Gemcitabine inhibits cisplatin resistance in cisplatin-resistant A549 cells by upregulating trx-interacting protein and inducing cell cycle arrest
Gemcitabine inhibits cisplatin resistance in cisplatin-resistant A549 cells by upregulating trx-interacting protein and inducing cell cycle arrest
复制标题
吉西他滨通过上调 trx 相互作用蛋白并诱导细胞周期阻滞抑制顺铂耐药 A549 细胞的顺铂耐药
DOI：
10.1016/j.bbrc.2020.01.130
复制
发表时间：
2020-04-09
影响因子：
3.1
通讯作者：
Zhang, Bin
中科院分区：
文献类型：
--
作者：
Cao, Wenjie;Yang, Qin;Zhang, Bin
顺铂是治疗非小细胞肺癌的主要化疗药物。然而，这些患者通常面临顺铂耐药。本研究探讨吉西他滨、伊立替康、培美曲塞、多西紫杉醇单药或联合顺铂治疗顺铂耐药非小细胞肺癌的作用及机制。四甲基偶氮唑盐比伊立替康、培美曲塞和多西紫杉醇对顺铂耐药的A549细胞具有更强的细胞毒作用。吉西他滨联合顺铂对顺铂耐药细胞有协同抑制作用。RNA测序和基因本体论/京都百科全书的基因和基因组分析表明，细胞周期、信号通路和Trx相互作用蛋白是影响联合治疗效果的因素。流式细胞仪和Western印迹结果显示，吉西他滨和顺铂联合作用后，顺铂耐药A549细胞发生G0/G1期阻滞，TRX结合蛋白表达上调。沉默Trx相互作用蛋白可减弱耐药细胞对药物组合的反应。与顺铂单独作用相比，Trx相互作用蛋白激动剂与顺铂联合使用对耐药细胞具有附加的细胞毒作用。与单独使用吉西他滨或PBS相比，吉西他滨和顺铂联合使用显著抑制了体内顺铂耐药A549肿瘤的生长，并伴随着Trx相互作用蛋白的增加和Ki67表达的减少。因此，我们得出结论，吉西他滨和顺铂作为FDA批准的联合治疗顺铂耐药的非小细胞肺癌是一种可行的体内外治疗方法。(C)2020 Elsevier Inc.保留所有权利。
Cisplatin is a main chemotherapeutic drug used to treat non-small-cell lung cancer patients. However, these patients commonly face cisplatin resistance. The roles and underlying mechanisms of gemcitabine, irinotecan, pemetrexed and docetaxel used as single agents or combined with cisplatin for overcoming cisplatin-resistant non-small-cell lung cancer were explored in this study. MTT assays showed that gemcitabine alone exhibited stronger cytotoxicity on cisplatin-resistant A549 cells than irinotecan, pemetrexed and docetaxel. Meanwhile, gemcitabine combined with cisplatin showed a synergistic inhibitory effect on cisplatin-resistant cells. RNA sequencing and Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analysis showed that cell cycle signaling pathways and trx-interacting protein were factors in the efficacy of the cotreatment. Flow cytometry and Western blot results showed that when cisplatin-resistant A549 cells were cotreated with gemcitabine and cisplatin, G0/G1 phase arrest occurred, and trx-interacting protein was upregulated. Silencing trx-interacting protein attenuated the response of the resistant cells to the drug combination. A trx-interacting protein agonist together with cisplatin showed an additive cytotoxic effect on the resistant cells compared with cisplatin alone. The gemcitabine and cisplatin combination, compared to gemcitabine or PBS alone, markedly suppressed the growth of cisplatin-resistant A549 tumors in vivo, accompanied by an increase in trx-interacting protein and a decrease in Ki67 expression. Therefore, we concluded that gemcitabine and cisplatin, as an FDA-approved combination, is a viable therapy for cisplatin-resistant non-small-cell lung cancer ex vivo and in vivo. (C) 2020 Elsevier Inc. All rights reserved.