Gao Chunyu, Teng Hongbo, Zhang Wenxin, Zhao Yaru, Cui Chunguo, Patrice Zerbo, Wang Liyan, Zhao Yan
College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, China.
International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Changchun, Jilin, China.
Front Chem. 2025 Jul 31;13:1630939. doi: 10.3389/fchem.2025.1630939. eCollection 2025.
Due to the lack of effective treatment methods and targeted drugs, triple-negative breast cancer (TNBC) is not only difficult to treat clinically, but also has a poor prognosis for patients. This study aims to develop novel anti-TNBC drug candidates by designing 90 derivatives of 3,4--lupane triterpene derivatives, a natural product of the genus Eleutherogenus.
Firstly, 90 derivatives were synthesized and screened, and the compound I-27 showed excellent cytotoxicity (IC=1.02 μM) for MDA-MB-231 cells for further activity verification. Then in vitro tests were carried out to detect the effects of the compound on the proliferation, migration, invasion and apoptosis of TNBC cells. With the help of transcriptomics, the mechanism of action was explored and verified. At the same time, its inhibitory effect on tumor volume and lung metastasis was verified through a mouse model of in vivo test, and its mechanism of action was further verified.
In vitro tests showed that compound I.-27 could effectively inhibit the proliferation, migration and invasion of TNBC cells, and induce apoptosis. Transcriptomic analysis revealed that it has a dual mechanism of action. On the one hand, it inhibits tumor angiogenesis through the ID1/TSP-1 pathway. On the other hand, it promotes apoptosis through the PI3K/AKT/FoxO1 signaling pathway. In vivo tests, the compound significantly reduced tumor volume and inhibited lung metastasis through mouse models. It further confirmed that ID1 is a key target for anti-tumor.
In this study, an anti-TNBC drug with multiple mechanisms was developed from the triterpenoids of 3,4-3,4--lupane triterpene derivatives for the first time, and the mechanism of action was clarified by combining transcriptomics, molecular docking and gene knockout technologies. Compound I-27 provides a potential breakthrough for the treatment of triple-negative breast cancer as a potential therapeutic candidate with a novel action mechanism and high potency.
由于缺乏有效的治疗方法和靶向药物，三阴性乳腺癌（TNBC）不仅临床治疗困难，而且患者预后较差。本研究旨在通过设计90种刺五加属天然产物3,4-羽扇烷三萜衍生物的衍生物，开发新型抗TNBC候选药物。
首先合成并筛选了90种衍生物，化合物I-27对MDA-MB-231细胞显示出优异的细胞毒性（IC = 1.02 μM），用于进一步的活性验证。然后进行体外试验，检测该化合物对TNBC细胞增殖、迁移、侵袭和凋亡的影响。借助转录组学，探索并验证其作用机制。同时，通过体内试验的小鼠模型验证其对肿瘤体积和肺转移的抑制作用，并进一步验证其作用机制。
体外试验表明，化合物I-27可有效抑制TNBC细胞的增殖、迁移和侵袭，并诱导凋亡。转录组分析显示其具有双重作用机制。一方面，它通过ID1/TSP-1途径抑制肿瘤血管生成。另一方面，它通过PI3K/AKT/FoxO1信号通路促进凋亡。在体内试验中，该化合物通过小鼠模型显著减小肿瘤体积并抑制肺转移。进一步证实ID1是抗肿瘤的关键靶点。
本研究首次从3,4-羽扇烷三萜衍生物的三萜类化合物中开发出一种具有多种作用机制的抗TNBC药物，并通过结合转录组学、分子对接和基因敲除技术阐明了其作用机制。化合物I-27作为一种具有新型作用机制和高效力的潜在治疗候选物，为三阴性乳腺癌的治疗提供了潜在的突破。
