Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, People's Republic of China.
Department of Colorectal Surgery, Tianjin Union Medicine Center, Tianjin, People's Republic of China.
Onco Targets Ther. 2015 Aug 28;8:2319-27. doi: 10.2147/OTT.S88661. eCollection 2015.
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.
米可利醇（MCL）是一种具有广谱抗癌活性的新型化合物。然而，关于其在乳腺癌中的作用和机制知之甚少。为了探讨 MCL 作为化疗增敏剂的潜在治疗应用，本研究探讨了 MCL 对乳腺癌中顺铂敏感性的影响及其潜在机制。在 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴化物细胞毒性测定和异种移植肿瘤模型中，MCL 增强了 MCF-7 乳腺癌细胞系在体外和体内对顺铂的敏感性。用低剂量顺铂（10 µM）处理 MCF-7 细胞足以富集 ALDH(+)细胞的比例，并上调 Krüppel-like factor 4 (KLF4)表达。敲低和过表达实验的结果表明，KLF4 是诱导乳腺癌细胞产生顺铂耐药表型所必需和充分的。此外，KLF4 过表达后 MCF-7 细胞中的谷胱甘肽 (GSH)含量升高。用 GSH 合成抑制剂丁硫氨酸亚砜胺处理可消除 KLF4 介导的对顺铂的耐药性。MCL 在顺铂处理后诱导 KLF4 过表达的 MCF-7 细胞中 GSH 耗竭和严重细胞死亡。因此，这些结果表明，MCL 介导的 GSH 直接耗竭代表了逆转 MCF-7 细胞中 KLF4 诱导的顺铂耐药的主要机制。
