期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 707, 期 1-3, 页码 130-139出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2013.03.014
关键词
Curcumin analog; Thioredoxin reductase; Oxidative stress; Cisplatin-resistant A549 cells
资金
- National High-tech RD 863 Program [2008AA02Z304]
- National Nature Science Foundation of China [30973619, 81172931]
- Fundamental Research Funds for the Central Universities of China [09ykpy66]
(1E,4Z,6E)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(5-methylfuran-2-yl)hepta-1,4,6-trien-3-one (2a), a novel curcumin analog, was previously synthesized in our laboratory as a potential thioredoxin reductase (TrxR) inhibitor with excellent growth inhibitory effects on several TrxR over-expressed cancer cells. In this study, our further studies show that 2a is able to inhibit the growth of cisplatin-resistant A549 (A549/CDDP) cells much more effectively in a dose-dependent manner than that of A549 cells in antiproliferative activity experiments. Moreover, 2a-pretreated A549/CDDP cells are sensitive to cisplatin treatment, which is accompanied by the inhibition of TrxR activity in A549/CDDP cells. As a consequence of targeting TrxR, 2a in turn remarkably up-regulates intracellular reactive oxygen species level, depletes glutathione (GSH), and reduces the GSH/GSSG ratio, suggesting that the intracellular redox balance is shifted to a more oxidative state. Consequently, concomitant with the cell growth inhibition of 2a, apoptosis is induced by 2a probably through increased oxidative stress in A549/CDDP cells. In conclusion, these observations demonstrated that TrxR inhibitors would be promising drugs to achieve a successful combinatory or single cancer chemotherapy. (C) 2013 Elsevier BY. All rights reserved.
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