Reversal of breast cancer resistance protein-mediated drug resistance by estrogen antagonists and agonists

Yoshikazu Sugimoto, Satomi Tsukahara, Yasuo Imai, Yoshikazu Sugimoto, Kazumitsu Ueda, Takashi Tsuruo

Research output: Contribution to journalArticle

105 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)105-112
Number of pages8
JournalMolecular Cancer Therapeutics
Volume2
Issue number1
Publication statusPublished - 2003 Jan
Externally publishedYes

Fingerprint

Estrogen Antagonists
Drug Resistance
irinotecan
Breast Neoplasms
Topotecan
Proteins
Mitoxantrone
Estrone
Diethylstilbestrol
Tamoxifen
K562 Cells
Estrogens
Toremifene
Estrogen Receptor Modulators
ATP-Binding Cassette Transporters
Protein Binding
Antineoplastic Agents

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Drug Discovery
  • Pharmacology

Cite this

Reversal of breast cancer resistance protein-mediated drug resistance by estrogen antagonists and agonists. / Sugimoto, Yoshikazu; Tsukahara, Satomi; Imai, Yasuo; Sugimoto, Yoshikazu; Ueda, Kazumitsu; Tsuruo, Takashi.

In: Molecular Cancer Therapeutics, Vol. 2, No. 1, 01.2003, p. 105-112.

Research output: Contribution to journalArticle

Sugimoto, Yoshikazu ; Tsukahara, Satomi ; Imai, Yasuo ; Sugimoto, Yoshikazu ; Ueda, Kazumitsu ; Tsuruo, Takashi. / Reversal of breast cancer resistance protein-mediated drug resistance by estrogen antagonists and agonists. In: Molecular Cancer Therapeutics. 2003 ; Vol. 2, No. 1. pp. 105-112.
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