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AIM Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor which regulates the expression of a battery of cytoprotective genes.In this study, we investigated whether Nrf2 was associated with drug resistant in doxorubicin resistant BEL7402 (BEL-7402/ADM) cells, and if apigenin (APG) could reverse drug resistance in BEL-7402/ADM ceils.METHODS Reverse of drug resistance was assayed by MTT and fluorometric analysis.Inhibition of Nrf2 signaling pathway by APG was detected through real-time quantitative PCR and Western blot analysis.RESULTS At physiological concentrations, APG significantly sensitized BEL-7402/ADM cells to doxorubicin, cisplatin, vincristine and 5-fluorouracil.However, knock-down of Nrf2 using siRNA essentially abolished the enhanced sensitivity by APG, implying the importance of inhibiting Nrf2 for its cytotoxic action.Moreover, APG increased intracellular drug concentration in a dose-dependent manner by inhibiting Nrf2 pathway.Mechanistically, APG dramaticly reduced Nrf2 expression at both the mRNA and protein levels through down-regulating PI3K-AKT pathway.Consequently,expression of Nrf2-downstream genes HO-1, AKR1B10, and MRP5 was reduced.CONCLUSION APG can reverse drug resistance via inhibiting PI3K-AKT/Nrf2/ARE pathway, indicating the effectiveness of using APG as a adjuvant sensitizer to combat chemoresistance.