喜树碱可抑制NRF2-ARE活性，并使肝癌细胞对抗癌药物敏感。

Camptothecin suppresses NRF2-ARE activity and sensitises hepatocellular carcinoma cells to anticancer drugs.

作者信息

Chen Feng, Wang Huihui, Zhu Jiayu, Zhao Rui, Xue Peng, Zhang Qiang, Bud Nelson M, Qu Weidong, Feng Bo, Pi Jingbo

机构信息

Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China.

Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Road, Heping Area, Shenyang 110001, China.

出版信息

Br J Cancer. 2017 Nov 7;117(10):1495-1506. doi: 10.1038/bjc.2017.317. Epub 2017 Sep 14.

DOI:10.1038/bjc.2017.317

PMID:28910823

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5680465/

Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

摘要

背景

化疗耐药是人类肝细胞癌（HCC）治疗中的主要障碍。核因子红细胞2相关因子2（NRF2）尽管在化学预防中发挥重要作用，但也会导致化疗和放疗耐药。本研究聚焦于喜树碱作为一种新型NRF2抑制剂，以使HCC对化疗敏感。

方法

采用免疫染色、蛋白质印迹法、逆转录定量实时PCR（RT-qPCR）和荧光素酶报告基因检测法，测定人HCC活检组织和经喜树碱处理的培养细胞中NRF2的表达和转录活性。在体外和异种移植模型中评估喜树碱对癌细胞化疗敏感性的影响。

结果

与相应的癌旁组织相比，HCC活检组织中NRF2的表达和转录活性显著升高，且与血清甲胎蛋白呈正相关，血清甲胎蛋白是病理进展的临床指标。在寻找靶向NRF2用于化疗的化学物质时，我们发现喜树碱是一种有效的NRF2抑制剂。喜树碱显著抑制包括HepG2、SMMC-7721和A549在内的不同类型癌细胞中NRF2的表达和转录活性。因此，喜树碱在体外和异种移植模型中使这些细胞对化疗药物敏感。