Marine Natural Product Chagosendine C Induces Cuproptosis in Colorectal Cancer Cells by Targeting FDX1
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. <i>In vitro</i>, CHC significantly inhibited HCT116 and RKO CRC cell growth, induced G1 phase arrest and cell death, and overcame oxaliplatin resistance. <i>In vivo</i>, 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.
Authors
- Hongmei Hu
- Chengji Wang (ORCID: https://orcid.org/0000-0003-3331-9117)
- Xu‐Wen Li (ORCID: https://orcid.org/0000-0001-7919-9726)
- Yang Jin (ORCID: https://orcid.org/0009-0000-7353-9849)
- Qing Zhang (ORCID: https://orcid.org/0009-0003-6048-203X)
- Ruling Shen (ORCID: https://orcid.org/0000-0002-7529-810X)
- Mengting Xu (ORCID: https://orcid.org/0000-0002-6751-1986)
- Changwei Shao (ORCID: https://orcid.org/0000-0002-6953-2203)
- Sanhong Liu (ORCID: https://orcid.org/0000-0002-8695-0343)
- Xiaoyu Tao (ORCID: https://orcid.org/0009-0000-0634-6254)
- Linyang Li (ORCID: https://orcid.org/0009-0005-4892-6253)
- Hongru Wang (ORCID: https://orcid.org/0000-0001-8305-5231)
- Dianping Yu
- Yue‐Wei Guo (ORCID: https://orcid.org/0000-0003-0413-2070)
- Qun Wang (ORCID: https://orcid.org/0000-0003-4853-1727)
- Weidong Zhang (ORCID: https://orcid.org/0000-0002-4700-1276)
- Hanchi Xu
- Xiangxin Geng
Institutions
- Second Military Medical University (CN)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- State Administration of Traditional Chinese Medicine of the People's Republic of China (CN)
- Peking Union Medical College Hospital (CN)
- Institute of Organic Chemistry with Centre of Phytochemistry (BG)
- Shanghai University of Traditional Chinese Medicine (CN)
- Shanghai Institute of Materia Medica (CN)
- Drug Discovery Laboratory (Norway) (NO)
- Institute of Medicinal Plant Development (CN)
- State Key Laboratory of Chemical Engineering (CN)
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2025-09-22
- DOI
- https://doi.org/10.1021/jacs.5c07917
- Citations
- 4
- Primary Topic
- Marine Sponges and Natural Products
- Type
- article
- Field-Weighted Citation Impact
- 4.93