Directly targeting glutathione peroxidase 4 may be more effective than disrupting glutathione on ferroptosis-based cancer therapy

Publication date: Available online 18 January 2020Source: Biochimica et Biophysica Acta (BBA) - General SubjectsAuthor(s): Yunpeng Wei, Huanhuan Lv, Atik Badshah Shaikh, Wei Han, Hongjie Hou, Zhihao Zhang, Shenghang Wang, Peng ShangAbstractBackgroundCancer is one of the major threats to human health and current cancer therapies have been unsuccessful in eradicating it. Ferroptosis is characterized by iron-dependence and lipid hydroperoxides accumulation, and its primary mechanism involves the suppression of system Xc−-GSH (glutathione)-GPX4 (glutathione peroxidase 4) axis. Co-incidentally, cancer cells are also metabolically characterized by iron addiction and ROS tolerance, which makes them vulnerable to ferroptosis. This may provide a new tactic for cancer therapy.Scope of reviewThe general features and mechanisms of ferroptosis, and the basis that makes cancer cells vulnerable to ferroptosis are described. Further, we emphatically discussed that disrupting GSH may not be ideal for triggering ferroptosis of cancer cells in vivo, but directly inhibiting GPX4 and its compensatory members could be more effective. Finally, the various approaches to directly inhibit GPX4 without disturbing GSH were described.Major conclusionsTargeting system Xc− or GSH may not effectively trigger cancer cells' ferroptosis in vivo the existence of other compensatory pathways. However, directly targeting GPX4 and its compensatory members without disrupting GSH may be more effective to induce f...

Source: Biochimica et Biophysica Acta (BBA) General Subjects - January 18, 2020 Category: Biochemistry Source Type: research