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RETRACTED ARTICLE: The Noncytotoxic Dose of Sorafenib Sensitizes Bel-7402/5-FU Cells to 5-FU by Down-Regulating 5-FU-Induced Nrf2 Expression

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This article was retracted on 04 August 2023

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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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Acknowledgments

This work was supported by Chinese National Natural Science Foundation Projects (NSFC 81072053 and 81171397).

Conflict of interest

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Authors and Affiliations

  1. Department of Thoracic Oncology, First Affiliated Hospital of Medical School, Xi’an Jiaotong University, Yanta West Road No. 277, Shaanxi, 710061, China

    Suna Zhou & Jiansheng Wang

  2. Department of Radiotherapy, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China

    Suna Zhou

  3. Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China

    Wenguang Ye & Mingxin Zhang

  4. Department of Nuclear Medicine, First Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, China

    Xiaoyi Duan

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  1. Suna Zhou
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  2. Wenguang Ye
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  4. Mingxin Zhang
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  5. Jiansheng Wang
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Zhou, S., Ye, W., Duan, X. et al. RETRACTED ARTICLE: The Noncytotoxic Dose of Sorafenib Sensitizes Bel-7402/5-FU Cells to 5-FU by Down-Regulating 5-FU-Induced Nrf2 Expression. Dig Dis Sci 58, 1615–1626 (2013). https://doi.org/10.1007/s10620-012-2537-1

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  • DOI: https://doi.org/10.1007/s10620-012-2537-1

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