Luteolin Sensitizes Two Oxaliplatin-Resistant Colorectal Cancer Cell Lines to Chemotherapeutic Drugs Via Inhibition of the Nrf2 Pathway
Luteolin Sensitizes Two Oxaliplatin-Resistant Colorectal Cancer Cell Lines to Chemotherapeutic Drugs Via Inhibition of the Nrf2 Pathway
复制标题
木犀草素通过抑制 Nrf2 通路使两种奥沙利铂耐药的结直肠癌细胞系对化疗药物敏感
DOI：
10.7314/apjcp.2014.15.6.2911
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发表时间：
2014-01-01
影响因子：
--
通讯作者：
Tang, Xiu-Wen
中科院分区：
文献类型：
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作者：
Chian, Song;Li, Yin-Yan;Tang, Xiu-Wen
奥沙利铂是结直肠癌的一线治疗药物，但癌细胞对该药物的耐药性会影响其疗效。为了探索耐药机制，我们用奥沙利铂长期处理结直肠癌细胞（HCT 116和SW 620），并建立稳定的奥沙利铂耐药细胞系（HCT 116-OX和SW 620-OX）。与亲本细胞系相比，奥沙利铂耐药细胞系中各种化疗药物（奥沙利铂、顺铂和多柔比星）的IC（50）增加，并伴有核因子红细胞-2 p45相关因子2（Nrf 2）和NADPH醌氧化还原酶1（NQO 1）的激活。此外，木犀草素抑制奥沙利铂耐药细胞系中的Nrf 2途径，呈剂量依赖性。木犀草素还抑制Nrf 2靶基因[NQO 1、血红素加氧酶-1（HO-1）和GST α 1/2]的表达，并降低野生型小鼠小肠细胞中的还原型谷胱甘肽。在Nrf 2-/-小鼠中没有明显作用。木犀草素与其他化疗药物组合在耐药细胞系中具有更大的抗癌活性（组合指数值低于1），表明协同效应。因此，Nrf 2的适应性激活可能有助于获得性耐药的发展，而毛地黄黄酮可以恢复奥沙利铂耐药细胞系对化疗药物的敏感性。Nrf 2通路的抑制可能是这种恢复的治疗反应的机制。
Oxaliplatin is a first-line therapy for colorectal cancer, but cancer cell resistance to the drug compromises its efficacy. To explore mechanisms of drug resistance, we treated colorectal cancer cells (HCT116 and SW620) long-term with oxaliplatin and established stable oxaliplatin-resistant lines (HCT116-OX and SW620-OX). Compared with parental cell lines, IC(50)s for various chemotherapeutic agents (oxaliplatin, cisplatin and doxorubicin) were increased in oxaliplatin-resistant cell lines and this was accompanied by activation of nuclear factor erythroid-2 p45-related factor 2 (Nrf2) and NADPH quinone oxidoreductase 1 (NQO1). Furthermore, luteolin inhibited the Nrf2 pathway in oxaliplatin-resistant cell lines in a dose-dependent manner. Luteolin also inhibited Nrf2 target gene [NQO1, heme oxygenase-1 (HO-1) and GST alpha 1/2] expression and decreased reduced glutathione in wild type mouse small intestinal cells. There was no apparent effect in Nrf2-/- mice. Luteolin combined with other chemotherapeutics had greater anti-cancer activity in resistant cell lines (combined index values below 1), indicating a synergistic effect. Therefore, adaptive activation of Nrf2 may contribute to the development of acquired drug-resistance and luteolin could restore sensitivity of oxaliplatin-resistant cell lines to chemotherapeutic drugs. Inhibition of the Nrf2 pathway may be the mechanism for this restored therapeutic response.