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

• Type of Material: Article
• Authors: Feng Chen, China Medical University; Huihui Wang, China Medical University; Jiayu Zhu, China Medical University; Rui Zhao, China Medical University; Peng Xue, Fudan University; Qiang Zhang, Emory University; M Bud Nelson, MedBlue Incubator Inc; Weidong Qu, Fudan University; Bo Feng, China Medical University; Jingbo Pi, China Medical University
• Language: English
• Date: 2017-11-07
• Publisher: Springer Nature [academic journals on nature.com]: Hybrid Journals
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) named above.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/bjc.2017.317
• Title of Journal or Parent Work: British Journal of Cancer
• ISSN: 0007-0920
• Volume: 117
• Issue: 10
• Start Page: 1495
• End Page: 1506
• Grant/Funding Information: This research was supported in part by National Natural Science Foundation of China 81502841 (to HW) and 81573106 (to JP), the Startup Funding of China Medical University (to JP), Liaoning Pandeng Scholar (to JP) and Program for Liaoning Innovative Research Team in University (LT2015028). The content is solely the responsibility of the authors. All authors have agreed to its content.
• Keywords: INDUCED ANTIOXIDANT RESPONSE; NRF2; KEAP1; OXIDATIVE STRESS; Oncology; chemosensitivity; Life Sciences & Biomedicine; camptothecin; TRANSCRIPTION FACTOR NRF2; Science & Technology; hepatocellular carcinoma; RESISTANCE; DUAL ROLES; ARE; HUMAN KERATINOCYTES; LUNG-CANCER; ADAPTIVE RESPONSE; LEUKEMIA-CELLS
• Research Categories: Health Sciences, Oncology

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.