蛋白酶体抑制剂YSY01-A对非小细胞肺癌的作用机制及其与顺铂联用作用的研究

doi:10.5246/jcps.2015.09.077

中国药学(英文版) ›› 2015, Vol. 24 ›› Issue (9): 607-616.DOI: 10.5246/jcps.2015.09.077

蛋白酶体抑制剂YSY01-A对非小细胞肺癌的作用机制及其与顺铂联用作用的研究

孙婷¹, 袁霞¹, 黄薇¹, 郭维¹, 葛泽梅², 李润涛^2*, 崔景荣^1*

1. 北京大学医学部天然药物及仿生药物国家重点实验室, 北京 100191
2. 北京大学医学部药学院化学生物学系, 北京 100191

收稿日期:2015-05-17 修回日期:2015-06-28 出版日期:2015-09-18 发布日期:2015-07-12
通讯作者: Tel.: 86-10-82802467, 86-10-82801504, E-mail: jrcui@bjmu.edu.cn, lirt@bjmu.edu.cn
基金资助:
Eleventh Five-Year Plan for National Science and Technology Major Project (Grant No. 2009ZX0930010), National Science Foundation of China (Grant No. 81172915) and a grant from Major New Drug Research and Development Platform of Peking University (Grant No. 2009ZX09301010).

Effects and mechanism of proteasome inhibitor YSY01-A alone or in combination with cisplatin against A549 cells in vitro

Ting Sun¹, Xia Yuan¹, Wei Huang¹, Wei Guo¹, Zemei Ge², Runtao Li^2*, Jingrong Cui^1*

1. State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China
2. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2015-05-17 Revised:2015-06-28 Online:2015-09-18 Published:2015-07-12
Contact: Tel.: 86-10-82802467, 86-10-82801504, E-mail: jrcui@bjmu.edu.cn, lirt@bjmu.edu.cn
Supported by:
Eleventh Five-Year Plan for National Science and Technology Major Project (Grant No. 2009ZX0930010), National Science Foundation of China (Grant No. 81172915) and a grant from Major New Drug Research and Development Platform of Peking University (Grant No. 2009ZX09301010).

摘要/Abstract

摘要：

化合物YSY01-A是一种新型蛋白酶体抑制剂, 前期研究已初步证实其具有显著的抗肿瘤作用, 但是该化合物对人非小细胞肺癌细胞的作用及相关机制研究尚不明确。本实验旨在评价化合物YSY01-A单用及其与顺铂联用时, 对非小细胞肺癌细胞A549的体外作用, 并探讨可能的分子机制。研究表明, 化合物YSY01-A对A549细胞具有显著的增殖抑制作用, 且与顺铂联用后显示出较强的协同作用。分子机制研究表明, 化合物YSY01-A能使PI3K表达下降, Akt的磷酸化水平降低, 显著增加通路负性调节蛋白PTEN的表达。与顺铂联用后, 化合物YSY01-A能显著提高细胞内的铂蓄积量, 并上调CTR1蛋白的表达。综上所述, 化合物YSY01-A具有较好的治疗非小细胞肺癌临床前景, 并且可与顺铂联用增加抗肿瘤疗效。

关键词: 蛋白酶体抑制剂, A549, 顺铂联用, PTEN, CTR1, 抗肿瘤

Abstract:

YSY01-A, as a novel proteasome inhibitor, has shown remarkable proliferation inhibitory effect on certain types of tumor cells. However, few studies have reported its effect on non-small cell lung cancer (NSCLC), and its underlying mechanism remains unknown. In our present study, we aimed to figure out the inhibitory effects as well as the mechanism of proteasome inhibitor YSY01-A against A549 cells both individually and in combination with cisplatin. A549 cell proliferation inhibition was assessed by SRB assay. Its related protein expression levels were determined by western blot assay. Moreover, the change of intracellular cisplatin accumulation was examined by ICP-MS assay. The results suggested that YSY01-A significantly (P<0.001) inhibited the proliferation of A549 cells (IC₅₀ was 36.2 nM for 72 h) in a concentration-dependent and time-dependent manner. Compared with the negative control group, YSY01-A (60 nM, 48 h) down-regulated PI3K/Akt pathway in A549 cells by increasing the expression level of PTEN (P<0.01), and decreasing the expression level of PI3K (P<0.001) and p-Akt/Akt (P<0.001). When combined with cisplatin, YSY01-A of different concentrations (5, 10, 20 nM) could significantly increase the inhibition effects on A549 cells compared with the cisplatin alone treatment, showing a synergistic effect. At the same time, YSY01-A could remarkably block the cisplatin-induced down-regulation of hCTR1 in a concentration-dependent manner and increase cisplatin uptake from 2.01 to 2.47 fold (P<0.001). In conclusion, compound YSY01-A could significantly inhibit proliferation of NSCLC A549 cells, showing a strong synergistic effect when combined with cisplatin. Down-regulation of PI3K/Akt pathway might be the mechanism of inhibitory effect of YSY01-A, and the combination with cisplatin might increase the expression of CTR1 and intracellular cisplatin accumulation.

Key words: Proteasome inhibitor, A549, Cisplatin combination, PTEN, CTR1, Antitumor

中图分类号:

R962

Supporting:

孙婷, 袁霞, 黄薇, 郭维, 葛泽梅, 李润涛, 崔景荣. 蛋白酶体抑制剂YSY01-A对非小细胞肺癌的作用机制及其与顺铂联用作用的研究[J]. 中国药学(英文版), 2015, 24(9): 607-616.

Ting Sun, Xia Yuan, Wei Huang, Wei Guo, Zemei Ge, Runtao Li, Jingrong Cui . Effects and mechanism of proteasome inhibitor YSY01-A alone or in combination with cisplatin against A549 cells in vitro[J]. Journal of Chinese Pharmaceutical Sciences, 2015, 24(9): 607-616.

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蛋白酶体抑制剂YSY01-A对非小细胞肺癌的作用机制及其与顺铂联用作用的研究

Effects and mechanism of proteasome inhibitor YSY01-A alone or in combination with cisplatin against A549 cells in vitro

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