Fluence of metformin on ferroptosis (literature review)

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Abstract

Metformin biguanide is the most widely used oral antidiabetic drug for the treatment of type 2 diabetes mellitus (T2DM). Metformin inhibits gluconeogenesis by suppressing complex I of the respiratory chain, thereby reducing oxygen consumption. In connection with the mechanism of action of metformin, it is of interest to discuss the effect of this drug on the induction or inhibition of one of the types of regulated cell death - ferroptosis. The aim of this study is to summarize the data on the effect of metformin on the development of ferroptosis and the possible use of this drug in chemotherapy through the induction or inhibition of ferroptosis. The work used review and original publications indexed in MedLine, Cochrane Library, PubMed.

The literature accumulates data on the treatment of cancer by inducing ferroptosis. Metformin can reduce the risk of cancer in patients with type 2 diabetes and inhibit cell growth of various cancers, including pancreatic cancer, colon cancer, prostate cancer, ovarian cancer, and breast cancer. Induction of ferroptosis in cancer tissue appears to be optimal when bypassing chemoresistance. Metformin induces ferroptosis by acting on the miR-324-3p/GPX4 axis. For example, in liver cancer, the combination of metformin and sorafenib induces ferroptosis through the p62-Keap1-Nrf2 pathway. Cancer cells require significantly higher concentrations of iron ions for proliferation and progression. The involvement of metformin in iron-dependent cell death has been demonstrated using breast cancer as an example. Ferroptosis is triggered by iron-dependent lipid peroxidation and its regulation is actively assisted by the cystine-glutamate antiporter SLC7A11, which works in close interaction with glutathione peroxidase 4 and glutathione, which regulates peroxidation. The SLC7A11 antiporter regulates glutathione synthesis and these three factors play a key role in the implementation of ferroptosis. A feature of the action of metformin on ferroptosis processes is the relationship with the type of pathology, activation or inhibition of ferroptosis by this agent is intended to optimize biochemical processes. A number of studies are given as examples in which metformin causes inhibition of ferroptosis. In the future, precise verification of the metabolic pathways by which metformin induces or inhibits ferroptosis is of paramount importance for the effective treatment of a wide range of pathologies.

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About the authors

A. A. Nikolaev

Astrakhan State Medical University of the Ministry of Health of the Russian Federation

Author for correspondence.
Email: chimnik@mail.ru

Dr.Sc. (Med.), Professor

Russian Federation, Bakinskaya str., 121, Astrakhan, 414000

M. V. Ushakova

Astrakhan State Medical University of the Ministry of Health of the Russian Federation

Email: chimnik@mail.ru

Ph.D. (Biol.), Associate Professor

Russian Federation, Bakinskaya str., 121, Astrakhan, 414000

M. V. Boskhomdzhieva

Budgetary institution of the Republic of Kalmykia "Republican Oncology Dispensary named after Timoshkaeva E.S."

Email: chimnik@mail.ru

Deputy Chief Physician for Medical Work

Russian Federation, Suseeva str. 17, Elista, Republic of Kalmykia, 358000

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