铁线莲提取物D-鼠李糖β常春藤甙抗乳腺癌转移作用及机制研究

Clematis ganpiniana has been recognized as an anti-cancer Chinese herbal medicine for thousands of years. D Rhamnose β-hederin is one kind of pentacyclic triterpenoid saponins purified from Clematis ganpiniana. In the previous study, we have found that DRβ-H showed strong inhibitory activity on the growth of various breast cancer cells and induced apoptosis in these cells. DRβ-H induced mitochondria-mediated apoptosis of breast cancer cells and induced apoptosis by inhibiting PI3K/AKT pathway and activating ERK pathway. Moreover, DRβ-H inhibitted the migration and invasion of MDA-MB-231 cells at the non- cytotoxic concentrations. DRβ-H could also up-regulate the exprssion of RNPC1. In this study, we will first explore the anti-metastasis effect on breast cancer of DRβ-H in vitro and vivo. Second, we will explore the underlying molecular mechanisms in vitro, especially about the pathway about RNPC1 and EMT. Third, we will verify the anti-metastasis effect of DRβ-H in vivo. Thereore, we will demonstrate the anti-metastasis effect and mechanism on breast cancer of DRβ-H. DRβ-H could be a promising candidate for chemotherapy of breast cancer.

铁线莲是中国传统药材，其应用于抗肿瘤药方已有上千年的历史。D-鼠李糖β常春藤甙(D Rhamnose β-hederin, DRβ-H)是从铁线莲中提取出的三萜皂甙类化合物，在前期工作中我们发现：DRβ-H对多种乳腺癌细胞有很强的生长抑制和诱导凋亡作用。DRβ-H通过抑制PI3K/AKT通路、激活ERK通路，改变线粒体外膜的通透性等复杂机制诱导乳腺癌细胞凋亡。DRβ-H还可以抑制高转移性乳腺癌细胞MDA-MB-231迁移及侵袭，并增加细胞RNPC1的表达。本课题拟通过体内外实验，首先在体内外证实DRβ-H抗乳腺癌转移作用，其次在体外探索DRβ-H通过与RNPC1及EMT相关途径抑制乳腺癌细胞迁移及侵袭，最后在体内确证DRβ-H抗乳腺癌转移机制，从而阐明DRβ-H抑制与RNPC1相关的EMT过程抗乳腺癌转移的科学假说。为DRβ-H应用于乳腺癌的综合治疗奠定理论基础。

D-鼠李糖β常春藤甙(D Rhamnose β-hederin, DRβ-H)是从铁线莲中提取出的三萜皂甙类化合物，该化合物对多种乳腺癌细胞有很强的生长抑制和诱导凋亡作用。DRβ-H还可以抑制高转移性乳腺癌细胞MDA-MB-231迁移及侵袭，并增加细胞RNPC1的表达。本项目分为以下两部分内容：1. 探索DRβ-H抑制乳腺癌转移的作用及机制，即首先通过体外功能实验，初步证实DRβ-H抗乳腺癌转移作用。其次通过体外分子生物学实验，进一步探索DRβ-H抑制乳腺癌细胞迁移及侵袭机制，特别是与RNPC1及EMT过程相关通路。2. 探索其他铁线莲提取物（不同皂甙类化合物单体） 的抗肿瘤活性及机制。最终得出结论：1. DRβ-H通过影响RNPC1及EMT过程相关通路来抑制乳腺癌细胞迁移及侵袭。2. 铁线莲常春藤皂甙通过线粒体途径诱导乳腺癌细胞凋亡。综合上述结果，本实验为D-鼠李糖β常春藤甙及铁线莲常春藤皂甙成为新型抗乳腺癌药物的应用提供了坚实的理论基础，但尚需大量的临床实验来进一步探索。项目成果方面，标注本项目资助的已发表文章共7篇，其中6篇SCI收录，1篇北大核心期刊收录。协助培养硕士研究生一名。项目总经费17万元，目前使用14.49万元，支出基本与预算相符，剩余2.51万元将作为后续发表文章等费用。