Journal
GENES & DISEASES
Volume 9, Issue 2, Pages 334-346Publisher
ELSEVIER
DOI: 10.1016/j.gendis.2020.09.005
Keywords
Cancer therapy; Erastin; Ferroptosis; GPX4; Lipid peroxidation; Nanomedicine; RSL3; System Xc
Funding
- National Institutes of Health [R01CA240966]
- US Department of Defense award [W81XWH1910587]
- U.S. Department of Defense (DOD) [W81XWH1910587] Funding Source: U.S. Department of Defense (DOD)
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Ferroptosis is a new form of regulated cell death that is characterized by iron dependency and lipid peroxidation. It is involved in various pathological conditions and holds promise for cancer therapy. Inhibiting lipid peroxidation and targeting GPX4, a key enzyme in the prevention of lipid hydroperoxide accumulation, can induce ferroptosis. Several agents and strategies have been developed to induce ferroptosis, which can effectively target therapy-resistant cancer cells.
Ferroptosis, a new form of non-apoptotic, regulated cell death characterized by iron dependency and lipid peroxidation, is involved in many pathological conditions such as neurodegenerative diseases, heart ischemia/reperfusion injury, acute renal failure, and cancer. While metabolic dysfunctions can lead to excessive lipid peroxidation culminating in ferroptotic cell death, glutathione peroxidase 4 (GPX4) resides in the center of a network that functions to prevent lipid hydroperoxides from accumulation, thereby suppressing ferroptosis. Indeed, RSL3 and other small-molecule GPX4 inhibitors can induce ferroptosis in not only cultured cancer cells but also tumor xenografts implanted in mice. Similarly, erastin and other system Xc(-) inhibitors can deplete intracellular glutathione required for GPX4 function, leading to lipid peroxidation and ferroptosis. As therapy-resistant cancer cells are sensitive to GPX4-targeted therapeutic regimens, the agents capable of inducing ferroptosis hold great promises to improve current cancer therapy. This review will outline the molecular basis of ferroptosis, but focus on the strategies and the agents developed in recent years for therapeutic induction of ferroptosis. The potentials of these ferroptosis-inducing agents, which include system Xc(-) inhibitors, GPX4 inhibitors, and iron-based nanoparticles, in cancer therapy will be subsequently discussed. Copyright (C) 2020, Chongqing Medical University. Production and hosting by Elsevier B.V.
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