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Metformin prevention of doxorubicin resistance in MCF-7 and MDA-MB-231 involves oxidative stress generation and modulation of cell adaptation genes
Metformin was shown to sensitize multidrug resistant breast cancer cells; however, the mechanisms involved in this capacity need to be clarified. We investigated oxidative stress and inflammatory-related pathways during the induction of doxorubicin resistance in MCF-7 and MDA-MB-231 human breast can...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458149/ https://www.ncbi.nlm.nih.gov/pubmed/30971831 http://dx.doi.org/10.1038/s41598-019-42357-w |
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author | Marinello, Poliana Camila Panis, Carolina Silva, Thamara Nishida Xavier Binato, Renata Abdelhay, Eliana Rodrigues, Juliana Alves Mencalha, André Luiz Lopes, Natália Medeiros Dias Luiz, Rodrigo Cabral Cecchini, Rubens Cecchini, Alessandra Lourenço |
author_facet | Marinello, Poliana Camila Panis, Carolina Silva, Thamara Nishida Xavier Binato, Renata Abdelhay, Eliana Rodrigues, Juliana Alves Mencalha, André Luiz Lopes, Natália Medeiros Dias Luiz, Rodrigo Cabral Cecchini, Rubens Cecchini, Alessandra Lourenço |
author_sort | Marinello, Poliana Camila |
collection | PubMed |
description | Metformin was shown to sensitize multidrug resistant breast cancer cells; however, the mechanisms involved in this capacity need to be clarified. We investigated oxidative stress and inflammatory-related pathways during the induction of doxorubicin resistance in MCF-7 and MDA-MB-231 human breast cancer cells (DOX-res group), and evaluated metformin-induced cellular responses that resulted in the prevention of doxorubicin resistance (Met-DOX group). Microarray analysis demonstrated that DOX-res changed the expression of genes involved in oxidative stress (OS) and the TGF- β1 pathway. The DOX-res group presented increased thiols and reduced lipoperoxidation, increased levels of nitric oxide, nuclear NF-kB and Nrf2, and reduced nuclear p53 labelling. Analysis of the TGF-β1 signaling pathway by RT-PCR array showed that DOX-res developed adaptive responses, such as resistance against apoptosis and OS. Metformin treatment modified gene expression related to OS and the IFN-α signaling pathway. The Met-DOX group was more sensitive to DOX-induced OS, presented lower levels of nitric oxide, nuclear NF-kB and Nrf2, and increased nuclear p53. Analysis of the IFN-α signaling pathway showed that Met-DOX presented more sensitivity to apoptosis and OS. Our findings indicate that metformin is a promising tool in the prevention of chemoresistance in patients with breast cancer submitted to doxorubicin-based treatments. |
format | Online Article Text |
id | pubmed-6458149 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-64581492019-04-15 Metformin prevention of doxorubicin resistance in MCF-7 and MDA-MB-231 involves oxidative stress generation and modulation of cell adaptation genes Marinello, Poliana Camila Panis, Carolina Silva, Thamara Nishida Xavier Binato, Renata Abdelhay, Eliana Rodrigues, Juliana Alves Mencalha, André Luiz Lopes, Natália Medeiros Dias Luiz, Rodrigo Cabral Cecchini, Rubens Cecchini, Alessandra Lourenço Sci Rep Article Metformin was shown to sensitize multidrug resistant breast cancer cells; however, the mechanisms involved in this capacity need to be clarified. We investigated oxidative stress and inflammatory-related pathways during the induction of doxorubicin resistance in MCF-7 and MDA-MB-231 human breast cancer cells (DOX-res group), and evaluated metformin-induced cellular responses that resulted in the prevention of doxorubicin resistance (Met-DOX group). Microarray analysis demonstrated that DOX-res changed the expression of genes involved in oxidative stress (OS) and the TGF- β1 pathway. The DOX-res group presented increased thiols and reduced lipoperoxidation, increased levels of nitric oxide, nuclear NF-kB and Nrf2, and reduced nuclear p53 labelling. Analysis of the TGF-β1 signaling pathway by RT-PCR array showed that DOX-res developed adaptive responses, such as resistance against apoptosis and OS. Metformin treatment modified gene expression related to OS and the IFN-α signaling pathway. The Met-DOX group was more sensitive to DOX-induced OS, presented lower levels of nitric oxide, nuclear NF-kB and Nrf2, and increased nuclear p53. Analysis of the IFN-α signaling pathway showed that Met-DOX presented more sensitivity to apoptosis and OS. Our findings indicate that metformin is a promising tool in the prevention of chemoresistance in patients with breast cancer submitted to doxorubicin-based treatments. Nature Publishing Group UK 2019-04-10 /pmc/articles/PMC6458149/ /pubmed/30971831 http://dx.doi.org/10.1038/s41598-019-42357-w Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Marinello, Poliana Camila Panis, Carolina Silva, Thamara Nishida Xavier Binato, Renata Abdelhay, Eliana Rodrigues, Juliana Alves Mencalha, André Luiz Lopes, Natália Medeiros Dias Luiz, Rodrigo Cabral Cecchini, Rubens Cecchini, Alessandra Lourenço Metformin prevention of doxorubicin resistance in MCF-7 and MDA-MB-231 involves oxidative stress generation and modulation of cell adaptation genes |
title | Metformin prevention of doxorubicin resistance in MCF-7 and MDA-MB-231 involves oxidative stress generation and modulation of cell adaptation genes |
title_full | Metformin prevention of doxorubicin resistance in MCF-7 and MDA-MB-231 involves oxidative stress generation and modulation of cell adaptation genes |
title_fullStr | Metformin prevention of doxorubicin resistance in MCF-7 and MDA-MB-231 involves oxidative stress generation and modulation of cell adaptation genes |
title_full_unstemmed | Metformin prevention of doxorubicin resistance in MCF-7 and MDA-MB-231 involves oxidative stress generation and modulation of cell adaptation genes |
title_short | Metformin prevention of doxorubicin resistance in MCF-7 and MDA-MB-231 involves oxidative stress generation and modulation of cell adaptation genes |
title_sort | metformin prevention of doxorubicin resistance in mcf-7 and mda-mb-231 involves oxidative stress generation and modulation of cell adaptation genes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458149/ https://www.ncbi.nlm.nih.gov/pubmed/30971831 http://dx.doi.org/10.1038/s41598-019-42357-w |
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