Reversal of breast cancer resistance protein-mediated drug resistance by estrogen antagonists and agonists.
Article Details
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Sugimoto Y, Tsukahara S, Imai Y, Sugimoto Y, Ueda K, Tsuruo T
Reversal of breast cancer resistance protein-mediated drug resistance by estrogen antagonists and agonists.
Mol Cancer Ther. 2003 Jan;2(1):105-12.
- PubMed ID
- 12533678 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Diethylstilbestrol ATP-binding cassette sub-family G member 2 Protein Humans UnknownInhibitorDetails Estrone ATP-binding cassette sub-family G member 2 Protein Humans UnknownInhibitorDetails Mitoxantrone ATP-binding cassette sub-family G member 2 Protein Humans UnknownSubstrateDetails Topotecan ATP-binding cassette sub-family G member 2 Protein Humans UnknownSubstrateDetails - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Diethylstilbestrol ATP-binding cassette sub-family G member 2 IC 50 (nM) 500 N/A N/A Details Diethylstilbestrol ATP-binding cassette sub-family G member 2 IC 50 (nM) >500 N/A N/A Details Estrone ATP-binding cassette sub-family G member 2 IC 50 (nM) 3000 N/A N/A Details Estrone ATP-binding cassette sub-family G member 2 IC 50 (nM) >10000 N/A N/A Details