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

Three 1-deoxynojirimycin (DNJ) derivatives (named <b>C4</b>-<b>C6</b>) including DNJ and tegafur (TGF) were designed and synthesized, and their antiproliferative effects were investigated. <b>C4</b>-<b>C6</b>, especially <b>C6</b>, exerted good lipophilicity, α-glucosidase inhibitory activity, and antitumor effects. Mechanism studies indicated that <b>C6</b> significantly induced cell apoptosis and S-phase block and inhibited migration of HCT-116 cells. Besides, <b>C6</b> induced mitochondrial damage by decreasing the mitochondrial membrane potential, improving the accumulation of ROS, upregulating the expression of Bax, and downregulating Bcl-2. Moreover, <b>C6</b> 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, <b>C6</b> induced DNA damage by down-regulating the expression of thymidylate synthase. These results indicated that <b>C6</b> is a potential antitumor agent and kills HCT-116 cells through DNA damage, mitochondrial dysfunction, and oxidative stress.