Tsai Sheng-Chieh, Chang Po-Chih, Lin Yu Tong, Huang Po-Tsang, Chen Jeff Yi-Fu, Lin Chang-Shen, Wu Bin-Nan, Chang Hui-Min, Wu Wan-Ju, Chang Chi-I, Lee Chien-Hsing
Division of Pharmacology and Traditional Chinese Medicine, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City 80708, Taiwan.
School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung City 804201, Taiwan.
Int J Biol Sci. 2024 Nov 11;20(15):6090-6113. doi: 10.7150/ijbs.99859. eCollection 2024.
Ferroptosis, a mode of cell death characterized by iron-dependent phospholipid peroxidation, has a substantial therapeutic potential for the treatment of various cancers. This study investigated the effects of trifluoperazine (TFP), an FDA-approved drug traditionally utilized for mental health disorder, on oral cancer cells, with a particular focus on the mechanisms involved in its potential anti-tumor properties. Our findings indicate that TFP significantly elevates the levels of lipid-derived reactive oxygen species (ROS) and induces ferroptotic cell death in oral cancer cells through pathways involving autophagy, the SLC7A11/GPX4 axis, and mitochondrial damage. Additionally, molecular docking analyses revealed that TFP acts as an inhibitor of GPX4. The elevated expression level of GPX4 in oral cancer biopsies was also found to correlate with a poor prognosis. Together, these results provide evidence that TFP selectively induces GPX4-mediated, autophagy-dependent ferroptosis, thereby exerting anti-cancer effects against oral cancer and preventable death.
铁死亡是一种以铁依赖性磷脂过氧化为特征的细胞死亡方式，在各种癌症的治疗中具有巨大的治疗潜力。本研究调查了三氟拉嗪（TFP），一种传统上用于治疗精神健康障碍的FDA批准药物，对口腔癌细胞的影响，特别关注其潜在抗肿瘤特性所涉及的机制。我们的研究结果表明，TFP显著提高了脂质衍生的活性氧（ROS）水平，并通过涉及自噬、SLC7A11/GPX4轴和线粒体损伤的途径诱导口腔癌细胞发生铁死亡。此外，分子对接分析表明TFP可作为GPX4的抑制剂。还发现口腔癌活检中GPX4的高表达水平与预后不良相关。总之，这些结果提供了证据，表明TFP选择性地诱导GPX4介导的、自噬依赖性铁死亡，从而对口腔癌发挥抗癌作用并预防死亡。
