1. Academic Validation
  2. Identification of a ferritinophagy inducer via sinomenine modification for the treatment of colorectal cancer

Identification of a ferritinophagy inducer via sinomenine modification for the treatment of colorectal cancer

  • Eur J Med Chem. 2024 Feb 21:268:116250. doi: 10.1016/j.ejmech.2024.116250.
Ling Zhu 1 Chen Chen 1 Yuxing Cai 1 Yalin Li 1 Lijie Gong 1 Tianyu Zhu 1 Lingyi Kong 2 Jianguang Luo 3
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: cpu_lykong@126.com.
  • 3 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: luojg@cpu.edu.cn.
Abstract

Ferritinophagy is a cellular process to release redox-active iron. Excessive activation of ferritinophagy ultimately results in Ferroptosis characterized by ROS accumulation which plays important roles in the development and progression of Cancer. Sinomenine, a main bioactive alkaloid from the traditional Chinese medicine Sinomenum acutum, inhibits the proliferation of Cancer cells by promoting ROS production. Herein, new compounds were designed and synthesized through the stepwise optimization of sinomenine. Among them, D3-3 induced the production of lipid ROS, and significantly promoted colorectal Cancer cells to release the ferrous ion in an autophagy-dependent manner. Moreover, D3-3 enhanced the interaction of FTH1-NCOA4, indicating the activation of ferritinophagy. In vivo experiments showed that D3-3 restrained tumor growth and promoted lipid peroxidation in the HCT-116 xenograft model. These findings demonstrated that D3-3 is an inducer of ferritinophagy, eventually triggering Ferroptosis. Compound D3-3, as the first molecule to be definitively demonstrated to induce ferritinophagy, is worth further evaluation as a promising drug candidate in the treatment of colorectal Cancer.

Keywords

Colorectal cancer; FTH1-NCOA4 protein-protein interaction; Ferritinophagy; Lipid ROS; Sinomenine derivatives.

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