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    已发表论文

    乌心石内酯 (Micheliolide) 顺利获得谷胱甘肽 (glutathione) 下调克服在 KLF4 调节下所产生的乳腺癌细胞的顺铂 (cisplatin) 耐药性

     

    Authors Jia Y, Zhang C, Zhou L, Xu H, Shi Y, Tong Z
    Received 15 May 2015
    Accepted for publication 30 July 2015
    Published 28 August 2015 Volume 2015:8 Pages 2319—2327
    DOI http://dx.doi.org/10.2147/OTT.S88661
    Checked for plagiarism Yes
    Review by Single-blind
    Peer reviewers approved by Dr Jia Fan
    Peer reviewer comments 3
    Editor who approved publication:  Dr Faris Farassati


    Abstract: Micheliolide (MCL) is a promising novel compound with broad-spectrum anticancer activity. However, little is known regarding its action and mechanism in breast cancer. To explore the potential therapeutic application of MCL as a chemosensitivity modulator, this study investigated the effects of MCL on cisplatin sensitivity in breast cancer and the underlying mechanisms. In the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cytotoxicity assay and a xenograft tumor model, MCL enhanced the cisplatin sensitivity of the breast cancer cell line MCF-7 both in vitro and in vivo. Treatment of MCF-7 cells with low-dose cisplatin (10 µM) was sufficient to enrich the proportion of ALDH+ cells and upregulate Krüppel-like factor 4 (KLF4) expression. The results obtained from knockdown and overexpression experiments demonstrate that KLF4 is both necessary and sufficient to induce a cisplatin resistance phenotype in breast cancer cells. Furthermore, the glutathione (GSH) content was elevated in MCF-7 cells after overexpression of KLF4. KLF4-mediated resistance to cisplatin was found to be abrogated by treatment with buthionine sulfoximine, an inhibitor of GSH synthesis. MCL induced GSH depletion and severe cell death in KLF4-overexpressing MCF-7 cells following exposure to cisplatin. Therefore, these results suggest that MCL-mediated direct depletion of GSH represents a major mechanism in reversing KLF4-induced cisplatin resistance in MCF-7 cells.
    Keywords: KLF4, cisplatin resistance, glutathione, breast cancer, Micheliolide




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