Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China; Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China.
Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China.
Phytomedicine. 2023 Jun;114:154769. doi: 10.1016/j.phymed.2023.154769. Epub 2023 Mar 15.
Triple negative breast cancer (TNBC) is an extremely aggressive and rapidly progressing cancer, wherein existing therapies provide little benefit to patients. β, β-Dimethylacrylshikonin (DMAS), an active naphthoquinone derived from comfrey root, has potent anticancer activity. However, the antitumor function of DMAS against TNBC remains to be proved.
Explore effects of DMAS on TNBC and clarify the mechanism.
Network pharmacology, transcriptomics and various cell functional experiments were applied to TNBC cells to explore the effects of DMAS on TNBC. The conclusions were further validated in xenograft animal models.
MTT, EdU, transwell, scratch tests, flow cytometry, immunofluorescence, and immunoblot were utilized to assess the activity of DMAS on three TNBC cell lines. The anti-TNBC mechanism of DMAS was clarified by overexpression and knockdown of STAT3 in BT-549 cells. In vivo efficacy of DMAS was analysed using a xenograft mouse model.
In vitro analysis revealed that DMAS inhibited the G2/M phase transition and suppressed TNBC proliferation. Additionally, DMAS triggered mitochondrial-dependent apoptosis and reduced cell migration by antagonizing epithelial-mesenchymal transition. Mechanistically, DMAS exerted its antitumour effects by inhibiting STAT3Y705 phosphorylation. STAT3 overexpression abolished the inhibitory effect of DMAS. Further studies showed that treatment with DMAS inhibited TNBC growth in a xenograft model. Notably, DMAS potentiated the sensitivity of TNBC to paclitaxel and inhibited immune evasion by downregulating the immune checkpoint PD-L1.
For the first time, our study revealed that DMAS potentiates paclitaxel activity, suppresses immune evasion and TNBC progression by inhibiting STAT3 pathway. It has the potential as a promising agent for TNBC.
三阴性乳腺癌（TNBC）是一种极具侵袭性且快速进展的癌症，现有疗法对患者疗效甚微。β，β-二甲基丙烯酰紫草素（DMAS）是一种从紫草根中提取的活性萘醌，具有很强的抗癌活性。然而，DMAS 对 TNBC 的抗肿瘤作用仍有待证实。
探讨 DMAS 对 TNBC 的作用，并阐明其机制。
采用网络药理学、转录组学和各种细胞功能实验研究 DMAS 对 TNBC 细胞的作用，进一步在异种移植动物模型中验证结论。
采用 MTT、EdU、Transwell、划痕实验、流式细胞术、免疫荧光和免疫印迹实验评估 DMAS 对三种 TNBC 细胞系的作用。通过在 BT-549 细胞中转染 STAT3 过表达和敲低质粒，明确 DMAS 抗 TNBC 的作用机制。采用异种移植小鼠模型分析 DMAS 的体内疗效。
体外分析显示，DMAS 抑制 G2/M 期过渡并抑制 TNBC 增殖。此外，DMAS 通过拮抗上皮-间充质转化，触发线粒体依赖性细胞凋亡并减少细胞迁移。机制上，DMAS 通过抑制 STAT3Y705 磷酸化发挥抗肿瘤作用。STAT3 过表达消除了 DMAS 的抑制作用。进一步的研究表明，DMAS 抑制异种移植模型中 TNBC 的生长。值得注意的是，DMAS 通过下调免疫检查点 PD-L1 增强了 TNBC 对紫杉醇的敏感性并抑制了免疫逃逸。
本研究首次揭示 DMAS 通过抑制 STAT3 通路增强紫杉醇的活性、抑制免疫逃逸和 TNBC 进展，具有作为 TNBC 有前途治疗药物的潜力。
