| Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export. | |
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MedLine Citation:
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PMID: 19673889 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Ryohei Katayama; Sumie Koike; Shigeo Sato; Yoshikazu Sugimoto; Takashi Tsuruo; Naoya Fujita |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-07-17 |
Journal Detail:
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Title: Cancer science Volume: 100 ISSN: 1349-7006 ISO Abbreviation: Cancer Sci. Publication Date: 2009 Nov |
Date Detail:
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Created Date: 2009-10-20 Completed Date: 2009-11-03 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101168776 Medline TA: Cancer Sci Country: England |
Other Details:
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Languages: eng Pagination: 2060-8 Citation Subset: IM |
Affiliation:
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Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Japanese Foundation for Cancer Research, Tokyo, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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antagonists & inhibitors*,
physiology Animals Antineoplastic Agents / pharmacology* Camptothecin / analogs & derivatives, pharmacology Cell Line, Tumor Female Humans Methotrexate / pharmacokinetics Mice Mice, Inbred BALB C Neoplasm Proteins / antagonists & inhibitors*, physiology Neoplastic Stem Cells / drug effects* Quinolines / pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/ABCG2 protein, human; 0/ATP-Binding Cassette Transporters; 0/Antineoplastic Agents; 0/Neoplasm Proteins; 0/Quinolines; 100286-90-6/irinotecan; 158681-49-3/dofequidar; 59-05-2/Methotrexate; 7689-03-4/Camptothecin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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