Erastin/sorafenib induces cisplatin-resistant non-small cell lung cancer cell ferroptosis through inhibition of the Nrf2/xCT pathway
Erastin/sorafenib induces cisplatin-resistant non-small cell lung cancer cell ferroptosis through inhibition of the Nrf2/xCT pathway
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DOI：
10.3892/ol.2019.11066
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发表时间：
2020-01-01
期刊：
影响因子：
2.9
通讯作者：
Zhao, Li
中科院分区：
文献类型：
--
作者：
Li, Yu;Yan, Hengyi;Zhao, Li
非小细胞肺癌（NSCLC）长期以来一直是最致命的癌症类型之一，因为它在早期缺乏典型的临床症状，即使在完全手术切除后肿瘤复发的风险很高。基于顺铂（CDDP）的多疗程化疗是非小细胞肺癌的标准辅助治疗；然而，它对患者总体生存的益处有限。本研究从非小细胞肺癌患者临床标本的手术切除中获得具有cddp耐药特征的NSCLC细胞（N5CP细胞），培养并筛选生成研究模型。本研究旨在确定肿瘤细胞对CDDP耐药的机制，并确定CDDP失败后非小细胞肺癌的新治疗方法。CDDP介导的NF-E2相关因子2 (Nrf2)/ System x c轻链（xCT）通路激活与细胞对CDDP的抗性相关。因此，erastin/sorafenib调控Nrf2或xCT的表达可能会改变肿瘤细胞对CDDP的敏感性。小分子erastin和sorafenib有效诱导N5CP细胞铁凋亡，这是由细胞内脂质活性氧积累介导的。此外，低剂量的erastin或sorafenib可与CDDP联合使用，有效触发N5CP细胞铁下垂。此外，研究表明，erastin和sorafenib单独使用或与低剂量CDDP联合使用均能有效抑制N5CP细胞的体内生长。因此，包括erastin和sorafenib在内的铁吊诱导剂可能被认为是NSCLC患者，特别是CDDP失败患者的一种新的治疗方案。
Non-small cell lung cancer (NSCLC) has long been one of the most lethal types of cancer due to its lack of typical clinical symptoms at early stages and high risk of tumour recurrence, even following complete surgical resection. Multicourse chemotherapy based on cisplatin (CDDP) is the standard adjuvant treatment for NSCLC; however, its benefits for the overall survival of patients are limited. In this study, NSCLC cells possessing CDDP-resistant characteristics (N5CP cells), obtained from surgical resection of clinical specimens of patients with NSCLC, were cultured and screened to generate research models. This study aimed to identify the mechanism underlying tumour cell resistance to CDDP and to identify a novel treatment for NSCLC following CDDP failure. CDDP-mediated NF-E2 related factor 2 (Nrf2)/light chain of System x c (xCT) pathway activation was associated with the resistance of cells to CDDP. Therefore, erastin/sorafenib regulation of Nrf2 or xCT expression may alter the sensitivity of tumour cells to CDDP. The small molecules erastin and sorafenib effectively induced N5CP cell ferroptosis, which was mediated by the accumulation of intracellular lipid reactive oxygen species. Additionally, low doses of erastin or sorafenib could be used in association with CDDP to effectively trigger N5CP cell ferroptosis. Furthermore, it was indicated that erastin and sorafenib, alone or in combination with a low dose of CDDP, effectively inhibited the growth of N5CP cells in vivo. Therefore, ferroptosis inducers, including erastin and sorafenib, may be considered a novel treatment regimen for patients with NSCLC, particularly patients with CDDP failure.