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.
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.
Authors: Peter Ferenci; Michael Fried; Douglas Labrecque; J Bruix; M Sherman; M Omata; J Heathcote; T Piratsivuth; Mike Kew; Jesse A Otegbayo; S S Zheng; S Sarin; S Hamid; Salma Barakat Modawi; Wolfgang Fleig; Suliman Fedail; Alan Thomson; Aamir Khan; Peter Malfertheiner; George Lau; F J Carillo; Justus Krabshuis; Anton Le Mair Journal: J Gastrointestin Liver Dis Date: 2010-09 Impact factor: 2.008
Authors: Guobin He; Guann-Yi Yu; Vladislav Temkin; Hisanobu Ogata; Christian Kuntzen; Toshiharu Sakurai; Wolfgang Sieghart; Markus Peck-Radosavljevic; Hyam L Leffert; Michael Karin Journal: Cancer Cell Date: 2010-03-16 Impact factor: 31.743
Authors: Scott M Wilhelm; Christopher Carter; Liya Tang; Dean Wilkie; Angela McNabola; Hong Rong; Charles Chen; Xiaomei Zhang; Patrick Vincent; Mark McHugh; Yichen Cao; Jaleel Shujath; Susan Gawlak; Deepa Eveleigh; Bruce Rowley; Li Liu; Lila Adnane; Mark Lynch; Daniel Auclair; Ian Taylor; Rich Gedrich; Andrei Voznesensky; Bernd Riedl; Leonard E Post; Gideon Bollag; Pamela A Trail Journal: Cancer Res Date: 2004-10-01 Impact factor: 13.312