Resveratrol Reduces the Hypoxia-Induced Resistance to Doxorubicin in Breast Cancer Cells

• MITANI Takakazu

  Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University

• ITO Yuta

  Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University

• HARADA Naoki

  Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University

• NAKANO Yoshihisa

  Osaka Women’s Junior College

• INUI Hiroshi

  Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University

• ASHIDA Hitoshi

  Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University

• YAMAJI Ryoichi

  Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University

抄録

Resveratrol (3,4′,5-trihydroxy-trans-stilbene) is known to enhance the cytotoxicity of the anticancer drug doxorubicin. On the other hand, breast cancer MCF-7 cells acquire resistance to doxorubicin under hypoxic conditions. In this study, we investigated the effect of resveratrol on hypoxia-induced resistance to doxorubicin in MCF-7 cells. Resveratrol and its derivative 3,5-dihydroxy-4′-methoxy-trans-stilbene, but not 3,5-dimethoxy-4′-hydroxy-trans-stilbene, cancelled hypoxia-induced resistance to doxorubicin at a concentration of 10 μM. Carbonyl reductase 1 (CBR1) catalyzes the conversion of doxorubicin to its metabolite doxorubicinol, which is much less effective than doxorubicin. Hypoxia increased the expression of CBR1 at both mRNA and protein levels, and knockdown of CBR1 inhibited hypoxia-induced resistance to doxorubicin in MCF-7 cells. Knockdown of hypoxia-inducible factor (HIF)-1α repressed the hypoxia-induced expression of CBR1. Resveratrol repressed the expression of HIF-1α protein, but not HIF-1α mRNA, and decreased hypoxia-activated HIF-1 activity. Resveratrol repressed the hypoxia-induced expression of CBR1 at both mRNA and protein levels. Likewise, 3,5-dihydroxy-4′-methoxy-trans-stilbene decreased the hypoxia-induced expression of CBR1 protein, but not 3,5-dimethoxy-4′-hydroxy-trans-stilbene. Furthermore, resveratrol decreased the expression of HIF-1α protein even in the presence of the proteasome inhibitor MG132 in hypoxia. Theses results indicate that in MCF-7 cells, HIF-1α-increased CBR1 expression plays an important role in hypoxia-induced resistance to doxorubicin and that resveratrol and 3,5-dihydroxy-4′-methoxy-trans-stilbene decrease CBR1 expression by decreasing HIF-1α protein expression, perhaps through a proteasome-independent pathway, and consequently repress hypoxia-induced resistance to doxorubicin.

収録刊行物

• Ｊｏｕｒｎａｌ　ｏｆ　Ｎｕｔｒｉｔｉｏｎａｌ　Ｓｃｉｅｎｃｅ　ａｎｄ　Ｖｉｔａｍｉｎｏｌｏｇｙ

  Ｊｏｕｒｎａｌ　ｏｆ　Ｎｕｔｒｉｔｉｏｎａｌ　Ｓｃｉｅｎｃｅ　ａｎｄ　Ｖｉｔａｍｉｎｏｌｏｇｙ 60 (2), 122-128, 2014

  一般財団法人 学会誌刊行センター

キーワード

• resveratrol
• doxorubicin
• carbonyl reductase 1
• hypoxia-inducible factor-1α
• breast cancer cells

詳細情報

• CRID: 1390001206324880128
• NII論文ID: 130004491365
• NII書誌ID: AA00703822
• DOI: 10.3177/jnsv.60.122
• COI: 1:CAS:528:DC%2BC2cXotVSnsrY%3D
• ISSN: 18817742
• ISSN: 03014800
• NDL書誌ID: 025440376
• PubMed: 24975222
• Web Site: http://id.ndl.go.jp/bib/025440376
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I025440376
• Web Site: https://search.jamas.or.jp/link/ui/2015033099
• 本文言語コード: en
• データソース種別:
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  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
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