The ATP-binding cassette transporters (ABC-Ts) actively efflux structurally and mechanistically unrelated anti-cancer drugs from cells. As a consequence, it can confer multi-drug resistance (MDR) to cancer cells. ABC-Ts are also reported to be phenotypic markers and functional regulators of cancer stem cells (CSCs) 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 and/or ABCC1/MDR-associated protein 1 (MRP1). The Phase III clinical trials previously revealed that dofequidar is suggested to have 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 anti-cancer drugs in CSC-like side population (SP) cells isolated from various cancer cell lines. Dofequidar treatment greatly reduced the cell number in SP fraction. Estimation of ABC-T expression revealed that ABCG2/BCRP mRNA level, but not ABCB1/P-gp or ABCC1/MRP1 mRNA level, in all the tested SP cells was higher than that in non-SP (NSP) cells. The in vitro vesicle transporter assay clarified that dofequidar had the ability to suppress ABCG2/BCRP function. Dofequidar treatment sensitized SP cells to anti-cancer agents in vitro. We compared the antitumor efficacy of CPT-11 alone with that of CPT-11 plus dofequidar in xenografted SP cells. Although xenografted SP tumos showed resistance to CPT-11, treatment of CPT-11 plus dofequidar greatly reduced the SP-derived tumor growth in vivo. Our results suggest the possibilityof selective eradication of CSCs by inhibiting ABCG2/BCRP.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 913.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009