新型蛋白酶体抑制剂YSY-01A对人胃癌MGC-803的作用及相关蛋白研究

doi:10.5246/jcps.2014.09.077

中国药学(英文版) ›› 2014, Vol. 23 ›› Issue (9): 601-609.DOI: 10.5246/jcps.2014.09.077

新型蛋白酶体抑制剂YSY-01A对人胃癌MGC-803的作用及相关蛋白研究

陈溢欣¹, 袁霞¹, 葛泽梅², 冉福香¹, 吴军¹, 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:2014-05-15 修回日期:2014-05-28 出版日期:2014-09-23 发布日期:2014-06-08
通讯作者: Tel.:86-10-82802467, 86-10-82801504
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 of compound YSY-01A, a novel proteasome inhibitor, on MGC-803 cells and its related mechanism

Yixin Chen¹, Xia Yuan¹, Zemei Ge², Fuxiang Ran¹, Jun Wu¹, 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:2014-05-15 Revised:2014-05-28 Online:2014-09-23 Published:2014-06-08
Contact: Tel.:86-10-82802467, 86-10-82801504
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YSY-01A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, 但是该化合物对人胃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YSY-01A对人胃癌细胞MGC-803的体外和体内作用, 并探讨可能的分子机制。体外研究表明, 化合物YSY-01A对人胃癌细胞MGC-803具有显著的增殖抑制作用; 体内研究表明, 化合物YSY-01A单用及与5-FU联用时均可以显著地抑制裸鼠MGC-803异种移植瘤的生长, 并且化合物YSY-01A与5-FU具有协同作用。分子机制研究证实, YSY-01A可以显著地抑制TNF-α和IFN诱导的NF-κB核转位, 显著地下调IKK-β、IL-1β、iNOS蛋白的表达和上调COX-2蛋白的表达。综上所述, 化合物YSY-01A具有较好的抗肿瘤作用, 其机制与NF-κB通路相关蛋白有关。

关键词: 蛋白酶体抑制剂, YSY-01A, MGC-803, NF-κB, 抗肿瘤

Abstract:

As a novel proteasome inhibitor, remarkable proliferation inhibitory effect of compound YSY-01A was shownon tumor cells in previous studies. However, few studies has reported its effect on gastric cancer and related mechanism. We evaluated the anti-proliferative effect of compound YSY-01A using MGC-803 cells and its anti-tumor effect using xenograft nu-BALB/c mouse model. Cell proliferation inhibition was assessed by SRB assay. Related protein expression levels were determined by Western blot assay. We observed that the compound YSY-01A had a significant proliferation inhibitory effect on MGC-803 cells in vitro. Experiment in vivo showed that the compound YSY-01A had a remarkable growth inhibitory effect on MGC-803 cells xenograft tumor when it was used either alone or in combination with the conventional chemotherapeutic agent5-fluorouracil (5-FU). Furthermore, YSY-01A and 5-FU had a synergistic effect on xenograft tumor. Results of molecular experiment showed that the compound YSY-01A had a remarkable inhibitory effect on TNF-α and IFN induced NF-κB nuclear translocation. At the same time, the compound YSY-01A could reduce the expression of IKK-β, IL-1β and iNOS, while it significantly enhanced the expression of COX-2 in MGC-803 cells. Taken together, compound YSY-01A had an impressive tumor inhibitory effect, and it worked in NF-κB-related pathway, suggesting that the compound YSY-01A was an effective therapeutic drug for patients with gastric cancer. Higher tumor cell growth inhibition after the treatment in a combination with 5-FU indicated that combining YSY-01A with 5-FU might be more effective for displaying tumor cell growth inhibitory effects on gastric cancer cells.

Key words: Proteasome inhibitor, YSY-01A, MGC-803 cell line, NF-κB, Anti-tumor

中图分类号:

R962

Supporting:

陈溢欣, 袁霞, 葛泽梅, 冉福香, 吴军, 李润涛, 崔景荣. 新型蛋白酶体抑制剂YSY-01A对人胃癌MGC-803的作用及相关蛋白研究[J]. 中国药学(英文版), 2014, 23(9): 601-609.

Yixin Chen, Xia Yuan, Zemei Ge, Fuxiang Ran, Jun Wu, Runtao Li, Jingrong Cui . Effects of compound YSY-01A, a novel proteasome inhibitor, on MGC-803 cells and its related mechanism[J]. Journal of Chinese Pharmaceutical Sciences, 2014, 23(9): 601-609.

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新型蛋白酶体抑制剂YSY-01A对人胃癌MGC-803的作用及相关蛋白研究

Effects of compound YSY-01A, a novel proteasome inhibitor, on MGC-803 cells and its related mechanism

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