Camptothecin suppresses NRF2-ARE activity and sensitises hepatocellular carcinoma cells to anticancer drugs.
Camptothecin suppresses NRF2-ARE activity and sensitises hepatocellular carcinoma cells to anticancer drugs.
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喜树碱抑制 NRF2-ARE 活性并使肝细胞癌细胞对抗癌药物敏感
DOI：
10.1038/bjc.2017.317
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发表时间：
2017-11-07
影响因子：
8.8
通讯作者：
Pi J
中科院分区：
文献类型：
--
作者：
Chen F;Wang H;Zhu J;Zhao R;Xue P;Zhang Q;Bud Nelson M;Qu W;Feng B;Pi J
化疗耐药是肝细胞癌（HCC）治疗的主要障碍。尽管在化学预防中发挥重要作用，但核因子红细胞2相关因子2（NRF 2）也有助于化学和放射抗性。目前的研究集中在喜树碱作为一种新的NRF 2抑制剂，使肝癌对化疗敏感。采用免疫组化、Western blot、RT-qPCR和荧光素酶报告基因检测方法检测NRF 2在人肝癌组织和喜树碱处理的培养细胞中的表达和转录活性。在体外和异种移植物中评估喜树碱对癌细胞的化疗敏感性的影响。与相应的癌旁组织相比，NRF 2在HCC活检组织中的表达和转录活性显著升高，并且与血清甲胎蛋白（病理进展的临床指标）呈正相关。在寻找靶向NRF 2的化学物质用于化疗时，我们发现喜树碱是一种有效的NRF 2抑制剂。喜树碱显著抑制不同类型的癌细胞包括HepG 2、SMMC-7721和A549中的NRF 2表达和转录活性。结果，喜树碱在体外和异种移植物中使这些细胞对化疗药物敏感。喜树碱是一种新型NRF 2抑制剂，可与其他化疗药物联合使用，以增强其治疗高NRF 2表达癌症的疗效。
Resistance to chemotherapy is a major obstacle in the treatment of human hepatocellular carcinoma (HCC). Despite playing an important role in chemoprevention, nuclear factor erythroid 2-related factor 2 (NRF2) also contributes to chemo- and radio-resistance. The current study focusses on camptothecin as a novel NRF2 inhibitor to sensitise HCC to chemotherapy. The expression and transcriptional activity of NRF2 in human HCC biopsies and camptothecin-treated culture cells were determined using immunostaining, western blot, reverse-transcription quantitative real-time PCR (RT–qPCR) and luciferase reporter assay. The effect of camptothecin on chemosensitivity of cancer cells was assessed in vitro and in xenografts. The expression and transcriptional activity of NRF2 were substantially elevated in HCC biopsies compared with corresponding adjacent tissues, and positively correlated with serum α-fetoprotein, a clinical indicator of pathological progression. In searching chemicals targeting NRF2 for chemotherapy, we discovered that camptothecin is a potent NRF2 inhibitor. Camptothecin markedly suppressed NRF2 expression and transcriptional activity in different types of cancer cells including HepG2, SMMC-7721 and A549. As a result, camptothecin sensitised these cells to chemotherapeutic drugs in vitro and in xenografts. Camptothecin is a novel NRF2 inhibitor that may be repurposed in combination with other chemotherapeutics to enhance their efficacy in treating high NRF2-expressing cancers.
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影响因子：
29.4
作者：
El-Serag HB
通讯作者：
El-Serag HB
影响因子：
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作者：
Hu, Xiu-Feng;Yao, Jun;Feng, Xiao-Shan
通讯作者：
Feng, Xiao-Shan
影响因子：
5.1
作者：
Gao, Ai-Mei;Ke, Zun-Ping;Chen, Hui
通讯作者：
Chen, Hui
影响因子：
8
作者：
Chowdhry, S.;Zhang, Y.;McMahon, M.;Sutherland, C.;Cuadrado, A.;Hayes, J. D.
通讯作者：
Hayes, J. D.
影响因子：
7.4
作者：
Guo Y;Yu S;Zhang C;Kong AN
通讯作者：
Kong AN