Purpose: ATP-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-related protein 1 (MRP1), confer resistance to various anticancer agents. We previously reported that some flavonoids have BCRP-inhibitory activity. Here we show the reversal effects of an extensive panel of flavonoids upon BCRP-, P-gp-, and MRP1-mediated drug resistance. Methods: Reversal effects of flavonoids upon BCRP-, P-gp-, or MRP1-mediated drug resistance were examined in the BCRP- or MDR1-transduced human leukemia K562 cells or in the MRP1-transfected human epidermoid carcinoma KB-3-1 cells using cell growth inhibition assays. The IC50 values were determined from the growth inhibition curves. The RI50 values were then determined as the concentration of inhibitor that causes a twofold reduction of the IC 50 in each transfectant. The reversal of BCRP activity was tested by measuring the fluorescence of intracellular topotecan. Results: The BCRP-inhibitory activity of 32 compounds was screened, and 20 were found to be active. Among these active compounds, 3′,4′,7-trimethoxyflavone showed the strongest anti-BCRP activity with RI50 values of 0.012 μM for SN-38 and 0.044 μM for mitoxantrone. We next examined the effects of a panel of 11 compounds on P-gp- and MRP1-mediated drug resistance. Two of the flavones, 3′,4′,7-trimethoxyflavone and acacetin, showed only low anti-P-gp activity, with the remainder displaying no suppressive effects against P-gp. None of the flavonoids that we tested inhibited MRP1. Conclusion: Our present results thus indicate that many flavonoids selectively inhibit BCRP only. Moreover, we examined the structure-BCRP inhibitory activity relationship from our current study.
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