Patterns of cell death induced by metformin in human MCF-7 breast cancer cells.

Autor: Dias Lopes NM; Laboratory of Molecular Pathology, State University of Londrina, Londrina, PR, Brazil., Marinello PC; Laboratory of Molecular Pathology, State University of Londrina, Londrina, PR, Brazil., Sanches LJ; Laboratory of Molecular Pathology, State University of Londrina, Londrina, PR, Brazil., da Silva Brito WA; Laboratory of Molecular Pathology, State University of Londrina, Londrina, PR, Brazil., Lovo-Martins MI; Laboratory of Experimental Immunopathology, State University of Londrina, Londrina, PR, Brazil., Pinge-Filho P; Laboratory of Experimental Immunopathology, State University of Londrina, Londrina, PR, Brazil., Luiz RC; Laboratory of Molecular Pathology, State University of Londrina, Londrina, PR, Brazil., Cecchini R; Laboratory of Pathophysiology and Free Radicals, State University of Londrina, Londrina, PR, Brazil., Cecchini AL; Laboratory of Molecular Pathology, State University of Londrina, Londrina, PR, Brazil. Electronic address: alcecchini@uel.br.
Jazyk: angličtina
Zdroj: Pathology, research and practice [Pathol Res Pract] 2020 Nov; Vol. 216 (11), pp. 153199. Date of Electronic Publication: 2020 Sep 06.
DOI: 10.1016/j.prp.2020.153199
Abstrakt: The ability to evade apoptosis is an important mechanism of drug resistance and tumor progression in breast cancer. The induction of different pathways of cell death could be an important strategy to limit tumor progression. Metformin, a drug used to treat type two diabetes, has demonstrated promising results in breast cancer experiments. However, little is known about the patterns of cell death induced by this drug. We analyzed the involvement of apoptosis, necroptosis and ferroptosis in the toxicity of metformin in MCF-7 cells, evaluating proliferation, viability and oxidative stress. It was used different inhibitors of cell death: Z-VAD, a pan-caspase inhibitor that blocks apoptosis; Necrostatin-1, which inhibits RIPK1 activity and blocks necroptosis; and the iron chelator, deferoxamine, that chelates iron and prevents ferroptosis. The participation of oxidative stress was analyzed through the evaluation of total thiols, reduced glutathione (GSH) and malondialdehyde (MDA). Our results showed that metformin increased cell death, reduced proliferation, thiol and GSH and increased MDA in cells. After the association between metformin and Z-VAD or Necrostatin-1, the drug toxicity was abolished. Ferroptosis did not significantly enrolled in metformin action against MCF-7 cells. The preservation of cellular antioxidants was found in all situations that cell death was blocked. Together, these results reveals that metformin induces necroptosis and apoptosis in MCF-7 cells and oxidative stress generation play a role in these two pathways of cell death. This information could help future studies to improve strategies to breast cancer treatment.
(Copyright © 2020 Elsevier GmbH. All rights reserved.)
Databáze: MEDLINE
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