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

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Abstract
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 (all p < 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 (all p < 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 (all p < 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.
Funding Information
  • Hellenic Society of Medical Oncology (HeSMO) (8177/10-02-2021, 9597/19-6-2024)

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