Original ContributionLuteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs
Section snippets
Chemicals and cell culture
Unless otherwise stated, all chemicals were from Sigma–Aldrich Co., Ltd. (Shanghai, China), and all antibodies were from Santa Cruz Biotechnology (Shanghai, China). Antibody against actin was from Sigma. Antiserum against aldoketo reductases 1C1 and C2 (AKR1C) or KEAP1 was provided by Professor John Hayes and Dr. Mike McMahon (University of Dundee, Dundee, UK) [19], [20].
MCF7 (human breast carcinoma), Caco2 (human colon cancer), and A549 (NSCLC) cell lines were obtained from the ATCC. AREc32,
Luteolin is an inhibitor of ARE-driven gene expression
Previously we reported a stable cell line, AREc32, which carries a luciferase reporter gene under the control of the ARE [21]. Both the basal and the inducible ARE-luciferase activities in these cells are primarily regulated by Nrf2 [21]. Therefore, this cell line provides an ideal cell-based assay to screen for antagonists of Nrf2. Twelve common flavonoids were screened (Table 1). The bioavailability of flavonoids is expected to be relatively low and they have been detected in human plasma in
Discussion
Drug resistance during chemotherapy is the major obstacle to successful treatment of many cancers. It has long been recognized that GSH homeostasis, which is critically regulated by Nrf2, plays an important role in cancer treatment. Elevated GSH levels, typically associated with higher levels of GSH-related enzymes and drug transporters, have been reported in many types of tumor [37], [38]. The involvement of Nrf2 in chemoresistance was further highlighted by recent evidence that frequent
Acknowledgments
We thank Professor C. Roland Wolf (University of Dundee, UK) for the generous gift of plasmid pRS-hNrf2. We also thank Professor John D. Hayes and Dr. Mike McMahon (both at the University of Dundee), for providing antiserum against AKR1C or KEAP1, and Dr. R. Rice (University of California, Davis, CA, USA) for the provision of plasmid pGL3-RARE. We are grateful to Professor I.C. Bruce (Zhejiang University School of Medicine) for critically reading the manuscript. This work was supported by the
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