Discovery of Cytotoxic Nitric Oxide-Releasing Piperlongumine Derivatives Targeting Wnt/β-Catenin in Colon Cancer Cells

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2024-08, Vol.87 (8), p.1893-1902
• Main Authors: Zou, Yu, He, Yuying, Tan, Lijuan, Xu, Xiaofei, Qi, Changxing, Zhang, Yonghui
• Format: Article
• Language: English
• Subjects: apoptosis; cancer therapy; cell lines; cell proliferation; colorectal neoplasms; cytotoxicity; neoplasm cells; nitric oxide; oxidative stress; reactive oxygen species
• ISSN: 0163-3864; 1520-6025; 1520-6025
• DOI: 10.1021/acs.jnatprod.4c00084

Piperlongumine (1) increases reactive oxygen species (ROS) levels and induces apoptosis in cancer cells through various pathways. Nitric oxide (NO) donors have demonstrated potent anticancer activities with exogenous NO being oxidized by ROS in the tumor microenvironment to form highly reactive N-oxides (RNOS). This amplifies oxidative stress cascade reactions, ultimately inducing cancer cell apoptosis. To exploit this synergy, a series of NO-releasing piperlongumine derivatives (2–5) were designed and synthesized. These compounds were expected to release NO in cancer cells, simultaneously generating piperlongumine derivative fragments to enhance the anticancer effects. Compound 6, structurally similar to compounds 2–5 but not releasing NO, served as a control. Among these derivatives, compound 5 exhibited the most potent antiproliferative activity against HCT-116 cells and efficiently released NO in this cell line. Further investigation revealed that compound 5 inhibited colon cancer cell proliferation by modulating β-catenin expression, which is a pivotal protein in the Wnt/β-catenin signaling pathway. These findings highlight compound 5 as a promising candidate for colon cancer treatment targeting the Wnt/β-catenin pathway.