acacetin and 3--4--7-trimethoxyflavone

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.. 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 IC(50) values were determined from the growth inhibition curves. The RI(50) 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.. 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 RI(50) values of 0.012 microM for SN-38 and 0.044 muM 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.. 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.

Topics: Antineoplastic Agents, Hormonal; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Biological Transport; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Flavones; Flavonoids; Humans; Inhibitory Concentration 50; K562 Cells; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Structure-Activity Relationship; Topotecan