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浙江大学学报（医学版）
浙江大学学报（医学版）  2015, Vol. 44 Issue (5): 493-499    DOI: 10.3785/j.issn.1008-9292.2015.09.04
专题报道     
拉帕替尼与绿原酸联合应用抑制巨噬细胞M2型极化及抗乳腺癌转移的作用研究
张洁琼1, 姚张婷1, 梁桂开1, 陈羲1, 吴洪海1, 金露2, 丁玲1
1. 浙江大学药学院浙江省抗肿瘤药物临床前研究重点实验室, 浙江杭州 310058;
2. 温州医科大学附属第二医院神经内科, 浙江温州 325027
Combination of lapatinib with chlorogenic acid inhibits breast cancer metastasis by suppressing macrophage M2 polarization
ZHANG Jie-qiong1, YAO Zhang-ting1, LIANG Gui-kai1, CHEN Xi1, WU Hong-hai1, JIN Lu2, DING Ling1
1. College of Pharmaceutical Sciences, Zhejiang University, Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, Hangzhou 310058, China;
2. Department of Neurology, the Second Affiliated Hospital Wenzhou Medical University, Wenzhou 325027, China
全文: PDF(2287 KB)  
摘要: 

目的:研究拉帕替尼与绿原酸联合应用对抑制巨噬细胞M2型极化的影响及其在乳腺癌转移中的作用。方法:采用IL-13建立巨噬细胞M2型极化的体外模型,流式细胞术检测拉帕替尼和绿原酸合用对巨噬细胞M2型表面标志物CD206的影响;实时定量PCR检测拉帕替尼和绿原酸合用对巨噬细胞M2型特异性基因表达的影响;采用自发乳腺癌且发生肺转移的MMTV-PyVT小鼠模型考察两药合用对乳腺癌肺转移的影响,观察肺转移灶组织HE染色结果并统计转移灶点数;免疫荧光法分析乳腺癌组织中巨噬细胞的M2型极化情况。结果:拉帕替尼与绿原酸合用能够有效抑制IL-13诱导的F4/80hi CD206hi细胞(即M2型巨噬细胞)增多[(42.17%±2.59%)与(61.15%±7.58%),P<0.05];两药合用能明显下调由IL-13诱导的Ym1基因的上调[(1.8±0.0)与(1.0±0.0),P<0.05],且其作用比绿原酸单给药组强[(0.9±0.1)与(1.8±0.0),P<0.05];拉帕替尼与绿原酸合用能显著减少小鼠肺转移灶点数[P<0.05];两药合用与对照组比较能降低瘤内CD206阳性细胞所占巨噬细胞的比例[(6.08%±2.60%)与(29.04%±5.86%),P<0.05]。结论:拉帕替尼与绿原酸的联合用药能有效抑制巨噬细胞的M2型极化以及乳腺癌的转移。
关键词 ： 乳腺肿瘤/药物疗法,  肿瘤转移,  脱氧胞苷/类似物和衍生物,  脱氧胞苷/治疗应用,  抗肿瘤药(中药)/治疗应用,  绿原酸/治疗应用,  巨噬细胞,  白细胞介素13    
Abstract：

Objective:To determine the effect of the combination of lapatinib with chlorogenic acid on metastasis of breast cancer in mouse model. Methods:The classical macrophage M2 polarization model induced by interlukin13in vitro was adopted in the study. Flow cytometric analysis was performed to detect the expression of M2 marker CD206. The transcription of M2-associated genes was measured by RT-PCR. HE staining was used to analyze the metastatic nodes of breast cancer in lungs of MMTV-PyVT mice. Immunostaining analysis was used to detect the expression of related proteins in breast cancer. Results:The combination of lapatinib and chlorogenic acid inhibited the expression of CD206 induced by IL-13[(42.17%±2.59%) vs (61.15%±7.58%), P<0.05]. The combination more markedly suppressed expression of M2-associated gene Ym1 than lapatinib alone[(0.9±0.1) vs (1.8±0.0), P<0.05]. The combination of lapatinib and chlorogenic acid significantly reduced metastatic nodes in lung[P<0.05], and also significantly decreased the percentage of CD206+ cells in breast cancer compared to controls[(6.08%±2.60%) vs(29.04%±5.86%), P<0.05]. Conclusion:The combination of lapatinib and chlorogenic acid can effectively inhibit macrophage M2 polarization and metastasis of breast cancer.
Key words： Breast neoplasms/drug therapy    Neoplasm metastasis    Deoxycytidine/analogs &    derivatives    Deoxycytidine/therapeutic use    Antineoplastic drugs(TCD)/therapeutic use    Chlorogenic acid/therapeutic use    Macrophages    Interleukin-13
收稿日期: 2015-05-15
CLC:  R965  
基金资助:

浙江省自然科学基金(LY14H310008);浙江省教育厅科研项目(Y201226213)
通讯作者: 丁玲(1981-),女,博士,副教授,主要从事肿瘤药理学研究;E-mail:ld362@zju.edu.cn;金露(1978-),女,硕士,主治医师,主要从事神经病理学研究;E-mail:wzjinlu@126.com     E-mail: ld362@zju.edu.cn;wzjinlu@126.com
作者简介: 张洁琼(1991-),女,硕士研究生,主要从事肿瘤药理学研究;E-mail:zhangjq0425@zju.edu.cn;http://orcid.org/0000-0002-2807-5173
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引用本文:

张洁琼等. 拉帕替尼与绿原酸联合应用抑制巨噬细胞M2型极化及抗乳腺癌转移的作用研究[J]. 浙江大学学报（医学版）, 2015, 44(5): 493-499.
ZHANG Jie-qiong, YAO Zhang-ting, LIANG Gui-kai, CHEN Xi, WU Hong-hai, JIN Lu, DING Ling. Combination of lapatinib with chlorogenic acid inhibits breast cancer metastasis by suppressing macrophage M2 polarization. Journal of ZheJiang University(Medical Science), 2015, 44(5): 493-499.

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http://www.zjujournals.com/xueshu/med/CN/10.3785/j.issn.1008-9292.2015.09.04      或      http://www.zjujournals.com/xueshu/med/CN/Y2015/V44/I5/493

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