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 IC₅₀ 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.