RETRACTED ARTICLE: The Noncytotoxic Dose of Sorafenib Sensitizes Bel-7402/5-FU Cells to 5-FU by Down-Regulating 5-FU-Induced Nrf2 Expression
Abstract
Background Acquired resistance to 5-fluorouracil (5-FU) is a serious therapeutic obstacle in advanced hepatocellular carcinoma (HCC) patients.Aim To investigate whether nuclear factor erythroid 2-related factor 2 (Nrf2) was associated with drug resistance in 5-FU resistant Bel-7402 (Bel-7402/5-FU) cells, and if sorafenib, an oral multikinase inhibitor targeting the tumor and vasculature, could reverse drug resistance in Bel-7402/5-FU cells at the noncytotoxic dosage.Methods We used MTT to detect the resistance reversal activity of sorafenib, compared Nrf2 expression in various conditions by western blot and qRT-PCR, and analyzed subcellular localization of Nrf2 by immunofluorescence.Results The endogenous expression of Nrf2 in Bel-7402/5-FU cells was similar to that observed in Bel-7402 cells. However, Nrf2 expression levels were increased by 5-FU treatment in Bel-7402/5-FU cells higher than that in Bel-7402 cells, which is to highlight the Nrf2 contribution to the enhanced resistance of Bel-7402/5-FU cells to 5-FU. Moreover, intracellular Nrf2 protein level was significantly down-regulated by Nrf2-shRNA in Bel-7402/5-FU cells, resulting in partial reversal of 5-FU resistance. Sorafenib down-regulated the increased expression of Nrf2 induced by 5-FU treatment and partly reversed 5-FU resistance in Bel-7402/5-FU cells.Conclusions These results suggested that more sensitive cell defense mediated by Nrf2 was associated with drug resistance of Bel-7402/5-FU cells. Sorafenib reversed drug resistance, and its reversal mechanism might be due to the suppression of Nrf2 expression induced by 5-FU, indicating the feasibility of using Nrf2 inhibitors to increase efficacy of chemotherapeutic drugs in HCC patients.
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Upregulation of Nrf2-mediated antioxidant proteins renders cancer cells resistant to chemotherapeutic drugs (e.g., cisplatin, 5-fluorouracil, docetaxel, and bortezomib) and radiotherapy.
“The resultant upregulation of Nrf2-mediated antioxidant proteins renders cancer cells resistant to chemotherapeutic drugs (e.g., cisplatin, 5-fluorouracil, docetaxel, and bortezomib) and radiotherapy [47,161,165,178,179,180,181,182,183,184].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [181]
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- Authors
- Zhou, S., Ye, W., Duan, X., Zhang, M., & Wang, J.
- Affiliations
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- Tang Du Hospital (CN)
- Corresponding author
- Wang, Jiansheng
- Venue
- Digestive Diseases and Sciences
- Published
- 2013-01-12
- Volume
- 58
- Issue
- 6
- Pages
- 1615-1626
- ISSN
- 0163-2116 (ISSN-L)
- 1573-2568
- OpenAlex
- W2000445643
- Cited by
- 18
- References
- 42
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 1 · 2013: 1
- FWCI
- 0.30
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- retraction (2023-08-04)
- Open access
- closed
- Licence
- Locations
- Digestive Diseases and Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- sorafenib, 5-fluorouracil, Nrf2, drug resistance reversal, hepatocellular carcinoma, BEL-7402 cells, Nrf2 inhibitors, chemosensitization
- MeSH terms
- Sorafenib, Antimetabolites, Antineoplastic, Antineoplastic Agents, Dose-Response Relationship, Drug, Fluorescent Antibody Technique, Fluorouracil, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Niacinamide, Phenylurea Compounds, Biomarkers, Tumor, Blotting, Western, Down-Regulation, Drug Resistance, Neoplasm, Reverse Transcriptase Polymerase Chain Reaction, ATP-Binding Cassette, Sub-Family C Proteins, Cell Line, Tumor, Protein Kinase Inhibitors, NF-E2-Related Factor 2
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