Abstract
Overexpression of ATP-binding cassette (ABC) transporters is one of the most important mechanisms responsible for multi-drug resistance (MDR). VS-4718, a tyrosine kinase inhibitor targeting focal adhesion kinase (FAK) with a potential anticancer effect, is currently evaluated in clinical trials. In this study, we investigated whether VS-4718 could reverse MDR mediated by ABC transporters, including ABCB1, ABCG2, and ABCC1. The results showed that VS-4718 significantly reversed ABCB1- and ABCG2-mediated MDR, but not MDR mediated by ABCC1. Treatment of VS-4718 did not alter the protein level and subcellular localization of ABCB1 or ABCG2. Mechanism studies indicated that the reversal effects of VS-4718 were related to attenuation of the efflux activity of ABCB1 and ABCG2 transporters. ATPase analysis indicated that VS-4718 stimulated the ATPase activity of ABCB1 and ABCG2. Docking study showed that VS-4718 interacted with the substrate-binding sites of both ABCB1 and ABCG2, suggesting that VS-4718 may affect the activity of ABCB1 and ABCG2 competitively. This study provided a novel insight for MDR cancer treatment. It indicated that combination of VS-4718 with antineoplastic drugs could attenuate MDR mediated by ABCB1 or ABCG2 in ABCB1- or ABCG2-overexpressing cancer cells.
Highlights
Multidrug resistance (MDR) remains a major challenge that contributes to the failure of cancer chemotherapy (Szakács et al, 2006; Kartal-Yandim et al, 2016)
AIC50 values were determined by MTT assay as described in “Materials and Methods,” and were obtained from three independent experiments in triplicate. bResistance fold (RF) was calculated from dividing the IC50 values of resistance cells (HEK293/ABCB1) by the IC50 of parental cells (HEK293/pcDNA3.1) in the presence or absence of VS-4718 or positive control inhibitor. *indicates p < 0.05 vs. group treated with antineoplastic drug only
It is well documented that the ATP binding cassette (ABC) transporters expressed on cancer cell membrane are responsible for MDR, which leads to the failure of chemotherapy
Summary
Multidrug resistance (MDR) remains a major challenge that contributes to the failure of cancer chemotherapy (Szakács et al, 2006; Kartal-Yandim et al, 2016). Divided into 7 subfamilies from ABCA to ABCG, the human ABC protein family has 49 ABC proteins and 48 of them have functions (Stavrovskaya and Stromskaya, 2008; Eckford and Sharom, 2009). They are widely expressed in the placenta, blood brain barrier (BBB), intestines, liver, and kidneys to restrict the bioavailability of administered drugs (Linton, 2007; Linton and Higgins, 2007), transporting and regulating levels of physiological substrates such as lipids, porphyrins, and sterols (Wu and Ambudkar, 2014). Inhibiting the efflux function of ABC transporters is of great importance to enhance the efficacy of chemotherapy (Shukla et al, 2008)
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