From DNMT1 degrader to ferroptosis promoter: Drug repositioning of 6-Thioguanine as a ferroptosis inducer in gastric cancer
Jinping Zhang, Mei‐Mei Gao, Yingjie Niu, Jiangang Sun
Abstract
Though various therapeutic strategies have been developed to overcome gastric cancer, the overall prognosis and therapeutic effect are still not optimistic. As a novel identified type of cell death, ferroptosis has been considered as a promising tumor suppression mechanism with therapeutic potential against gastric cancer. In this work, we screened a collection of 4890 bioactivity compounds and committed to find novel agents that can induce apoptosis in gastric cancer. Among these compounds, 6-TG was identified as a potential ferroptosis inducer in gastric cancer cells for the first time. It could inactivate system xc−, block the generation of GSH, down-regulate the expression of GPX4, increase the level of lipid ROS, and finally trigger the Fe2+-mediated ferroptosis in MGC-803 and AGS cell lines. The date in vivo also suggested that compound 6-TG performed anti-tumor activity via inducing ferroptosis. These findings gave a support for 6-TG may play as a novel leading compound for gastric cancer treatment as a ferroptosis inducer.