Estrogen receptor α induction by mitoxantrone increases Abcg2 expression in placental trophoblast cells

Kenji Oda, Tomohiro Nishimura, Kei Higuchi, Naomi Ishido, Kaori Ochi, Hisashi Iizasa, Yoshimichi Sai, Masatoshi Tomi, Emi Nakashima

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


Substrate-induced upregulation of ATP-binding cassette subfamily G member 2 (ABCG2) has been well studied in cancer cells, but it is also important to understand whether ABCG2 is upregulated by its substrates in tissues in which it is constitutively expressed. In the present study, we aimed to clarify the regulatory mechanism of Abcg2 expression by its substrate, mitoxantrone, in placental cells. Abcg2 mRNA expression in rat placental TR-TBT 18d-1 cells treated with 10μM mitoxantrone for 24h was increased, compared with that in nontreated cells, whereas 10μM pheophorbide-a had no effect. Methylated CpG level in the promoter region of the Abcg2 gene was low and was not altered by mitoxantrone. On the contrary, mitoxantrone markedly increased the expression of estrogen receptor (ER) α and progesterone receptor (PR) B. Fulvestrant, an ER antagonist, attenuated the mitoxantrone-induced increase of Abcg2 mRNA expression, whereas mifepristone, a PR antagonist, had little effect. 17β-estradiol, an ER ligand, positively regulated the mitoxantrone-induced increase of Abcg2 expression. DNA demethylation by 5-aza-2-deoxycytidine treatment increased ERα expression, but mitoxantrone failed to facilitate the demethylation of ERα promoter in TR-TBT 18d-1 cells. In conclusion, Abcg2 expression is induced by mitoxantrone via the induction of ERα in TR-TBT 18d-1 cells.

Original languageEnglish
Pages (from-to)3364-3372
Number of pages9
JournalJournal of Pharmaceutical Sciences
Issue number9
Publication statusPublished - 2013 Sept


  • ABC transporter
  • Cell culture
  • Disposition
  • Membrane transporter
  • Placenta

ASJC Scopus subject areas

  • Pharmaceutical Science


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