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 [¹²⁵I]-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 [¹²⁵I]-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.

ATP结合盒（ABC）转运蛋白的过度表达是多药耐药（MDR）的重要机制之一。一些酪氨酸激酶抑制剂 (TKI)，例如 CM082，可能是一种潜在的 ABC 转运蛋白抑制剂，因此有可能逆转 MDR。我们使用 3-(4,5-二甲基噻唑-2-基)-2,5-二甲基四唑溴化物 (MTT) 测定来测定 CM082 的细胞毒性和逆转作用。建立异种移植模型来评价体内逆转MDR功效。通过流式细胞术测量 ABCG2 底物的细胞内积累和流出。^{我们通过用[ 125} I]-碘芳基叠氮哌唑嗪 (IAAP)光标记 ABCG2 来研究 ABCG2 的结合位点。利用实时定量PCR和蛋白质印迹分析mRNA和蛋白质表达。我们发现CM082可以在体外和体内增强ABCG2过表达细胞中底物的功效。此外，CM082 通过抑制外排活性显着增加 ABCG2 底物的细胞内积累。CM082刺激ABCG2 ATP酶活性并以浓度依赖性方式与ABCG2的[ ^{125 I]-IAAP光标记竞争。}然而，CM082 不会改变蛋白质和 mRNA 水平的 ABCG2 表达，也不会抑制 AKT 和细胞外信号调节激酶 (ERK) 的血管内皮生长因子 (VEGF) 下游信号传导。鼓励进一步的研究来确认CM082与ABCG2底物的抗癌药物联合使用是否可以改善ABCG2过度表达的癌症患者的癌症治疗的临床结果。