一种新型合成二氢茚并[1,2-b]吲哚衍生物（LS-2-3j）逆转了癌细胞中 ABCB1 和 ABCG2 介导的多药耐药性。

A Novel Synthetic Dihydroindeno[1,2-b] Indole Derivative (LS-2-3j) Reverses ABCB1- and ABCG2-Mediated Multidrug Resistance in Cancer Cells.

机构信息

School of Ocean, Shandong University, Weihai 264209, China.

Department of Biomedical Engineering, Faculty of Electronic Information and Electrical Engineering, Dalian University of Technology, Dalian 116024, China.

出版信息

Molecules. 2018 Dec 10;23(12):3264. doi: 10.3390/molecules23123264.

DOI:10.3390/molecules23123264

PMID:30544754

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6321174/

Abstract

10-oxo-5-(3-(pyrrolidin-1-yl) propyl)-5,10-dihydroindeno [1,2-b] indol-9-yl propionate (LS-2-3j) is a new chemically synthesized indole compound and some related analogues are known to be inhibitors (such as alectinib and Ko143) of ATP-binding cassette (ABC) transporters, especially the ABC transporter subfamily B member 1 (ABCB1) and the ABC transporter subfamily G member 2 (ABCG2). This study aimed to evaluate the multidrug resistance (MDR) reversal effects and associated mechanisms of LS-2-3j in drug-resistant cancer cells. The inhibition of cell proliferation in tested agents was evaluated by the 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay. Accumulation or efflux of chemotherapy drugs was analyzed by flow cytometry. The ATPase activity was measured using an ATPase activity assay kit. The mRNA transcripts and protein expression levels were detected by real-time PCR and Western blot, respectively. In this connection, LS-2-3j significantly enhanced the activity of chemotherapeutic drugs in MDR cells and could significantly increase the intracellular accumulation of doxorubicin (DOX) and mitoxantrone (MITX) by inhibiting the function of the efflux pumps in ABCB1- or ABCG2-overexpressing cells. Furthermore, reduced ATPase activity, mRNA transcription, and protein expression levels of ABCB1 and ABCG2 were observed in a concentration dependent manner in MDR cancer cells.

摘要

10-氧代-5-(3-(吡咯烷-1-基)丙基)-5,10-二氢茚并[1,2-b]吲哚-9-基丙酸酯（LS-2-3j）是一种新合成的吲哚化合物，一些相关的类似物已知是三磷酸腺苷（ATP）结合盒（ABC）转运蛋白的抑制剂（如艾乐替尼和 Ko143），特别是 ABC 转运蛋白亚家族 B 成员 1（ABCB1）和 ABC 转运蛋白亚家族 G 成员 2（ABCG2）。本研究旨在评估 LS-2-3j 在耐药癌细胞中的多药耐药（MDR）逆转作用及其相关机制。通过 3-(4,5-二甲基噻唑)-2,5-二苯基四氮唑溴盐（MTT）测定评估测试药物对细胞增殖的抑制作用。通过流式细胞术分析化疗药物的积累或外排。使用 ATP 酶活性测定试剂盒测定 ATP 酶活性。通过实时 PCR 和 Western blot 分别检测 mRNA 转录本和蛋白质表达水平。在这方面，LS-2-3j 显著增强了 MDR 细胞中化疗药物的活性，并通过抑制 ABCB1 或 ABCG2 过表达细胞中外排泵的功能，显著增加多柔比星（DOX）和米托蒽醌（MITX）的细胞内积累。此外，在 MDR 癌细胞中观察到 ABCB1 和 ABCG2 的 ATP 酶活性、mRNA 转录和蛋白表达水平呈浓度依赖性降低。