Department of Oncology, Wuxi No.2 Chinese Medicine Hospital, Wuxi, Jiangsu, China.
Department of Oncology, Wuxi Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, Jiangsu, China.
Chem Biol Drug Des. 2024 Aug;104(2):e14560. doi: 10.1111/cbdd.14560.
Alantolactone (ALT), a natural sesquiterpene lactone from Inula helenium L., demonstrates potent antitumor activity in various human cancers, notably non-small cell lung cancer (NSCLC). Despite its recognized efficacy, the precise mechanisms of action remain elusive. Our study aimed to elucidate ALT's impact on NSCLC. Our findings suggested that ALT triggered apoptosis both in vitro and in vivo, underscoring its anticancer potential. Interestingly, the ferroptosis inhibitor (Fer-1), rather than necrostatin-1 (Nec-1) or Z-VAD-FMK, rescued ALT-induced cell death, implicating ferroptosis as pivotal. Subsequent analyses revealed ferroptosis as the primary mechanism underlying ALT-induced NSCLC cell death, supported by markers including ROS accumulation, MDA elevation, GSH depletion, Fe generation, and GPX4 reduction. Through DARTS/MS proteomics, we identified FTH1 as the target of ALT-induced ferroptosis. Immunoblotting confirmed ALT's inhibition of FTH1 protein expression and accelerated its degradation in NSCLC cells. Immunoprecipitation assays demonstrated increased FTH1 ubiquitination induced by ALT. Additionally, ALT induced ferroptosis and facilitated Fe accumulation via FTH1 ubiquitination. Importantly, ALT displayed potent antitumor effects in a subcutaneous xenograft model in BALB/c-nu/nu nude mice by enhancing ferroptosis. In summary, ALT induced ferroptosis by promoting intracellular Fe accumulation through accelerated FTH1 degradation, highlighting its potential as an antitumor agent targeting ferroptosis.
冬凌草甲素（ALT）是一种来自土木香的天然倍半萜内酯，在多种人类癌症中表现出很强的抗肿瘤活性，特别是非小细胞肺癌（NSCLC）。尽管其疗效已得到认可，但确切的作用机制仍不清楚。我们的研究旨在阐明 ALT 对 NSCLC 的影响。我们的研究结果表明，ALT 在体外和体内都能触发细胞凋亡，凸显了其抗癌潜力。有趣的是，铁死亡抑制剂（Fer-1），而不是 Nec-1 或 Z-VAD-FMK，能挽救 ALT 诱导的细胞死亡，表明铁死亡是关键。随后的分析表明，铁死亡是 ALT 诱导的 NSCLC 细胞死亡的主要机制，这一结论得到了包括 ROS 积累、MDA 升高、GSH 耗竭、Fe 生成和 GPX4 减少等标志物的支持。通过 DARTS/MS 蛋白质组学，我们鉴定出 FTH1 是 ALT 诱导铁死亡的靶标。免疫印迹证实 ALT 抑制了 NSCLC 细胞中 FTH1 蛋白的表达并加速其降解。免疫沉淀试验表明，ALT 诱导 FTH1 泛素化增加。此外，ALT 通过 FTH1 泛素化诱导铁死亡和促进 Fe 积累。重要的是，ALT 通过增强铁死亡在 BALB/c-nu/nu 裸鼠的皮下异种移植模型中显示出很强的抗肿瘤作用。总之，ALT 通过加速 FTH1 降解促进细胞内 Fe 积累诱导铁死亡，突出了其作为一种针对铁死亡的抗肿瘤药物的潜力。
