Phytoestrogens/flavonoids reverse breast cancer resistance protein/ABCG2-mediated multidrug resistance

Yasuo Imai, Satomi Tsukahara, Sakiyo Asada, Yoshikazu Sugimoto

Research output: Contribution to journalArticle

218 Citations (Scopus)

Abstract

Breast cancer resistance protein (BCRP), also called ABCG2, confers resistance to anticancer agents such as 7-ethyl-10-hydroxycamptothecin (SN-38), mitoxantrone, and topotecan. We found previously that sulfated estrogens are physiologic substrates of BCRP. Flavonoids with weak estrogenic activities are called phytoestrogens. In this study, we show that phytoestrogens/flavonoids, such as genistein, naringenin, acacetin, and kaempferol, potentiated the cytotoxicity of SN-38 and mitoxantrone in BCRP-transduced K562 (K562/BCRP) cells. Some glycosylated flavonoids, such as naringenin-7-glucoside, also effectively inhibited BCRP. These flavonoids showed marginal effect on the drug sensitivity of K562 cells. Genistein and naringenin reversed neither P-glycoprotein-mediated vincristine resistance nor multidrug resistance-related protein 1-mediated VP-16 resistance. Genistein and naringenin increased cellular accumulation of topotecan in K562/BCRP cells. K562/BCRP cells also accumulated less (3H]genistein than K562 cells. [3H]genistein transport in the basal-to-apical direction was greater in BCRP-transduced LLC-PK1 (LLC/BCRP) cells, which express exogenous BCRP in the apical membrane, than in parental cells. Fumitremorgin C abolished the increased transport of [3H]genistein in LLC/BCRP cells compared with parental cells. TLC analysis revealed that genistein was transported in its native form but not in its metabolized form. These results suggest that genistein is among the natural substrates of BCRP and competitively inhibits BCRP-mediated drug efflux. The results have two important clinical implications: (a) flavonoids and glycosylated flavonoids may be useful in overcoming BCRP-mediated drug resistance in tumor cells; and (b) coadministration of flavonoids with BCRP-substrate antitumor agents may alter the pharmacokinetics and consequently increase the toxicity of specific antitumor agents in cancer patients.

Original languageEnglish
Pages (from-to)4346-4352
Number of pages7
JournalCancer Research
Volume64
Issue number12
DOIs
Publication statusPublished - 2004 Jun 15

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Phytoestrogens
Multiple Drug Resistance
Flavonoids
Breast Neoplasms
Genistein
irinotecan
Proteins
Antineoplastic Agents
Topotecan
Mitoxantrone
K562 Cells
ATP Binding Cassette Transporter, Sub-Family G, Member 2
P-Glycoprotein
Glucosides
Vincristine
Etoposide
Drug Resistance

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phytoestrogens/flavonoids reverse breast cancer resistance protein/ABCG2-mediated multidrug resistance. / Imai, Yasuo; Tsukahara, Satomi; Asada, Sakiyo; Sugimoto, Yoshikazu.

In: Cancer Research, Vol. 64, No. 12, 15.06.2004, p. 4346-4352.

Research output: Contribution to journalArticle

Imai, Yasuo ; Tsukahara, Satomi ; Asada, Sakiyo ; Sugimoto, Yoshikazu. / Phytoestrogens/flavonoids reverse breast cancer resistance protein/ABCG2-mediated multidrug resistance. In: Cancer Research. 2004 ; Vol. 64, No. 12. pp. 4346-4352.
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