Peking University Shenzhen Hospital; Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Shenzhen 518036, Guangdong, China.
Department of Thyroid and Breast Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong, China.
Phytomedicine. 2023 Jun;114:154752. doi: 10.1016/j.phymed.2023.154752. Epub 2023 Mar 10.
Breast cancer (BC) is known as the most common cancer in women. Discovering novel and effective drugs is a priority for the treatment of BC. Oxypalmatine (OPT) is a natural protoberberine-type alkaloid isolated from Phellodendron amurense Rupr. (Rutaceae) with potential anti-cancer activity.
This investigation aimed to elucidate the biological role and potential mechanisms of OPT in BC cells, and intended to assess the therapeutic potential of OPT in BC patient-derived organoid models.
CCK-8 and EdU assays, and flow cytometry were used to test the activity of OPT against BC cells. In addition, patient-derived organoid models were constructed to assess the therapeutic efficiency of OPT in BC. Besides, network pharmacological analysis and RNA sequencing analysis were performed to predict the underlying anti-BC mechanism of OPT. Moreover, Western blot analysis was applied to test the expression of genes modulated by OPT.
OPT attenuated the proliferation and DNA replication, and induced apoptosis in multiple BC cells. Interestingly, OPT also exerted a cytotoxic effect on BC organoids characterized as luminal A, HER2-overexpressing, and triple-negative subtypes, indicating that OPT was a potential broad-spectrum anticancer drug. Network pharmacological analysis suggested that OPT might affect signals contributing to BC progression, including PI3K/AKT, MAPK, and VEGFA-VEGFR2 signaling pathways. Moreover, bioinformatics analysis of data from our RNA sequencing suggested that PI3K/AKT was a downstream pathway of OPT in BC. Finally, OPT was shown to inactivate PI3K/AKT signaling pathway in BC cells by Western blot analysis.
Collectively, our study demonstrated that OPT suppressed proliferation and induced apoptosis through mitigating the PI3K/AKT signaling pathway in BC cells. Moreover, our work first adopted BC organoid models to confirm OPT as an effective and promising drug, laying a foundation for the potential use of OPT in BC treatment.
乳腺癌（BC）是女性中最常见的癌症。发现新型有效药物是治疗 BC 的当务之急。氧化吴茱萸碱（OPT）是从黄皮树（芸香科）中分离得到的一种天然原小檗碱型生物碱，具有潜在的抗癌活性。
本研究旨在阐明 OPT 在 BC 细胞中的生物学作用和潜在机制，并评估 OPT 在 BC 患者衍生类器官模型中的治疗潜力。
使用 CCK-8 和 EdU 测定法以及流式细胞术来测试 OPT 对 BC 细胞的活性。此外，构建了患者衍生的类器官模型，以评估 OPT 在 BC 中的治疗效率。此外，还进行了网络药理学分析和 RNA 测序分析，以预测 OPT 的潜在抗 BC 机制。此外，通过 Western blot 分析来测试 OPT 调节的基因的表达。
OPT 减弱了多种 BC 细胞的增殖和 DNA 复制，并诱导了细胞凋亡。有趣的是，OPT 对腔 A、HER2 过表达和三阴性等特征的 BC 类器官也表现出细胞毒性作用，表明 OPT 是一种潜在的广谱抗癌药物。网络药理学分析表明，OPT 可能影响与 BC 进展相关的信号，包括 PI3K/AKT、MAPK 和 VEGFA-VEGFR2 信号通路。此外，我们 RNA 测序数据的生物信息学分析表明，PI3K/AKT 是 OPT 在 BC 中的下游通路。最后，通过 Western blot 分析显示 OPT 通过抑制 PI3K/AKT 信号通路来抑制 BC 细胞中的 PI3K/AKT 信号通路。
综上所述，我们的研究表明，OPT 通过抑制 PI3K/AKT 信号通路来抑制 BC 细胞的增殖并诱导细胞凋亡。此外，我们的工作首次采用 BC 类器官模型来证实 OPT 是一种有效且有前途的药物，为 OPT 在 BC 治疗中的潜在应用奠定了基础。
