蓝萼香茶菜二萜类成分抗乳腺癌干细胞活性及作用机制研究

Breast cancer is the most common malignant tumor in woman. Breast cancer stem cells (BCSCs) play a key role in the metastasis and recurrence of breast cancer. However, there is still lack of effective drugs that can inhibit breast cancer stem cells. Our previous study found that diterpenoids of Rabdosia japonica var. glaucocalyx, (DRJG) have obvious inhibitory effect on BCSCs for the first time. What’s more, it was found that the effective concentration of DRJG on BCSCs is almost ten times lower than that on normal breast cancer cells. The results suggest that DRJG may inhibit the growth of BCSCs through a specific target. However, we don’t know what are the active compounds in DRJG and what is the mechanism of DRJG inhibiting BCSCs. By combining metabolomics and network pharmacology technologies, this project intends to investigate the metabolic activity of the BCSCs after DRJG intervention through the change of concentration of endogenous compounds and active products inside and outside cells. By constructing the "breast cancer stem cells - related genes - target protein - key metabolites - DRJG" interaction network, we tend to search for the active ingredient of DRJG and its target and illustrate the mechanism of DRJG inhibiting BCSCs.

乳腺癌女性最常见的恶性肿瘤，乳腺癌干细胞在乳腺癌的转移和复发中起了关键作用，但是目前尚缺乏抑制乳腺癌干细胞的有效药物。我们前期研究发现蓝萼香茶菜二萜类成分对乳腺癌干细胞有明显的抑制作用，且其对乳腺癌干细胞的起效浓度只需普通乳腺癌细胞的十分之一，结果提示我们它可能通过结合特定的靶点专属性抑制了乳腺癌干细胞的生长，但是其起效的活性成分与作用机制尚不清楚。本项目拟采用代谢组学与网络药理学技术整合的方法，从整体内源性物质含量变化和细胞内外活性成分的浓度变化角度去揭示乳腺癌干细胞受到蓝萼香茶菜二萜类成分干预的代谢活动，进一步构建“乳腺癌干细胞-相关基因-靶蛋白-关键代谢物-蓝萼香茶菜二萜类成分”相互作用网络，发现蓝萼香茶菜二萜类提取物的关键活性成分及其靶标，从而阐述蓝萼香茶菜二萜类成分多成分多靶标抗乳腺癌干细胞的作用机制。

前期研究表明蓝萼香茶菜二萜类成分对乳腺癌干细胞有明显的抑制作用，且其对乳腺癌干细胞的起效浓度只需普通的乳腺癌细胞的十分之一，结果提示我们它可能通过特定的靶点专属性抑制了乳腺癌干细胞的生长，但是其起效的活性成分与作用机制尚不清楚。本项目通过分析筛选到了蓝萼香茶菜中的主要活性成分是以蓝萼甲素为代表的二萜类成分，其能够有效抑制乳腺癌干细胞的增值。同时，我们采用代谢组学的技术从整体内源性物质含量变化和细胞内外活性成分的浓度变化角度去揭示乳腺癌干细胞受到蓝萼香茶菜二萜类成分干预的代谢活动，我们一共发现了62个潜在的生物标志物，这些标志物的变化与相应代谢通路的改变息息相关，一共涉及到22条代谢通路，根据这些代谢物与通路的变化我们构建了蓝萼香茶菜二萜类活性成分抗乳腺癌干细胞的代谢通路网络，初步阐述了蓝萼香茶菜二萜类活性成分抗乳腺癌癌干细胞的作用机制。