The overexpression of
ATP-binding cassette (
ABC) transporter ABCB1 (
P-glycoprotein) or ABCG2 (BCRP/MXR/ABCP) in
cancer cells is frequently associated with the development of multidrug resistance (MDR) in
cancer patients, which remains a major obstacle to effective
cancer treatment. By utilizing energy derived from
ATP hydrolysis, both transporters have been shown to reduce the chemosensitivity of
cancer cells by actively effluxing cytotoxic anticancer drugs out of
cancer cells. Knowing that there are presently no approved drugs or other
therapeutics for the treatment of multidrug-resistant
cancers, in recent years, studies have investigated the repurposing of
tyrosine kinase inhibitors (TKIs) to act as agents against MDR mediated by ABCB1 and/or ABCG2.
SKLB610 is a multi-targeted TKI with potent activity against
vascular endothelial growth factor receptor 2 (VEGFR2),
platelet-derived growth factor receptor (PDGFR), and
fibroblast growth factor receptor 2 (FGFR2). In this study, we investigate the interaction of
SKLB610 with ABCB1 and ABCG2. We discovered that neither ABCB1 nor ABCG2 confers resistance to
SKLB610, but
SKLB610 selectively sensitizes ABCG2-overexpressing multidrug-resistant
cancer cells to cytotoxic
anticancer agents in a concentration-dependent manner. Our data indicate that
SKLB610 reverses ABCG2-mediated MDR by attenuating the
drug-efflux function of ABCG2 without affecting its total cell expression. These findings are further supported by results of SKLB610-stimulated ABCG2
ATPase activity and in silico docking of
SKLB610 in the
drug-binding pocket of ABCG2. In summary, we reveal the potential of
SKLB610 to overcome resistance to cytotoxic anticancer drugs, which offers an additional treatment option for patients with multidrug-resistant
cancers and warrants further investigation.