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The overexpression of ATP-binding cassette (ABC) transporters is one of the important mechanisms of multidrug resistance (MDR). Some tyrosine kinase inhibitors (TKIs) such as CM082 might be a potential ABC transporter inhibitor, thus potentially reversing MDR. We used a 3-(4,5-dimethylthiazol-2-yl)-2,5-dimethyltetrazolium bromide (MTT) assay to determine the cytotoxicity and reversal effect of CM082. A xenograft model was established to evaluate the reversal MDR efficacy in vivo . The intracellular accumulation and efflux of ABCG2 substrates were measured by flow cytometry. We investigated the binding sites of ABCG2 via photolabeling ABCG2 with [ 125 I]-iodoarylazidoprazosin (IAAP). Quantitative real-time PCR and western blot were utilized to analyze mRNA and protein expression. We found that CM082 could enhance the efficacy of substrate in ABCG2-overexpressing cells both in vitro and in vivo . Furthermore, CM082 significantly increased intracellular accumulation of ABCG2 substrates by inhibiting the efflux activity. CM082 stimulated ABCG2 ATPase activity and competed with [ 125 I]-IAAP photolabeling of ABCG2 in a concentration-dependent manner. However, CM082 did not alter ABCG2 expression at protein and mRNA levels or inhibit vascular endothelial growth factor (VEGF) downstream signaling of AKT and extracellular signal-regulated kinase (ERK). Further research is encouraged to confirm whether CM082 concomitant with anticancer drugs of ABCG2 substrates could improve the clinical outcomes of cancer treatment in cancer patients with ABCG2 overexpression.

CM082 Enhances the Efficacy of Chemotherapeutic Drugs by Inhibiting the Drug Efflux Function of ABCG2