Flavonoids inhibit breast cancer resistance protein-mediated drug resistance: transporter specificity and structure-activity relationship.
OBJECTIVE
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 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.


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 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.


CONCLUSIONS
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.
Katayama
Kazuhiro
K
Department of Chemotherapy, Kyoritsu University of Pharmacy, Tokyo, 105-8512, Japan.
Masuyama
Kazuto
K
Yoshioka
Sho
S
Hasegawa
Hitomi
H
Mitsuhashi
Junko
J
Sugimoto
Yoshikazu
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics; D001692:Biological Transport; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D047309:Flavones / Q000008:administration & dosage / Q000494:pharmacology; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D019772:Topotecan / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D018931:Antineoplastic Agents, Hormonal; D047309:Flavones; D005419:Flavonoids; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D019772:Topotecan; C524117:3',4',7-trimethoxyflavone; C116614:ABCG2 protein, human; C023717:acacetin; C421109:multidrug resistance-associated protein 1