Department of Surgery, Graduate School of Medicine (M.M., S.O., K.Ku., K.Ka., N.S., M.I., T.N., M.U.), and Laboratory of Synthetic Chemistry, Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences (M.F., Y.I.), Tohoku University, Sendai, Japan; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (E.E.C., S.V.A.); and Department of Clinical Oncology, Akita University Graduate School of Medicine, Akita, Japan (H.S.).
Department of Surgery, Graduate School of Medicine (M.M., S.O., K.Ku., K.Ka., N.S., M.I., T.N., M.U.), and Laboratory of Synthetic Chemistry, Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences (M.F., Y.I.), Tohoku University, Sendai, Japan; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (E.E.C., S.V.A.); and Department of Clinical Oncology, Akita University Graduate School of Medicine, Akita, Japan (H.S.)
Drug Metab Dispos. 2017 Nov;45(11):1166-1177. doi: 10.1124/dmd.117.076000. Epub 2017 Sep 13.
Multidrug resistance (MDR) caused by the overexpression of ATP-binding cassette (ABC) transporters in cancer cells is a major obstacle in cancer chemotherapy. Previous studies have shown that curcumin, a natural product and a dietary constituent of turmeric, inhibits the function of MDR-related ABC transporters, including ABCB1, ABCC1, and especially ABCG2. However, the limited bioavailability of curcumin prevents its use for modulation of the function of these transporters in the clinical setting. In this study, we investigated the effects of 24 synthetic curcumin analogs with increased bioavailability on the transport function of ABCG2. The screening of the 24 synthetic analogs by means of flow cytometry revealed that four of the curcumin analogs (GO-Y030, GO-Y078, GO-Y168, and GO-Y172) significantly inhibited the efflux of the ABCG2 substrates, mitoxantrone and pheophorbide A, from ABCG2-overexpressing K562/breast cancer resistance protein (BCRP) cells. Biochemical analyses showed that GO-Y030, GO-Y078, and GO-Y172 stimulated the ATPase activity of ABCG2 at nanomolar concentrations and inhibited the photolabeling of ABCG2 with iodoarylazidoprazosin, suggesting that these analogs interact with the substrate-binding sites of ABCG2. In addition, when used in cytotoxicity assays, GO-Y030 and GO-Y078 were found to improve the sensitivity of the anticancer drug, SN-38, in K562/BCRP cells. Taken together, these results suggest that nontoxic synthetic curcumin analogs with increased bioavailability, especially GO-Y030 and GO-Y078, inhibit the function of ABCG2 by directly interacting at the substrate-binding site. These synthetic curcumin analogs could therefore be developed as potent modulators to overcome ABCG2-mediated MDR in cancer cells.
多药耐药性（MDR）是癌症化疗的主要障碍，其由癌细胞中 ATP 结合盒（ABC）转运蛋白的过度表达引起。先前的研究表明，姜黄素，一种天然产物和姜黄的膳食成分，抑制 MDR 相关 ABC 转运蛋白的功能，包括 ABCB1、ABCC1，特别是 ABCG2。然而，姜黄素的生物利用度有限，阻止了其在临床环境中用于调节这些转运蛋白的功能。在这项研究中，我们研究了 24 种具有更高生物利用度的合成姜黄素类似物对 ABCG2 转运功能的影响。通过流式细胞术对 24 种合成类似物进行筛选，发现其中 4 种姜黄素类似物（GO-Y030、GO-Y078、GO-Y168 和 GO-Y172）显著抑制了 ABCG2 过表达 K562/乳腺癌耐药蛋白（BCRP）细胞中 ABCG2 底物米托蒽醌和原卟啉 A 的外排。生化分析表明，GO-Y030、GO-Y078 和 GO-Y172 在纳摩尔浓度下刺激 ABCG2 的 ATP 酶活性，并抑制 ABCG2 与碘代芳氮唑嗪的光标记，表明这些类似物与 ABCG2 的底物结合位点相互作用。此外，在细胞毒性测定中发现，GO-Y030 和 GO-Y078 可提高 K562/BCRP 细胞中抗癌药物 SN-38 的敏感性。综上所述，这些结果表明，具有更高生物利用度的非毒性合成姜黄素类似物，特别是 GO-Y030 和 GO-Y078，通过直接在底物结合位点相互作用来抑制 ABCG2 的功能。因此，这些合成姜黄素类似物可被开发为有效的调节剂，以克服癌细胞中 ABCG2 介导的多药耐药性。
