Saracatinib, a highly selective, dual Src/Abl kinase inhibitor, is currently in 
a Phase II clinical trial for the treatment of ovarian cancer. In our study, we 
investigated the effect of saracatinib on the reversal of multidrug resistance 
(MDR) induced by ATP-binding cassette (ABC) transporters in vitro and in vivo. 
Our results showed that saracatinib significantly enhanced the cytotoxicity of 
ABCB1 substrate drugs in ABCB1 overexpressing HeLa/v200, MCF-7/adr and 
HEK293/ABCB1 cells, an effect that was stronger than that of gefitinib, whereas 
it had no effect on the cytotoxicity of the substrates in ABCC1 overexpressing 
HL-60/adr cells and its parental sensitive cells. Additionally, saracatinib 
significantly increased the doxorubicin (Dox) and Rho 123 accumulation in 
HeLa/v200 and MCF-7/adr cells, whereas it had no effect on HeLa and MCF-7 cells. 
Furthermore, saracatinib stimulated the ATPase activity and inhibited 
photolabeling of ABCB1 with [(125)I]-iodoarylazidoprazosin in a 
concentration-dependent manner. In addition, the homology modeling predicted the 
binding conformation of saracatinib within the large hydrophobic drug-binding 
cavity of human ABCB1. However, neither the expression level of ABCB1 nor the 
phosphorylation level of Akt was altered at the reversal concentrations of 
saracatinib. Importantly, saracatinib significantly enhanced the effect of 
paclitaxel against ABCB1-overexpressing HeLa/v200 cancer cell xenografts in nude 
mice. In conclusion, saracatinib reverses ABCB1-mediated MDR in vitro and in 
vivo by directly inhibiting ABCB1 transport function, without altering ABCB1 
expression or AKT phosphorylation. These findings may be helpful to attenuate 
the effect of MDR by combining saracatinib with other chemotherapeutic drugs in 
the clinic.