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

IF 15.6 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of the American Chemical Society Pub Date : 2025-09-22 DOI:10.1021/jacs.5c07917

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

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引用次数: 0

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.

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海洋天然产物Chagosendine C通过靶向FDX1诱导结直肠癌细胞铜变性。

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。在这里，我们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。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。体内剂量为40 mg/kg的CHC可抑制小鼠结直肠肿瘤生长，无明显毒性作用。从机制上讲，CHC通过靶向FDX1诱导cuprotosis，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CRC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。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of the American Chemical Society 化学-化学综合

CiteScore

24.40

自引率

6.00%

发文量

2398

审稿时长

1.6 months

期刊介绍： The flagship journal of the American Chemical Society, known as the Journal of the American Chemical Society (JACS), has been a prestigious publication since its establishment in 1879. It holds a preeminent position in the field of chemistry and related interdisciplinary sciences. JACS is committed to disseminating cutting-edge research papers, covering a wide range of topics, and encompasses approximately 19,000 pages of Articles, Communications, and Perspectives annually. With a weekly publication frequency, JACS plays a vital role in advancing the field of chemistry by providing essential research.