近日，中国科学院上海药物研究所李序文团队报道了海洋天然产物Chagosendine C通过靶向FDX1诱导结直肠癌细胞铜变性。该研究于2025年9月22日发表在《美国化学会志》上。

结直肠癌（CRC）的治疗受到高复发率和耐药性的阻碍。铜细胞凋亡是一种铜诱导的细胞死亡机制，提供了一种新的治疗方法。

研究组发现了一种海洋天然产物chagosendine C (CHC)，它通过增加细胞内铜离子浓度来杀死肿瘤细胞。研究组快速合成并纯化了CHC及相关金属配位二聚体生物碱，用于进一步药理研究。体外，CHC显著抑制HCT116和RKO结直肠癌细胞生长，诱导G1期阻滞和细胞死亡，克服奥沙利铂耐药。

在体内，40 mg/kg的CHC可抑制小鼠结直肠肿瘤的生长，但无明显的毒性作用。从机制上讲，CHC通过靶向FDX1诱导铜变性，增加肿瘤细胞内铜离子和ROS水平，导致细胞死亡。因此，CHC是一种新的结直肠癌治疗策略，具有较强的抗肿瘤活性和克服奥沙利铂耐药的潜力，具有良好的临床前景。

附：英文原文

Title: Marine Natural Product Chagosendine C Induces Cuproptosis in Colorectal Cancer Cells by Targeting FDX1

Author: Xiaoyu Tao, Hongru Wang, Qun Wang, Chengji Wang, Chang-Wei Shao, Yang Jin, Dianping Yu, Hongmei Hu, Qing Zhang, Mengting Xu, Xiangxin Geng, Hanchi Xu, Linyang Li, Ruling Shen, Yue-Wei Guo, Xu-Wen Li, Sanhong Liu, Weidong Zhang

Issue&Volume: September 22, 2025

Abstract: Colorectal cancer (CRC) treatment is hampered by high recurrence rates and drug resistance. Cuproptosis, a copper-induced cell death mechanism, offers a new therapeutic approach. Here, we identified a marine natural product, chagosendine C (CHC), which kills tumor cells by increasing the intracellular copper ion concentration. CHC and related metal coordination homodimer alkaloids were rapidly synthesized and purified for further pharmacological study. In vitro, CHC significantly inhibited HCT116 and RKO CRC cell growth, induced G1 phase arrest and cell death, and overcame oxaliplatin resistance. In vivo, CHC suppressed colorectal tumor growth in mice at 40 mg/kg without obvious toxic effects. Mechanistically, CHC induces cuproptosis by targeting FDX1, increasing intracellular copper ions and ROS levels in tumor cells, and leading to cell death. Thus, CHC presents a novel CRC treatment strategy, showing strong antitumor activity and potential to overcome oxaliplatin resistance with promising clinical prospects.

DOI: 10.1021/jacs.5c07917

Source: https://pubs.acs.org/doi/full/10.1021/jacs.5c07917