Feng Li, Tianyu Li, Xuexiang Han, Hao Zhuang, Guangjun Nie, and Huaping Xu
ACS BIOMATER-SCI ENG, 2018, 4, 1954-1962
Selenium is a unique, essential trace element that plays an important role in the antioxidant defense and redox regulation of biological processes. We have reported that novel selenium-containing platinum-based anticancer molecules (EG-Se/Pt) had selective cytotoxicity toward cancer cells. Herein, we found the underlying mechanism of selective cytotoxicity to be closely related to the glutathione antioxidant defense system. Elevated ROS make cancer cells more vulnerable to further elevation of ROS. EG-Se/Pt can induce abnormal increases in ROS by depletion of glutathione. Consequently, the mitochondrial membrane potential collapses and cytochrome c is released, resulting in cell apoptosis. However, EG-Se/Pt analogues, such as EG-Se/Cu and EG-Se/Ni, did not exhibit glutathione depletion capacity or selective killing activity in our investigation, although they can effectively kill cancer cells. These results suggest that the glutathione antioxidant system is an effective target to enable therapeutic selectivity. The amphiphilic property of the selenium-platinum coordination molecules facilitates their assembly into nanoparticles and prolongs the circulation time of the drug in the bloodstream, which is important for in vivo drug delivery. Our in vivo anticancer study demonstrated that the tumor growth inhibition rate of EG-Se/Pt can reach 69 % (p<0.05). What is more encouraging is that EG-Se/Pt exhibited minimal side effects compared to cisplatin. This work also provides new opportunities for the development of therapeutic strategies against cancer.