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).
