多巴胺增强舒尼替尼治疗胰腺癌的药效

doi:10.5246/jcps.2020.10.064

中国药学(英文版) ›› 2020, Vol. 29 ›› Issue (10): 689-700.DOI: 10.5246/jcps.2020.10.064

多巴胺增强舒尼替尼治疗胰腺癌的药效

薛钧升^1#, 王思媛^1#, 郝方然¹, 田秀云², 苏红¹, 杨亮¹, 安启明², 郝纯毅^2*, 周田彦^1*

1. 北京大学医学部药学院药剂学系, 北京 100191
2. 北京大学肿瘤医院肝胆胰外二科; 恶性肿瘤发病机制及转化研究教育部/北京市重点实验室, 北京 100142

收稿日期:2020-05-18 修回日期:2020-07-20 出版日期:2020-10-31 发布日期:2020-08-19
通讯作者: Tel.: +86-10-82801717; +86-10-88196182, E-mail: tianyanzhou@bjmu.edu.cn; haochunyi@bjmu.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81473277). Innovation Team of Ministry of Education (Grant No. BMU2017TD003).

Dopamine increases the anti-cancer efficacy of sunitinib in the treatment of pancreatic cancer

Junsheng Xue^1#, Siyuan Wang^1#, Fangran Hao¹, Xiuyun Tian², Hong Su¹, Liang Yang¹, Qiming An², Chunyi Hao^2*, Tianyan Zhou^1*

1. Department of Pharmaceutics, School of Pharmaceutical Science, Peking University Health Science Center, Beijing 100191, China
2. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, China

Received:2020-05-18 Revised:2020-07-20 Online:2020-10-31 Published:2020-08-19
Contact: Tel.: +86-10-82801717; +86-10-88196182, E-mail: tianyanzhou@bjmu.edu.cn; haochunyi@bjmu.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 81473277). Innovation Team of Ministry of Education (Grant No. BMU2017TD003).

摘要/Abstract

摘要：

舒尼替尼(sunitinib, SUN)是一种多靶点酪氨酸激酶抑制剂(tyrosine kinase inhibitor, TKI), 在使用过程中会由于引发缺氧而增加肿瘤组织中的肿瘤干细胞(cancer stem-like cell, CSC)比例, 进而导致肿瘤的耐药和转移。本课题组研究证明, 多巴胺(dopamine, DA)可以通过激动多巴胺D1受体(D1 dopamine recpetor, D1DR)抑制耐药性乳腺癌和非小细胞肺癌中的CSC比例进而增强SUN的抗肿瘤药效。本研究考察了DA和SUN联合用药在胰腺癌中的抗肿瘤药效, 这是一种具有高致死率, 且药物治疗手段极其有限的恶性肿瘤。本研究的细胞毒实验、克隆形成实验和划痕实验结果显示该DA可以显著增强SUN对两种胰腺癌细胞PANC-1、SW1990的细胞生存、克隆形成能力和迁移能力。采用SW1990细胞和胰腺癌患者组织分别构建体内移植瘤模型, 发现DA可以显著增强SUN的体内药效, 并可被D1DR特异性激动剂SCH23390部分逆转。此外, DA+SUN联合用药组肿瘤中的CSC比例显著低于空白对照组和SUN单药组。动物体重、主要脏器H&E染色和血常规检查结果显示各给药方案安全性良好。综上, DA可显著增强SUN体内外的抗胰腺癌药效, 且安全性良好。DA和SUN的联合用药组合具有用于胰腺癌治疗的巨大潜力。

关键词: 舒尼替尼, 多巴胺, 肿瘤干细胞, 联合治疗, 胰腺癌

Abstract:

Sunitinib (SUN) is a multi-targeted receptor tyrosine kinase inhibitor (TKI) that may lead to drug resistance and metastasis because of increased cancer stem-like cells (CSCs) due to the induction of hypoxia. Our group has proved that dopamine (DA) can specifically reduce CSC frequency and enhance the response of SUN in drug-resistant breast cancerand non-small cell lung cancer (NSCLC). In this study, DA and SUN combination therapy was investigated in the treatment of pancreatic cancer, a malignant tumor with high mortality rate and very limited therapies. The cytotoxicity assay, clone formation assay and wound healing assay in two pancreatic cancer cell line PANC-1 and SW1990 showed that DA could significantly increase the effect of SUN on cell survival, clone formation ability and migration ability. Besides, SW1990 cell-derived xenograft model and a pancreatic cancer patient-derived xenograft (PDX) model were constructed, further proving that DA could increase the in vivo anti-tumor efficacy of SUN, and could be reversed by SCH23390, a D1 dopamine receptor (D1DR) antagonist. Moreover, the CSC frequency of the combination groups was lower than the control groups or SUN monotherapy groups. In addition, the body weight, H&E staining and blood routine test results showed that the combination therapy was safe. In summary, DA and SUN combination therapy could be a promising strategy for the treatment of pancreatic cancer.

Key words: Sunitinib, Dopamine, Cancer stem-like cell, Combination therapy, Pancreatic cancer

中图分类号:

R943

Supporting:

Supporting Information

Figure S1. The body weight-time curves of different groups in SW1990 xenograft model (A) and PDX model (B). n = 5, mean±SD.

Figure S2. The hemogram analysis of blood samples from SW1990 tumor-bearing mice of control, DA 2 mg/kg, SUN 40 mg/kg, DA 2 mg/kg + SUN 40 mg/kg groups (mean±SD, n = 5). WBC, white blood cell; GRN, granulocytes; PLT, platelet; PCT, plateletcrit; RDW, red blood cell volume distributing width; MCHC, mean corpuscular hemoglobin concentration; MCH, mean corpuscular hematocrit; MCV, mean corpuscular volume; HCT, hematocrit; HGB, hemoglobin; RBC, red blood cell.

Figure S3. The H&E staining results of main organs including heart, liver, spleen, lung and kidney from SW1990 tumor-bearing mice of control, DA 2 mg/kg, SUN 40 mg/kg, DA 2 mg/kg + SUN 40 mg/kg groups.

薛钧升, 王思媛, 郝方然, 田秀云, 苏红, 杨亮, 安启明, 郝纯毅, 周田彦. 多巴胺增强舒尼替尼治疗胰腺癌的药效[J]. 中国药学(英文版), 2020, 29(10): 689-700.

Junsheng Xue, Siyuan Wang, Fangran Hao, Xiuyun Tian, Hong Su, Liang Yang, Qiming An, Chunyi Hao, Tianyan Zhou. Dopamine increases the anti-cancer efficacy of sunitinib in the treatment of pancreatic cancer[J]. Journal of Chinese Pharmaceutical Sciences, 2020, 29(10): 689-700.

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多巴胺增强舒尼替尼治疗胰腺癌的药效

Dopamine increases the anti-cancer efficacy of sunitinib in the treatment of pancreatic cancer

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