Yuan Jie, Wang Geng, Beeraka Narasimha M, Zhang Hua, Wang Qun, Zhang Danfeng, Wang Minghua, Ravish Akshay, Chinnathambi Arunachalam, Alharbi Sulaiman Ali, Rangappa Kanchugarakoppal S, Nikolenko Vladimir N, Basappa Basappa, Yang Li
Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China; Department of General Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
Transl Oncol. 2025 Aug;58:102418. doi: 10.1016/j.tranon.2025.102418. Epub 2025 Jun 3.
Approximately 70 % of patients with breast cancer (BC) have estrogen receptor (ER)-positive tumors. Endocrine therapy is the principal treatment for these patients. Tamoxifen (TAM), a selective ER modulator, is commonly administered to premenopausal patients with ER-positive BC. However, resistance to TAM poses a major clinical hurdle as TAM-resistant BC cells often show increased proliferation and motility as well as undergo epithelial-mesenchymal transition (EMT).
Pyrimidine-based small molecules were reported as both nuclear factor kappa B (NF-κB) and Wnt/β-Catenin pathway regulators. This report discovered oxazine (TRX-01) linked pyrimidine as an inhibitor of NF-kB and triazole (TTP-5) linked pyrimidine as an inhibitor of Wnt/β-Catenin signaling in TAM-resistant MCF-7 breast cancer cells (MCF-7R).
Colony formation, wound healing, and Transwell assays were conducted to assess cell migration and invasion. MTT assay was used to evaluate cytotoxic effects. Western blotting was used to determine the signaling mechanisms for NF-κB and EMT phenotypes. Xenograft models were utilized to examine the in vivo effectiveness of TRX-01.
TRX-01 reversed TAM resistance in MCF-7R cells, whereas TTP-5 reduced the motility of MCF-7R cells. Additionally, TRX-01 inhibited the activation of the NF-κB signaling pathway in MCF-7R cells, whereas TTP-5 inhibited the EMT-like phenotype of MCF-7R cells by impairing the activation of Wnt/β-catenin signaling. The differences in the functions of the two pyrimidine structures are attributed to their additional structures bearing both TRX-01 and TTP-05.
Pyrimidine-based TRX-01 and TTP-5 lead structures are promising agents for inhibiting the progression of TAM-resistant breast cancer cells. These results support the need for additional comprehensive in vivo and clinical studies to confirm the efficacy and safety of these compounds.
大约70%的乳腺癌（BC）患者患有雌激素受体（ER）阳性肿瘤。内分泌治疗是这些患者的主要治疗方法。他莫昔芬（TAM），一种选择性ER调节剂，常用于绝经前ER阳性BC患者。然而，对TAM的耐药性构成了一个主要的临床障碍，因为TAM耐药的BC细胞通常表现出增殖和运动增加，以及经历上皮-间质转化（EMT）。
基于嘧啶的小分子被报道为核因子κB（NF-κB）和Wnt/β-连环蛋白途径调节剂。本报告发现恶嗪（TRX-01）连接的嘧啶作为NF-κB的抑制剂，三唑（TTP-5）连接的嘧啶作为TAM耐药的MCF-7乳腺癌细胞（MCF-7R）中Wnt/β-连环蛋白信号的抑制剂。
进行集落形成、伤口愈合和Transwell实验以评估细胞迁移和侵袭。MTT实验用于评估细胞毒性作用。蛋白质印迹法用于确定NF-κB和EMT表型的信号传导机制。利用异种移植模型检查TRX-01的体内有效性。
TRX-01逆转了MCF-7R细胞对TAM的耐药性，而TTP-5降低了MCF-7R细胞的运动性。此外，TRX-01抑制了MCF-7R细胞中NF-κB信号通路的激活，而TTP-5通过损害Wnt/β-连环蛋白信号的激活抑制了MCF-7R细胞的EMT样表型。两种嘧啶结构功能的差异归因于它们带有TRX-01和TTP-05的附加结构。
基于嘧啶的TRX-01和TTP-5先导结构是抑制TAM耐药乳腺癌细胞进展的有前景的药物。这些结果支持需要进行更多全面的体内和临床研究以确认这些化合物的疗效和安全性。
