化合物C17抑制乳腺癌肺转移

doi:10.5246/jcps.2019.10.068

中国药学(英文版) ›› 2019, Vol. 28 ›› Issue (10): 716-727.DOI: 10.5246/jcps.2019.10.068

化合物C17抑制乳腺癌肺转移

冯瑶瑶¹, 焦佩丽², 严晓雪³, 薛子溪³, 姚烨¹, 杨亮¹, 孔大明¹, 苏红¹, 雍灵¹, 陈国术^3*, 周田彦^1*

1. 北京大学医学部药学院分子药剂学与新释药系统北京市重点实验室, 北京 100191
2. 北京大学医学部药学院天然药物及仿生药物国家重点实验室, 北京 100191
3. 广州大学化学与化工学院化学基础实验室, 广东广州 510006

收稿日期:2019-05-24 修回日期:2019-07-12 出版日期:2019-10-31 发布日期:2019-07-25
通讯作者: Tel.: +86-20-39366902; +86-10-82801717, E-mail: gdgschen@gzhu.edu.cn; tianyanzhou@bjmu.edu.cn
基金资助:
Beijing Municipal Natural Science Foundation (Grant No. 7192100) and Innovation Team of Ministry of Education (Grant No. BMU2017TD003).

Compound C17 inhibits the lung metastasis of breast cancer

Yaoyao Feng¹, Peili Jiao², Xiaoxue Yan³, Zixi Xue³, Ye Yao¹, Liang Yang¹, Daming Kong¹, Hong Su¹, Ling Yong¹, Guoshu Chen^3*, Tianyan Zhou^1*

1. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
2. State Key Laboratory of Natural and Biomimetic Drugs, Department of Medicine Chemistry, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
3. Chemical Basic Laboratory, School of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou 510006, China

Received:2019-05-24 Revised:2019-07-12 Online:2019-10-31 Published:2019-07-25
Contact: Tel.: +86-20-39366902; +86-10-82801717, E-mail: gdgschen@gzhu.edu.cn; tianyanzhou@bjmu.edu.cn
Supported by:
Beijing Municipal Natural Science Foundation (Grant No. 7192100) and Innovation Team of Ministry of Education (Grant No. BMU2017TD003).

摘要/Abstract

摘要：

乳腺癌是女性中最为常见的癌症, 由于其转移的发生而具有很高的致死率, 而转移与肿瘤干细胞(cancer stem-like cells, CSCs)密切相关。激动多巴胺D1受体(dopamine D1 receptor, D1DR)能够降低耐药性乳腺癌和非小细胞肺癌中CSCs的比例。本研究旨在考察一种可口服的化合物C17抗乳腺癌转移的作用以及与激动D1DR相关的潜在机制。免疫荧光共聚焦结果显示C17上调了D1DR的表达。分别通过磺酰罗丹明B比色(Sulforhodamine B, SRB)法和克隆形成实验发现C17能够抑制细胞存活和集落形成。划痕愈合实验以及transwell迁移实验结果表明C17能够抑制4T1细胞的迁移。采用流式细胞术分析得出C17能够降低CSCs的比例。此外, C17可显著抑制4T1原位肿瘤的肺转移, 且无明显毒性, 同时C17能够上调乳腺癌原位瘤中E-cadherin的表达、下调Snail和N-cadherin的表达, 且上述作用的发挥与激动D1DR相关。本研究为转移性乳腺癌的治疗提供了一种顺应性和安全性良好的潜在候选化合物。

关键词: 乳腺癌, 转移, 肿瘤干细胞, 多巴胺D1受体, C17

Abstract:

Breast cancer is the most common cancer in females with extremely high lethality mainly due to the occurrence of metastasis, which is closely related to cancer stem-like cells (CSCs). It has been reported that CSC frequency in drug-resistant breast cancer and non-small cell lung cancer is reduced by activating dopamine D1 receptor (D1DR). In the present study, we aimed to investigate the effect of a compound C17 that can be used orally for breast cancer metastasis as well as the underlying mechanism involving the activation of D1DR. The confocal immunofluorescence analysis demonstrated that D1DR was up-regulated by C17. The cell survival and colony formation were inhibited by C17 through the detection by Sulforhodamine B colorimetric (SRB) assay and colony formation assay, respectively. Results from both wound healing assay and transwell assay demonstrated that C17 inhibited the migration of 4T1 cells. Flow cytometry analysis indicated that C17 significantly reduced the CSC frequency. In addition, C17 could inhibit the lung metastasis in 4T1 orthotopic mouse model of breast cancer without obvioustoxicity, and it could up-regulate the expression of intratumoral E-cadherin and down-regulate the expressions of Snail and N-cadherin in primary breast tumor, which might be related to the activation of D1DR. Our findings provided a potential candidate compound for the treatment of metastatic breast cancer with good compliance and safety.

Key words: Breast cancer, Metastasis, Cancer stem-like cells, Dopamine D1 receptor, C17

中图分类号:

R962

Supporting:

冯瑶瑶, 焦佩丽, 严晓雪, 薛子溪, 姚烨, 杨亮, 孔大明, 苏红, 雍灵, 陈国术, 周田彦. 化合物C17抑制乳腺癌肺转移[J]. 中国药学(英文版), 2019, 28(10): 716-727.

Yaoyao Feng, Peili Jiao, Xiaoxue Yan, Zixi Xue, Ye Yao, Liang Yang, Daming Kong, Hong Su, Ling Yong, Guoshu Chen, Tianyan Zhou. Compound C17 inhibits the lung metastasis of breast cancer[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(10): 716-727.

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化合物C17抑制乳腺癌肺转移

Compound C17 inhibits the lung metastasis of breast cancer

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