Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo
Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo
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木犀草素抑制 Nrf2 信号通路和体内肿瘤生长
DOI：
10.1016/j.bbrc.2014.04.039
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发表时间：
2014-05-16
影响因子：
3.1
通讯作者：
Tang, Xiuwen
中科院分区：
文献类型：
--
作者：
Chian, Song;Thapa, Ruby;Tang, Xiuwen
核因子红系2相关因子2(Nrf2)在多种类型的肿瘤中过度表达，促进肿瘤生长，并对抗癌治疗产生抵抗。因此，Nrf2被认为是肿瘤治疗的新靶点。此前，我们曾报道木犀草素在体外对Nrf2有很强的抑制作用。在这里，我们发现木犀草素以时间和剂量依赖的方式降低了小鼠肝脏中NAD(P)H氧化还原酶1的结构性表达。此外，木犀草素抑制抗氧化酶和谷胱甘肽转移酶的表达，减少在结构性和丁基化羟基苯甲醚诱导的条件下野生型小鼠肝脏中还原的谷胱甘肽。相比之下，在Nrf2(-/-)小鼠中没有检测到这种明显的反应。此外，口服木犀草素，无论是单独或联合腹腔注射细胞毒药物顺铂，都能显著抑制裸鼠皮下生长的非小细胞肺癌(NSCLC)A549细胞移植瘤的生长。移植瘤组织中细胞增殖、Nrf2表达和抗氧化酶均降低。此外，木犀草素增强了顺铂的抗癌作用。综上所述，我们的研究结果表明，木犀草素在体内抑制了Nrf2途径，可以作为非小细胞肺癌化疗的辅助药物。(C)2014 Elsevier Inc.保留所有权利。
Nuclear factor erythroid 2-related factor 2 (Nrf2) is over-expressed in many types of tumor, promotes tumor growth, and confers resistance to anticancer therapy. Hence, Nrf2 is regarded as a novel therapeutic target in cancer. Previously, we reported that luteolin is a strong inhibitor of Nrf2 in vitro. Here, we showed that luteolin reduced the constitutive expression of NAD(P)H quinone oxidoreductase 1 in mouse liver in a time- and dose-dependent manner. Further, luteolin inhibited the expression of antioxidant enzymes and glutathione transferases, decreasing the reduced glutathione in the liver of wild-type mice under both constitutive and butylated hydroxyanisole-induced conditions. In contrast, such distinct responses were not detected in Nrf2(-/-) mice. In addition, oral administration of luteolin, either alone or combined with intraperitoneal injection of the cytotoxic drug cisplatin, greatly inhibited the growth of xenograft tumors from non-small-cell lung cancer (NSCLC) cell line A549 cells grown subcutaneously in athymic nude mice. Cell proliferation, the expression of Nrf2, and antioxidant enzymes were all reduced in tumor xenograft tissues. Furthermore, luteolin enhanced the anti-cancer effect of cisplatin. Together, our findings demonstrated that luteolin inhibits the Nrf2 pathway in vivo and can serve as an adjuvant in the chemotherapy of NSCLC. (C) 2014 Elsevier Inc. All rights reserved.