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CHARACTERISTICS OF FERROPTOSE INDUCTORS (REVIEW)

DOI: https://doi.org/10.29296/25877313-2023-06-05
Issue: 
6
Year: 
2023

A.A. Nikolaev
Dr.Sc. (Med.), Professor,
Federal State Budgetary Educational Institution of Higher Education "Astrakhan State Medical University"
of the Ministry of Health of the Russian Federation (Astrakhan, Russia)
E-mail: chimnik@mail.ru
M.V. Ushakova
Ph.D. (Biol.), Associate Professor,
Federal State Budgetary Educational Institution of Higher Education "Astrakhan State Medical University"
of the Ministry of Health of the Russian Federation (Astrakhan, Russia)

Ferroptosis is an iron-dependent non-apoptotic form of regulated cell death. In 2012, the anti-cancer activity of erastin was shown, based on the induc-tion of a new type of cell death, which is prevented by iron chelators and lipophilic antioxidants. The term "ferroptosis" has been proposed to character-ize this iron-dependent, non-apoptotic form of cell death. The purpose of this work is to evaluate and classify the range of compounds capable of in-ducing ferroptosis in various cell types. Glutathione (GSH), a common intracellular antioxidant, is required for the activity of various antioxidant enzymes (eg, GPX4). Erastine inhibits the uptake of cystine by the cystine/glutamate antiporter, creating a defect in the cell's antioxidant defenses and leading to iron-dependent oxidative death. GPX4 is a selenium-containing enzyme that catalyzes the reduction of organic hydroperoxides and lipid peroxides by reduced glutathione. The study re-vealed two promising compounds, named RSL3 and RSL5 by the authors. Tert-butyl hydroperoxide (t-BuOOH) is such a lipid peroxide analog and is widely regarded as a lipid peroxidation stimulant. Exposure to t-BuOOH resulted in a ferrostatin-1 and liprostatin-1 sensitive increase in lipid peroxidation. An excess of non-heme iron (Fe2+ and Fe3+) causes ferroptosis. Live/dead cell viability analysis showed that Fe(III)-citrate, erastin and RSL3 induce cell death. Co-treatment with ferrostatin-1, an inhibitor of ferroptosis, inhibited cell death. Other materials can cause ferroptosis by inducing lipid peroxidation. Mitochondrial DNA damaging drugs such as zalcitabine induce autophagy-dependent ferroptosis in human pancreatic cancer cells. The implementation of the model of cell death in the form of ferroptosis is highly dependent on the state of cellular metabolism and degradation systems, such as autophagy, which form a complex network for the formation of oxidative stress. Pharmacological induction of ferroptosis is a promising direction in cancer chemotherapy.
Keywords: 
ferroptosis
induction
glutathione peroxidase
glutathione
targeted therapy.
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