Journal article
Camptothecin suppresses NRF2-ARE activity and sensitises hepatocellular carcinoma cells to anticancer drugs
British journal of cancer, Vol.117(10), pp.1495-1506
11/07/2017
DOI: 10.1038/bjc.2017.317
PMCID: PMC5680465
PMID: 28910823
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 a-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.
Details
- Title: Subtitle
- Camptothecin suppresses NRF2-ARE activity and sensitises hepatocellular carcinoma cells to anticancer drugs
- Creators
- Feng Chen - Shandong Provincial QianFoShan HospitalHuihui Wang - China Medical UniversityJiayu Zhu - China Medical UniversityRui Zhao - China Medical UniversityPeng Xue - Key Laboratory of Public Health Safety of Ministry of Education, School of Public Health, Fudan University, P.O. Box 249, 138 Yi Xue Yuan Road, Shanghai 200032, China.Qiang Zhang - Emory UniversityM. Bud Nelson - Research Triangle Park FoundationWeidong Qu - Key Laboratory of Public Health Safety of Ministry of Education, School of Public Health, Fudan University, P.O. Box 249, 138 Yi Xue Yuan Road, Shanghai 200032, China.Bo Feng - China Medical UniversityJingbo Pi - China Medical University
- Resource Type
- Journal article
- Publication Details
- British journal of cancer, Vol.117(10), pp.1495-1506
- DOI
- 10.1038/bjc.2017.317
- PMID
- 28910823
- PMCID
- PMC5680465
- NLM abbreviation
- Br J Cancer
- ISSN
- 0007-0920
- eISSN
- 1532-1827
- Publisher
- Springer Nature
- Number of pages
- 12
- Grant note
- 81502841; 81573106 / National Natural Science Foundation of China; National Natural Science Foundation of China (NSFC) Liaoning Pandeng Scholar LT2015028 / Program for Liaoning Innovative Research Team in University Startup Funding of China Medical University
- Language
- English
- Date published
- 11/07/2017
- Academic Unit
- Neurology
- Record Identifier
- 9984303011802771
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