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

doi:10.5246/jcps.2015.09.077

Abstract

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

CLC Number:

R962

Supporting:

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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