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

Yung-Ding Bow; Ching-Chung Ko; Wen-Tsan Chang; Sih-Yan Chou; Chun-Tzu Hung; Jau-Ling Huang; Chih-Hua Tseng; Yeh-Long Chen; Ruei-Nian Li; Chien-Chih Chiu

doi:10.1186/s12935-023-02984-w

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

Cancer Cell Int. 2023 Aug 16;23(1):171. doi: 10.1186/s12935-023-02984-w.

Authors

Yung-Ding Bow¹, Ching-Chung Ko^{2

3}, Wen-Tsan Chang^{4

5}, Sih-Yan Chou⁶, Chun-Tzu Hung⁶, Jau-Ling Huang⁷, Chih-Hua Tseng⁸, Yeh-Long Chen⁹, Ruei-Nian Li¹⁰, Chien-Chih Chiu^{11

12

13

14

15}

Affiliations

¹ PhD Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
² Department of Medical Imaging, Chi Mei Medical Center, Tainan, 71004, Taiwan.
³ Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, 71710, Taiwan.
⁴ Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, 80708, Taiwan.
⁵ Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
⁶ Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
⁷ Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan, 71101, Taiwan.
⁸ School of Pharmacy, College of Pharmacy, Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
⁹ Department of Medicinal and Applied Chemistry, Drug Development and Value Creation Research Center, Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan. yeloch@kmu.edu.tw.
¹⁰ Department of Biomedical Science and Environment Biology, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan. runili@kmu.edu.tw.
¹¹ Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan. cchiu@kmu.edu.tw.
¹² Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 80708, Taiwan. cchiu@kmu.edu.tw.
¹³ Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, 80424, Taiwan. cchiu@kmu.edu.tw.
¹⁴ Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan. cchiu@kmu.edu.tw.
¹⁵ National Laboratory Animal Center, National Applied Research Laboratories, Taipei, 11571, Taiwan. cchiu@kmu.edu.tw.

Abstract

Background: The 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.

Methods: We 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.

Results: DFIQ 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.

Conclusions: This 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.

Keywords: Autophagic flux disruption; Camptothecin derivative; Chemotherapy; Ferroptosis; Mitochondrial dysfunction; NSCLC; ROS imbalance.

Abstract

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