药学学报, 2016, 51(10): 1551-1557
引用本文:
南希艳, 武芸, 张礼和, 杨振军. 联合mTOR1/2抑制剂AZD8055和MEK1/2抑制剂PD0325901抑制三阴乳腺癌细胞研究[J]. 药学学报, 2016, 51(10): 1551-1557.
NAN Xi-yan, WU Yun, ZHANG Li-he, YANG Zhen-jun. Treatment of triple negative breast cancer cells with combination of mTOR1/2 inhibitor AZD8055 and MEK1/2 inhibitor PD0325901[J]. Acta Pharmaceutica Sinica, 2016, 51(10): 1551-1557.

联合mTOR1/2抑制剂AZD8055和MEK1/2抑制剂PD0325901抑制三阴乳腺癌细胞研究
南希艳, 武芸, 张礼和, 杨振军
北京大学药学院天然药物及仿生药物国家重点实验室, 北京 100191
摘要:
MEK1/2抑制剂在作用于三阴乳腺癌(TNBC)细胞时,会负反馈引起PI3K/AKT/mTOR信号通路的激活。对于PI3K抑制剂不敏感的TNBC细胞,无法选择PI3K抑制剂和MEK1/2抑制剂联合。本研究选择联合mTOR1/2抑制剂(AZD8055)和MEK1/2抑制剂(PD0325901)作用于TNBC细胞。在MDA-MB-435细胞中,AZD8055可以抑制由PD0325901导致的PI3K通路的负反馈激活,从而完全抑制MDA-MB-435细胞中ERK1/2通路和PI3K通路的活性。DNA复制实验与细胞增殖抑制结果证明二者具有协同抑制细胞增殖的作用,细胞周期实验证明二者联合后协同引起细胞周期中的G1期阻滞。
关键词:    三阴乳腺癌      mTOR1/2抑制剂      MEK1/2抑制剂      联合抑制     
Treatment of triple negative breast cancer cells with combination of mTOR1/2 inhibitor AZD8055 and MEK1/2 inhibitor PD0325901
NAN Xi-yan, WU Yun, ZHANG Li-he, YANG Zhen-jun
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
Abstract:
MEK inhibition activates PI3K/AKT/mTOR pathway in triple negative breast cancer (TNBC) cell lines. Combination of PI3K inhibitor and MEK1/2 inhibitor is not appropriate for PI3K inhibitor insensitive TNBC cell lines. This study was designed to investigate the effects of dual treatments with mTOR1/2 inhibitor AZD8055 and MEK1/2 inhibitor PD0325901 in MDA-MB-435 cell line. MEK1/2 inhibition led to activation of AKT, which is the downstream signaling protein of PI3K pathway. The combination inhibited the phosphorylation of AKT and therefore abolished the feedback interaction of two pathways. Cell proliferation assay and DNA replication assay demonstrated that the dual treatments led to a significant synergistic inhibition of cell cycle progression and cell proliferation.
Key words:    triple negative breast cancer    mTOR1/2 inhibitor    MEK1/2 inhibitor    dual combination   
收稿日期: 2016-05-11
DOI: 10.16438/j.0513-4870.2016-0456
基金项目: 教育部高等学校博士学科点专项科研基金资助项目(20120001120023);国家自然科学基金青年科学基金资助项目(81302626).
通讯作者: 武芸
Email: wuyun_sioc@hotmail.com
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