Liu Ting, Li Kangdi, Zhang Zhenxing, Peng Jinghui, Yang Jingzhao, Law Betty Yuen Kwan, Liu Xin, Li Wenhua
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University Wuhan, P. R. China.
The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
Am J Chin Med. 2023;51(2):425-444. doi: 10.1142/S0192415X23500222. Epub 2023 Jan 20.
Targeting the stemness of triple-negative breast cancer (TNBC) is a potential therapeutic approach for treating TNBC. Tetrandrine, a natural plant alkaloid, has several anticancer effects. Here, we aimed to evaluate the efficacy of tetrandrine in cancer stemness and epithelial to mesenchymal transition (EMT) in TNBC, and to explore the underlying mechanisms. The effects of tetrandrine on cell growth, cell viability, cell stemness capacity, cell migration, and cell invasion, as well as the molecules involved in these processes, were investigated in a cell culture system. An xenograft tumor and lung metastasis study was performed using nude mice to verify the effects and mechanisms of tetrandrine. Tetrandrine exhibited antiproliferative and cell cycle arrest activities in TNBC cell lines, significantly reduced aldehyde dehydrogenase and CD44[Formula: see text]CD24[Formula: see text] characteristic subpopulation, and successfully prevented mammosphere formation. It suppressed migration and invasion, enhanced anoikis, and regulated the expression of proteins involved in the EMT, including E-cadherin, Vimentin, and Occludin, in both TNBC cells and MDA-MB-231 spheroid cells. Further studies revealed that tetrandrine downregulated the expression of superoxide dismutase 1 (SOD1) and catalase and induced reactive oxygen species (ROS) production, which subsequently contributed to the inhibition of cell EMT and stemness. The studies also showed that tetrandrine inhibited tumor growth and metastasis of both adherent normal cells, and flow cytometry sorted specific CD44[Formula: see text]CD24[Formula: see text] breast cancer stem cells, which could be rescued by SOD1 overexpression. The results of this study suggest that tetrandrine could effectively inhibit breast cancer stem cell characteristics and the EMT process via the SOD1/ROS signaling pathway. Therefore, tetrandrine can be considered a promising anti-TNBC agent.
靶向三阴性乳腺癌（TNBC）的干性是治疗TNBC的一种潜在治疗方法。粉防己碱是一种天然植物生物碱，具有多种抗癌作用。在此，我们旨在评估粉防己碱对TNBC细胞干性和上皮-间质转化（EMT）的疗效，并探索其潜在机制。在细胞培养系统中研究了粉防己碱对细胞生长、细胞活力、细胞干性能力、细胞迁移和细胞侵袭的影响，以及参与这些过程的分子。使用裸鼠进行异种移植瘤和肺转移研究，以验证粉防己碱的作用和机制。粉防己碱在TNBC细胞系中表现出抗增殖和细胞周期阻滞活性，显著降低醛脱氢酶和CD44[公式：见正文]CD24[公式：见正文]特征亚群，并成功阻止乳腺球形成。它抑制迁移和侵袭，增强失巢凋亡，并调节TNBC细胞和MDA-MB-231球状体细胞中参与EMT的蛋白质表达，包括E-钙黏蛋白、波形蛋白和闭合蛋白。进一步研究表明，粉防己碱下调超氧化物歧化酶1（SOD1）和过氧化氢酶的表达并诱导活性氧（ROS）产生，随后这有助于抑制细胞EMT和干性。这些研究还表明，粉防己碱抑制贴壁正常细胞以及流式细胞术分选的特定CD44[公式：见正文]CD24[公式：见正文]乳腺癌干细胞的肿瘤生长和转移，而SOD1过表达可挽救这种抑制作用。本研究结果表明，粉防己碱可通过SOD1/ROS信号通路有效抑制乳腺癌干细胞特征和EMT过程。因此，粉防己碱可被认为是一种有前景的抗TNBC药物。
