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熊果酸对阿霉素耐药乳腺癌迁移和侵袭的抑制作用。

Inhibitory Effect of Ursolic Acid on the Migration and Invasion of Doxorubicin-Resistant Breast Cancer.

机构信息

State Key Laboratory of Electroanalytical Chemistry, Jilin Province Key Laboratory of Chinese Medicine Chemistry and Mass Spectrometry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.

Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

出版信息

Molecules. 2022 Feb 14;27(4):1282. doi: 10.3390/molecules27041282.

DOI:10.3390/molecules27041282
PMID:35209071
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8879026/
Abstract

The cause of death in most breast cancer patients is disease metastasis and the occurrence of multidrug resistance (MDR). Ornithine decarboxylase (ODC), which is involved into multiple pathways, is closely related to carcinogenesis and development. Ursolic acid (UA), a natural triterpenoid compound, has been shown to reverse the MDR characteristics of tumor cells. However, the effect of UA on the invasion and metastasis of tumor cells with MDR is not known. Therefore, we investigated the effects of UA on invasion and metastasis, ODC-related polyamine metabolism, and MAPK-Erk-VEGF/MMP-9 signaling pathways in a doxorubicin-resistant breast cancer cell (MCF-7/ADR) model. The obtained results showed that UA significantly inhibited the adhesion and migration of MCF-7/ADR cells, and had higher affinities with key active cavity residues of ODC compared to the known inhibitor di-fluoro-methyl-ornithine (DFMO). UA could downregulate ODC, phosphorylated Erk (P-Erk), VEGF, and matrix metalloproteinase-9 (MMP-9) activity. Meanwhile, UA significantly reduced the content of metabolites of the polyamine metabolism. Furthermore, UA increased the intracellular accumulation of Dox in MCF-7/ADR cells. Taken together, UA can inhibit against tumor progression during the treatment of breast cancer with Dox, and possibly modulate the Erk-VEGF/MMP-9 signaling pathways and polyamine metabolism by targeting ODC to exert these effects.

摘要

大多数乳腺癌患者的死亡原因是疾病转移和多药耐药（MDR）的发生。鸟氨酸脱羧酶（ODC）参与多种途径，与癌症的发生和发展密切相关。乌苏酸（UA）是一种天然三萜类化合物，已被证明可以逆转肿瘤细胞的 MDR 特征。然而，UA 对具有 MDR 的肿瘤细胞侵袭和转移的影响尚不清楚。因此，我们研究了 UA 对多柔比星耐药乳腺癌细胞（MCF-7/ADR）模型中侵袭和转移、ODC 相关多胺代谢以及 MAPK-Erk-VEGF/MMP-9 信号通路的影响。结果表明，UA 显著抑制 MCF-7/ADR 细胞的黏附和迁移，并且与已知抑制剂二氟甲基鸟氨酸（DFMO）相比，UA 与 ODC 的关键活性腔残基具有更高的亲和力。UA 可以下调 ODC、磷酸化 Erk（P-Erk）、VEGF 和基质金属蛋白酶-9（MMP-9）的活性。同时，UA 显著降低了多胺代谢产物的含量。此外，UA 增加了 MCF-7/ADR 细胞内多柔比星的积累。总之，UA 可以在多柔比星治疗乳腺癌的过程中抑制肿瘤进展，可能通过靶向 ODC 调节 Erk-VEGF/MMP-9 信号通路和多胺代谢来发挥这些作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fca/8879026/889637fed0ca/molecules-27-01282-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fca/8879026/437371458ec8/molecules-27-01282-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fca/8879026/544a99c50a53/molecules-27-01282-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fca/8879026/3675f0d84529/molecules-27-01282-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fca/8879026/3d68f6fd8c5e/molecules-27-01282-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fca/8879026/792df9f341c9/molecules-27-01282-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fca/8879026/747a51aa0f70/molecules-27-01282-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fca/8879026/889637fed0ca/molecules-27-01282-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fca/8879026/437371458ec8/molecules-27-01282-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fca/8879026/544a99c50a53/molecules-27-01282-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fca/8879026/3675f0d84529/molecules-27-01282-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fca/8879026/3d68f6fd8c5e/molecules-27-01282-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fca/8879026/792df9f341c9/molecules-27-01282-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fca/8879026/747a51aa0f70/molecules-27-01282-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fca/8879026/889637fed0ca/molecules-27-01282-g007.jpg

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