title: Reversal of breast cancer resistance protein-mediated drug resistance by estrogen antagonists and agonists.
abstract: Breast cancer resistance protein (BCRP), an ATP-binding cassette transporter, confers resistance to a series of anticancer agents such as SN-38, mitoxantrone, and topotecan. In a previous study, we found that estrogens reverse drug resistance of BCRP-expressing cells. In this study, estrogen antagonists, estrogen agonists, and their derivatives were evaluated for BCRP-reversing activity. First, compounds were tested for effects on the cellular accumulation of topotecan in BCRP-transduced K562 cells (K562/BCRP). Next, these compounds were examined for their ability to reverse SN-38 and mitoxantrone resistance in K562/BCRP cells. Among commercially available estrogen antagonists and agonists tested, diethylstilbestrol showed the strongest BCRP-reversing activity. Diethylstilbestrol increased the cellular accumulation of topotecan and reversed drug resistance in K562/BCRP cells but showed marginal or no effect in parental K562 cells. The reversal activities of estrone and diethylstilbestrol were more prominent for mitoxantrone than for SN-38. Tamoxifen and toremifene were also found to enhance topotecan uptake in K562/BCRP cells. Next, various tamoxifen derivatives were screened for anti-BCRP activity. In the first cycle of screening with 14 compounds, TAG-11 showed the strongest effect. In the second cycle of screening of 25 TAG-11-related compounds, TAG-139 showed the strongest effect. Reversal of SN-38 and mitoxantrone resistance in K562/BCRP cells by TAG-139 was 5-fold stronger than that by estrone. Dose-dependent characteristics of drug resistance reversal with estrone and TAG-139 were very similar, suggesting that estrone and tamoxifen derivatives interact with the same drug-binding site of BCRP. Derivatives of antiestrogens that exhibit no other biological effects promise to be useful in overcoming BCRP-mediated drug resistance.
authors.affiliation: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 170-8455, USA. ysugimoto@jfcr.or.jp
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Satomi
authors.initials: S
authors.lastname: Tsukahara
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Imai
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Kazumitsu
authors.initials: K
authors.lastname: Ueda
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsuruo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D001943:Breast Neoplasms; D002470:Cell Survival / Q000187:drug effects; D004054:Diethylstilbestrol / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004965:Estrogen Antagonists / Q000633:toxicity*; D004967:Estrogens / Q000494:pharmacology*; D004970:Estrone / Q000494:pharmacology; D005260:Female; D006801:Humans; D020014:K562 Cells; D007700:Kinetics; D008942:Mitoxantrone / Q000493:pharmacokinetics / Q000633:toxicity; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins; D013629:Tamoxifen / Q000494:pharmacology; D019772:Topotecan / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D004054:Diethylstilbestrol; D004965:Estrogen Antagonists; D004967:Estrogens; D004970:Estrone; D008942:Mitoxantrone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D013629:Tamoxifen; D019772:Topotecan; C116614:ABCG2 protein, human; C421109:multidrug resistance-associated protein 1