title: Saracatinib (AZD0530) is a potent modulator of ABCB1-mediated multidrug resistance in vitro and in vivo.
abstract: 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.
authors.affiliation: State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, People's Republic of China.
authors.forename: Ke-Jun
authors.initials: KJ
authors.lastname: Liu
authors.forename: Jie-Hua
authors.initials: JH
authors.lastname: He
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Su
authors.forename: Hong-May
authors.initials: HM
authors.lastname: Sim
authors.forename: Jing-Dun
authors.initials: JD
authors.lastname: Xie
authors.forename: Xing-Gui
authors.initials: XG
authors.lastname: Chen
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Yong-Ju
authors.initials: YJ
authors.lastname: Liang
authors.forename: Satyakam
authors.initials: S
authors.lastname: Singh
authors.forename: Kamlesh
authors.initials: K
authors.lastname: Sodani
authors.forename: Tanaji T
authors.initials: TT
authors.lastname: Talele
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Wu
authors.forename: Li-Wu
authors.initials: LW
authors.lastname: Fu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000077156:Gefitinib; D057809:HEK293 Cells; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D052117:Benzodioxoles; D004791:Enzyme Inhibitors; D011799:Quinazolines; D004317:Doxorubicin; C515233:saracatinib; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; D000251:Adenosine Triphosphatases; D017239:Paclitaxel; D000077156:Gefitinib