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| 標題: | A novel quinoline derivative, DFIQ, sensitizes NSCLC cells to ferroptosis by promoting oxidative stress accompanied by autophagic dysfunction and mitochondrial damage |
| 作者: | 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 |
| 貢獻者: | Kaohsiung Med Univ, Coll Life Sci, PhD Program Life Sci
Chi Mei Med Ctr, Dept Med Imaging
Chia Nan Univ Pharm & Sci, Dept Hlth & Nutr
Kaohsiung Med Univ Hosp, Dept Surg, Div Gen & Digest Surg
Kaohsiung Med Univ, Coll Med, Sch Med, Dept Surg
Kaohsiung Med Univ, Dept Biotechnol
Chang Jung Christian Univ, Coll Hlth Sci, Dept Biosci Technol
Kaohsiung Med Univ, Coll Pharm, Drug Dev & Value Creat Res Ctr, Sch Pharm
Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Drug Dev & Value Creat Res Ctr, Dept Med & Appl Chem,Dept Med Res
Kaohsiung Med Univ, Dept Biomed Sci & Environm Biol
Kaohsiung Med Univ Hosp, Dept Med Res
Natl Sun Yat Sen Univ, Dept Biol Sci
Kaohsiung Med Univ, Ctr Canc Res
Natl Appl Res Labs, Natl Lab Anim Ctr |
| 關鍵字: | NSCLC
Ferroptosis
Chemotherapy
Camptothecin derivative
Mitochondrial dysfunction
Autophagic flux disruption
ROS imbalance |
| 日期: | 2023 |
| 上傳時間: | 2024-12-25 11:03:28 (UTC+8) |
| 出版者: | BMC |
| 摘要: | 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. |
| 關聯: | Cancer Cell International, v.23, n.1, Article 171 |
| 顯示於類別: | [行政單位] 456
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