PDF(Pubmed)
Abstract：
Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance (MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor, tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for the first time that the MET inhibitor tepotinib can also reverse ABCG2-mediated MDR in vitro and in vivo by directly binding to the drug-binding site of ABCG2 and reversibly inhibiting ABCG2 drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and ABCG2 gene knockout cell model demonstrated that tepotinib specifically inhibits the two MDR transporters. In mice bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Therefore, our study provides a new potential of repositioning tepotinib as an ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize ABCG2-mediated MDR.
摘要：
ABCG2转运蛋白在癌细胞中的过表达与多药耐药（MDR）的发展有关。癌症治疗的障碍.我们最近的研究发现MET抑制剂，tepotinib,是ABCB1介导的MDR的有效逆转剂。在本研究中,我们首次报道了MET抑制剂泰泊替尼还可以通过直接结合ABCG2的药物结合位点并可逆地抑制ABCG2药物外排活性，在体外和体内逆转ABCG2介导的MDR，因此增强了耐药癌细胞中底物药物的细胞毒性。此外，ABCB1/ABCG2双转染细胞模型和ABCG2基因敲除细胞模型证明了替泊替尼特异性抑制两种MDR转运蛋白.在携带耐药肿瘤的小鼠中，tepotinib增加了ABCG2底物药物拓扑替康的肿瘤内积累并增强了其抗肿瘤作用。因此,我们的研究提供了一种新的潜力,即重新定位替泊替尼作为ABCG2抑制剂,并将替泊替尼与底物药物联合拮抗ABCG2介导的MDR.
