Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export

Ryohei Katayama, Sumie Koike, Shigeo Sato, Yoshikazu Sugimoto, Takashi Tsuruo, Naoya Fujita

研究成果: Article

57 引用 (Scopus)

抄録

The ATP-binding cassette (ABC) transporters (ABC-T) actively efflux structurally and mechanistically unrelated anticancer drugs from cells. As a consequence, they can confer multidrug resistance (MDR) to cancer cells. ABC-T are also reported to be phenotypic markers and functional regulators of cancer stem/initiating cells (CSC) and believed to be associated with tumor initiation, progression, and relapse. Dofequidar fumarate, an orally active quinoline compound, has been reported to overcome MDR by inhibiting ABCB1/P-gp, ABCC1/MDR-associated protein 1, or both. Phase III clinical trials suggested that dofequidar had efficacy in patients who had not received prior therapy. Here we show that dofequidar inhibits the efflux of chemotherapeutic drugs and increases the sensitivity to anticancer drugs in CSC-like side population (SP) cells isolated from various cancer cell lines. Dofequidar treatment greatly reduced the cell number in the SP fraction. Estimation of ABC-T expression revealed that ABCG2/breast cancer resistance protein (BCRP) mRNA level, but not the ABCB1/P-gp or ABCC1/MDR-associated protein 1 mRNA level, in all the tested SP cells was higher than that in non-SP cells. The in vitro vesicle transporter assay clarified that dofequidar had the ability to suppress ABCG2/BCRP function. Dofequidar treatment sensitized SP cells to anticancer agents in vitro. We compared the antitumor efficacy of irinotecan (CPT-11) alone with that of CPT-11 plus dofequidar in xenografted SP cells. Although xenografted SP tumors showed resistance to CPT-11, treatment with CPT-11 plus dofequidar greatly reduced the SP-derived tumor growth in vivo. Our results suggest the possibility of selective eradication of CSC by inhibiting ABCG2/BCRP. (Cancer Sci 2009).

元の言語English
ページ(範囲)2060-2068
ページ数9
ジャーナルCancer Science
100
発行部数11
DOI
出版物ステータスPublished - 2009 11

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irinotecan
Side-Population Cells
Fumarates
Breast Neoplasms
Pharmaceutical Preparations
Neoplastic Stem Cells
Neoplasms
Proteins
Multiple Drug Resistance
Population
Adenosine Triphosphate
Phase III Clinical Trials
Messenger RNA
ATP-Binding Cassette Transporters
dofequidar
Therapeutics
Antineoplastic Agents
Cell Count
Recurrence
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

これを引用

Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export. / Katayama, Ryohei; Koike, Sumie; Sato, Shigeo; Sugimoto, Yoshikazu; Tsuruo, Takashi; Fujita, Naoya.

:: Cancer Science, 巻 100, 番号 11, 11.2009, p. 2060-2068.

研究成果: Article

Katayama, Ryohei ; Koike, Sumie ; Sato, Shigeo ; Sugimoto, Yoshikazu ; Tsuruo, Takashi ; Fujita, Naoya. / Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export. :: Cancer Science. 2009 ; 巻 100, 番号 11. pp. 2060-2068.
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