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NF-E2-related factor 2 (Nrf2) is a transcription factor and a pivotal factor in the induction of the cell defense system.Recent reports show that Nrf2 plays critical roles in tumor heterogeneity and drug resistance.In the present study we investigated whether and how Nrf2 mediated the resistance of human cancer ceils to boningmycin (BON),a new antitumor antibiotic of the bleomycin family.We showed that the expression levels of Nrf2 in human non-small lung cancer A549 cells were much higher than those in human hepatoblastoma HepG2 cells,and their resistance to BON was opposite to Nrf2 expression (the IC50values of BON in A549 cells and HepG2 cells were 5.97 and 0.61 μmol/L,respectively).Similar results were observed with the anticancer agent cisdiamminedichloroplatinum (DDP),which was used as a positive control.In A549 cells,Nrf2 mRNA knockdown significantly increased their susceptibilities to BON and DDP.An enhanced resistance to BON and DDP was observed in HepG2 cells after overexpression of the wild-type Nrf2 protein.Treatment with a specific Nrf2 inhibitor,luteolin,significantly sensitized A549 cells to BON and DDP and increased BON-or DDP-induced apoptosis.The total levels of glutathione (GSH),the final product of the Nrf2 signaling pathway,were much higher in A549 cells than those in HepG2 cells.Supplementation of GSH in HepG2 cells significantly decreased their susceptibility to BON and DDP,wheras depleting GSH with the specific inhibitor L-buthionine sulfoximine in A549 cells significantly increased their susceptibility to BON and DDP.Our results demonstrate that Nrf2 mediates the resistance to BON through regulating glutathione levels in A549 cells and HepG2 cells.