomide exerted stronger inhibitory effects than cabergoline in MMQ cells in vitro and in vivo. Transcriptomics and gene ontology (GO) analyses identified genes significantly enriched in apoptotic processes and programmed cell death. Protein-Protein Interaction (PPI) networks defined the roles of hub genes (Mdm2, Cdkn1a, Plk2, and Ccng1) in leflunomide-induced cell death. GO and pathway enrichment analyses showed that the combination drug-specific differentially expressed genes were associated with inhibiting protein translation, but were active in gene expression processes. Hence, the anti-proliferative effects of leflunomide on prolactinoma cell lines may be mediated through programmed cell death pathways. Importantly, combining cabergoline with leflunomide effectively enhances the toxic effect of cabergoline, suggesting a potential therapeutic role for leflunomide in drug-resistant prolactinoma.
来氟米特的抗肿瘤作用已在多种类型的肿瘤中进行了研究；然而，其对垂体腺瘤，尤其是催乳素瘤的影响尚不清楚。因此，本研究评估了来氟米特在体外和体内对催乳素瘤细胞的作用，并阐明了潜在的机制。细胞计数试剂盒-8结果显示，来氟米特在体外以浓度依赖性方式抑制大鼠垂体肿瘤细胞系（GH3和MMQ）的增殖。然而，在体外和体内，卡麦角林与来氟米特的联合治疗在MMQ细胞中比卡麦角林发挥更强的抑制作用。转录组学和基因本体（GO）分析确定了在凋亡过程和程序性细胞死亡中显著富集的基因。蛋白质-蛋白质相互作用（PPI）网络确定了枢纽基因（Mdm2、Cdkn1a、Plk2和Ccng1）在来氟米特诱导的细胞死亡中的作用。GO和通路富集分析表明，联合药物特异性差异表达基因与抑制蛋白质翻译有关，但在基因表达过程中活跃。因此，来氟米特对催乳素瘤细胞系的抗增殖作用可能通过程序性细胞死亡途径介导。重要的是，将卡麦角林与来氟米特联合使用可有效增强卡麦角林的毒性作用，这表明来氟米特在耐药性催乳素瘤中具有潜在的治疗作用。
