Journal of Chinese Pharmaceutical Sciences ›› 2015, Vol. 24 ›› Issue (9): 607-616.DOI: 10.5246/jcps.2015.09.077

• Original articles • Previous Articles     Next Articles

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 Li2*, Jingrong Cui1*   

  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
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  • 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).


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

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