Flavonoids inhibit breast cancer resistance protein-mediated drug resistance: Transporter specificity and structure-activity relationship

Kazuhiro Katayama, Kazuto Masuyama, Sho Yoshioka, Hitomi Hasegawa, Junko Mitsuhashi, Yoshikazu Sugimoto

Research output: Contribution to journalArticle

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Abstract

Purpose: 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 IC50 values were determined from the growth inhibition curves. The RI50 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 RI50 values of 0.012 μM for SN-38 and 0.044 μM 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)789-797
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume60
Issue number6
DOIs
Publication statusPublished - 2007 Nov

Fingerprint

P-Glycoprotein
Structure-Activity Relationship
Drug Resistance
Flavonoids
Breast Neoplasms
Pharmaceutical Preparations
Proteins
irinotecan
P-Glycoproteins
Topotecan
Flavones
Mitoxantrone
ATP-Binding Cassette Transporters
K562 Cells
Growth
Antineoplastic Agents
Cell growth
Inhibitory Concentration 50
Squamous Cell Carcinoma
Leukemia

Keywords

  • BCRP/ABCG2
  • Flavonoid
  • Growth inhibition assay
  • MRP1/ABCC1
  • P-glycoprotein/ABCB1

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Flavonoids inhibit breast cancer resistance protein-mediated drug resistance : Transporter specificity and structure-activity relationship. / Katayama, Kazuhiro; Masuyama, Kazuto; Yoshioka, Sho; Hasegawa, Hitomi; Mitsuhashi, Junko; Sugimoto, Yoshikazu.

In: Cancer Chemotherapy and Pharmacology, Vol. 60, No. 6, 11.2007, p. 789-797.

Research output: Contribution to journalArticle

Katayama, Kazuhiro ; Masuyama, Kazuto ; Yoshioka, Sho ; Hasegawa, Hitomi ; Mitsuhashi, Junko ; Sugimoto, Yoshikazu. / Flavonoids inhibit breast cancer resistance protein-mediated drug resistance : Transporter specificity and structure-activity relationship. In: Cancer Chemotherapy and Pharmacology. 2007 ; Vol. 60, No. 6. pp. 789-797.
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AU - Katayama, Kazuhiro

AU - Masuyama, Kazuto

AU - Yoshioka, Sho

AU - Hasegawa, Hitomi

AU - Mitsuhashi, Junko

AU - Sugimoto, Yoshikazu

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N2 - Purpose: 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 IC50 values were determined from the growth inhibition curves. The RI50 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 RI50 values of 0.012 μM for SN-38 and 0.044 μM 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. Conclusion: 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.

AB - Purpose: 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 IC50 values were determined from the growth inhibition curves. The RI50 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 RI50 values of 0.012 μM for SN-38 and 0.044 μM 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. Conclusion: 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.

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