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1‑Deoxynojirimycin Derivative Containing Tegafur Induced HCT-116 Cell Apoptosis through Mitochondrial Dysfunction and Oxidative Stress Pathway

Three 1-deoxynojirimycin (DNJ) derivatives (named C4–C6) including DNJ and tegafur (TGF) were designed and synthesized, and their antiproliferative effects were investigated. C4–C6, especially C6, exerted good lipophilicity, α-glucosidase inhibitory activity, and antitumor effects. Mechanism studies...

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Bibliographic Details
Published in:ACS medicinal chemistry letters 2024-11, Vol.15 (11), p.1947-1952
Main Authors: Tang, Liqing, Xu, Yixing, He, Jianglong, Huang, Gaiqun, Jiang, Xueping, Li, Yuqi, Li, Hao, Zhang, Ran, Gui, Zhongzheng
Format: Article
Language:English
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Summary:Three 1-deoxynojirimycin (DNJ) derivatives (named C4–C6) including DNJ and tegafur (TGF) were designed and synthesized, and their antiproliferative effects were investigated. C4–C6, especially C6, exerted good lipophilicity, α-glucosidase inhibitory activity, and antitumor effects. Mechanism studies indicated that C6 significantly induced cell apoptosis and S-phase block and inhibited migration of HCT-116 cells. Besides, C6 induced mitochondrial damage by decreasing the mitochondrial membrane potential, improving the accumulation of ROS, upregulating the expression of Bax, and downregulating Bcl-2. Moreover, C6 induced excessive production of ROS to trigger oxidative stress, resulting in an increase in the level of MDA and NO, a decrease in the content of GSH and SOD, and an overexpression of Nrf2. Furthermore, C6 induced DNA damage by down-regulating the expression of thymidylate synthase. These results indicated that C6 is a potential antitumor agent and kills HCT-116 cells through DNA damage, mitochondrial dysfunction, and oxidative stress.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.4c00389