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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• 作者：Suna Zhou (1) (2)
  Wenguang Ye (3)
  Xiaoyi Duan (4)
  Mingxin Zhang (3)
  Jiansheng Wang (1)
  
• 关键词：HCC ; Sorafenib ; Nrf2 ; Drug resistance ; Reversal effect
• 刊名：Digestive Diseases and Sciences
• 出版年：2013
• 出版时间：June 2013
• 年：2013
• 卷：58
• 期：6
• 页码：1615-1626
• 全文大小：1302KB
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• 作者单位：Suna Zhou (1) (2)
  Wenguang Ye (3)
  Xiaoyi Duan (4)
  Mingxin Zhang (3)
  Jiansheng Wang (1)
  
  1. Department of Thoracic Oncology, First Affiliated Hospital of Medical School, Xi鈥檃n Jiaotong University, Yanta West Road No. 277, Shaanxi, 710061, China
  2. Department of Radiotherapy, Tangdu Hospital, Fourth Military Medical University, Xi鈥檃n, Shaanxi, China
  3. Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi鈥檃n, Shaanxi, China
  4. Department of Nuclear Medicine, First Affiliated Hospital of Medical School, Xi鈥檃n Jiaotong University, Xi鈥檃n, Shaanxi, China
  
• ISSN：1573-2568

文摘

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.