A novel quinoline derivative, DFIQ, sensitizes NSCLC cells to ferroptosis by promoting oxidative stress accompanied by autophagic dysfunction and mitochondrial damage

• Published in: Cancer cell international 2023-08, Vol.23 (1), p.1-171, Article 171
• Main Authors: Bow, Yung-Ding, Ko, Ching-Chung, Chang, Wen-Tsan, Chou, Sih-Yan, Hung, Chun-Tzu, Huang, Jau-Ling, Tseng, Chih-Hua, Chen, Yeh-Long, Li, Ruei-Nian, Chiu, Chien-Chih
• Format: Article
• Language: English
• Subjects: Antibodies; Antitumor agents; Apoptosis; Autophagic flux disruption; Autophagy; Camptothecin derivative; Cancer therapies; Cell death; Cells; Chemotherapy; Ferroptosis; Immunotherapy; Lipid peroxidation; Lipids; Lung cancer; Metabolism; Microscopy; Mitochondria; Mitochondrial dysfunction; Non-small cell lung carcinoma; NSCLC; Oxidative stress; PD-1 protein; PD-L1 protein; Proteins; Reactive oxygen species; Small cell lung carcinoma; Superoxide dismutase; Therapeutic targets; Tumor cell lines; Variance analysis
• ISSN: 1475-2867; 1475-2867
• DOI: 10.1186/s12935-023-02984-w

BackgroundThe development of nonapoptotic programmed cell death inducers as anticancer agents has emerged as a cancer therapy field. Ferroptosis, ferrous ion-driven programmed cell death that is induced by redox imbalance and dysfunctional reactive oxygen species (ROS) clearance, is triggered during sorafenib and PD-1/PD-L1 immunotherapy. DFIQ, a quinoline derivative, promotes apoptosis by disrupting autophagic flux and promoting ROS accumulation. Our pilot experiments suggest that DFIQ participates in ferroptosis sensitization. Thus, in this study, we aimed to reveal the mechanisms of DFIQ in ferroptosis sensitization and evaluate the clinical potential of DFIQ.MethodsWe treated the non-small cell lung cancer (NSCLC) cell lines H1299, A549, and H460 with the ferroptosis inducer (FI) DFIQ and analyzed viability, protein expression, ROS generation, and fluorescence staining at different time points. Colocalization analysis was performed with ImageJ.ResultsDFIQ sensitized cells to FIs such as erastin and RSL3, resulting in a decrease in IC50 of at least 0.5-fold. Measurement of ROS accumulation to explore the underlying mechanism indicated that DFIQ and FIs treatment promoted ROS accumulation and SOD1/SOD2 switching. Mitochondria, known ROS sources, produced high ROS levels during DFIQ/FI treatment. RSL3 treatment promoted mitochondrial damage and mitophagy, an autophagy-associated mitochondrial recycling system, and cotreatment with DFIQ induced accumulation of mitochondrial proteins, which indicated disruption of mitophagic flux. Thus, autophagic flux was measured in cells cotreated with DFIQ. DFIQ treatment was found to disrupt autophagic flux, leading to accumulation of damaged mitochondria and eventually inducing ferroptosis. Furthermore, the influence of DFIQ on the effects of clinical FIs, such as sorafenib, was evaluated, and DFIQ was discovered to sensitize NSCLC cells to sorafenib and promote ferroptosis.ConclusionsThis study indicates that DFIQ not only promotes NSCLC apoptosis but also sensitizes cells to ferroptosis by disrupting autophagic flux, leading to accumulation of dysfunctional mitochondria and thus to ferroptosis. Ferroptosis is a novel therapeutic target in cancer therapy. DFIQ shows the potential to enhance the effects of FIs in NSCLC and act as a potential therapeutic adjuvant in ferroptosis-mediated therapy.