Work

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

Year: 2024

Type: article

Abstract: 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.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.4c00389