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 this 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 Dox and Rho 123 accumulation in HeLa/v200 and MCF-7/adr cells, while it had no effect on HeLa and MCF-7 cells. Furthermore, saracatinib stimulated the ATPase activity and inhibited photolabeling of ABCB1 with [125I]-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.

Src Inhibition Blocks c-Myc Translation and Glucose Metabolism to Prevent the Development of Breast Cancer

“…2A and Supplementary Fig. S2A) without obvious toxicity to mice ((32) and data not shown). Saracatinib significantly reduced the development of hyperplastic, MIN, and IDC lesions (Fig.…”

Prognostic Value and Implication for Chemotherapy Treatment of ABCB1 in Epithelial Ovarian Cancer: A Meta-Analysis

“…On one hand, it seemed that extensive use of taxanes successfully improved the general survival of EOC patients comparing to other drugs [69] and attenuated the sensitivity of ABCB1 as a prognosis indicator. On the other, since both cellular and clinical researches revealed that ABCB1 in ovarian cancer could be up-regulated by chemotherapy [70, 71], taxane induced alteration in ABCB1 through the course of treatment might also be a confounding factor to the measurement of survival analysis because ABCB1 expression was seldom obtained in matched analysis [72–74]. In pre-clinical studies, inhibitors targeting ABCB1 could reverse chemotherapy resistance to some extent [75,76].…”

Hedyotis diffusa Willd overcomes 5-fluorouracil resistance in human colorectal cancer HCT-8/5-FU cells by downregulating the expression of P-glycoprotein and ATP-binding casette subfamily G member 2

“…Increasing evidence supports the hypothesis that ABCG2 plays an important role in cancer drug resistance (31)(32)(33); thus, the modulation of ABCG2 may be regarded as a therapeutic approach to overcome drug resistance. Numerous studies have attempted to develop reversing agents that target ABC transporters (34,35); however, poor solubility and reduced oral bioavailability have limited the clinical application of these agents, including the P-gp/ABCG2 dual inhibitor, Elacridar (36). Faced with limited methods to reduce the side-effects and lower the risk of developing drug-resistant CRC, the use of alternative remedies, such as traditional medicines and herbs, is gaining support among patients and clinicians alike (37).…”