Experimental Therapeutics, Moffitt Cancer Center, University of South Florida, Tampa, Florida 33612, USA.
Cancer Res. 2012 Aug 15;72(16):4204-13. doi: 10.1158/0008-5472.CAN-12-0743. Epub 2012 Jul 3.
Transmembrane drug export mediated by the ATP-binding cassette (ABC) transporter P-glycoprotein contributes to clinical resistance to antineoplastics. In this study, we identified the substituted quinoline HG-829 as a novel, noncompetitive, and potent P-glycoprotein inhibitor that overcomes in vitro and in vivo drug resistance. We found that nontoxic concentrations of HG-829 restored sensitivity to P-glycoprotein oncolytic substrates. In ABCB1-overexpressing cell lines, HG-829 significantly enhanced cytotoxicity to daunorubicin, paclitaxel, vinblastine, vincristine, and etoposide. Coadministration of HG-829 fully restored in vivo antitumor activity of daunorubicin in mice without added toxicity. Functional assays showed that HG-829 is not a Pgp substrate or competitive inhibitor of Pgp-mediated drug efflux but rather acts as a noncompetitive modulator of P-glycoprotein transport function. Taken together, our findings indicate that HG-829 is a potent, long-acting, and noncompetitive modulator of P-glycoprotein export function that may offer therapeutic promise for multidrug-resistant malignancies.
由 ATP 结合盒（ABC）转运蛋白 P-糖蛋白介导的跨膜药物外排导致临床对抗肿瘤药物产生耐药性。在这项研究中，我们鉴定出取代的喹啉 HG-829 是一种新型的、非竞争性的、有效的 P-糖蛋白抑制剂，可克服体外和体内的耐药性。我们发现，HG-829 的无毒浓度可恢复 P-糖蛋白溶瘤底物的敏感性。在 ABCB1 过表达的细胞系中，HG-829 显著增强了对柔红霉素、紫杉醇、长春碱、长春新碱和依托泊苷的细胞毒性。HG-829 的共同给药完全恢复了小鼠体内柔红霉素的抗肿瘤活性，而没有增加毒性。功能测定表明，HG-829 不是 Pgp 底物或 Pgp 介导的药物外排的竞争性抑制剂，而是作为 P-糖蛋白转运功能的非竞争性调节剂。总之，我们的研究结果表明，HG-829 是一种有效的、长效的、非竞争性的 P-糖蛋白外排功能调节剂，可能为多药耐药性恶性肿瘤提供治疗前景。
