文章：

肺癌患者临床预后中的DNA损伤应答网络与细胞内氧化还原状态

DNA Damage Response Network and Intracellular Redox Status in the Clinical Outcome of Patients with Lung Cancer

原文发布日期：18 December 2024

DOI: 10.3390/cancers16244218

类型: Article

开放获取: 是

英文摘要：

Background/Objectives: DNA damage response (DDR) is a network of molecular pathways associated with the pathogenesis and progression of several diseases, as well as the outcome of chemotherapy. Moreover, the intracellular redox status is essential for maintaining cell viability and controlling cellular signaling. Herein, we analyzed DDR signals and redox status in peripheral blood mononuclear cells (PBMCs) from patients with lung cancer with different response rates to platinum-based chemotherapy.Methods: Several DDR-associated signals and redox status, expressed as the GSH/GSSG ratio, were measured in two lung cancer cell lines (A549, H1299), two normal fibroblast cell lines (WS1, 1BR3hT), and PBMCs from 20 healthy controls and 32 patients with lung cancer at baseline (17 responders and 15 non-responders to subsequent platinum-based chemotherapy).Results: Higher levels of endogenous/baseline DNA damage, decreased GSH/GSSG ratios, and augmented apurinic/apyrimidinic sites, as well as lower nucleotide excision repair (NER) and increased interstrand cross-links (ICLs) repair efficiencies, were observed in lung cancer cell lines compared with normal ones (allp< 0.05). Moreover, PBMCs from patients with lung cancer showed reduced GSH/GSSG ratios, augmented apurinic/apyrimidinic sites, decreased NER and ICL repair capacities, and lower apoptosis rates, compared with healthy controls (allp< 0.001). Interestingly, PBMCs from patients who are responders are characterized by reduced GSH/GSSG ratios, augmented apurinic/apyrimidinic sites, decreased NER and ICL repair capacities, and higher apoptosis rates compared with patients who are non-responders (allp< 0.01).Conclusions: Together, DDR-associated parameters and redox status measured in PBMCs from patients with lung cancer at baseline are associated with the therapeutic benefit of platinum-based chemotherapy.

摘要翻译： 

背景/目的：DNA损伤应答（DDR）是一个分子通路网络，与多种疾病的发病机制、进展以及化疗疗效密切相关。此外，细胞内氧化还原状态对维持细胞活力和调控细胞信号传导至关重要。本研究分析了不同铂类化疗反应率的肺癌患者外周血单个核细胞（PBMCs）中的DDR信号和氧化还原状态。 方法：在两种肺癌细胞系（A549、H1299）、两种正常成纤维细胞系（WS1、1BR3hT）以及20名健康对照者和32名肺癌患者（其中17名对后续铂类化疗有反应，15名无反应）基线期的PBMCs中，检测了多种DDR相关信号以及以GSH/GSSG比值表示的氧化还原状态。 结果：与正常细胞系相比，肺癌细胞系表现出更高水平的内源性/基线DNA损伤、降低的GSH/GSSG比值、增加的脱嘌呤/脱嘧啶位点，以及更低的核苷酸切除修复（NER）效率和更高的链间交联（ICL）修复效率（所有p<0.05）。此外，与健康对照者相比，肺癌患者的PBMCs显示出降低的GSH/GSSG比值、增加的脱嘌呤/脱嘧啶位点、减弱的NER和ICL修复能力，以及更低的细胞凋亡率（所有p<0.001）。值得注意的是，与无反应患者相比，有反应患者的PBMCs特征为更低的GSH/GSSG比值、更多的脱嘌呤/脱嘧啶位点、更弱的NER和ICL修复能力，以及更高的细胞凋亡率（所有p<0.01）。 结论：综上所述，在肺癌患者基线期PBMCs中检测到的DDR相关参数和氧化还原状态与铂类化疗的治疗获益相关。

原文链接：

DNA Damage Response Network and Intracellular Redox Status in the Clinical Outcome of Patients with Lung Cancer