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.