Metformin prevention of doxorubicin resistance in MCF-7 and MDA-MB-231 involves oxidative stress generation and modulation of cell adaptation genes. View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

Poliana Camila Marinello, Carolina Panis, Thamara Nishida Xavier Silva, Renata Binato, Eliana Abdelhay, Juliana Alves Rodrigues, André Luiz Mencalha, Natália Medeiros Dias Lopes, Rodrigo Cabral Luiz, Rubens Cecchini, Alessandra Lourenço Cecchini

ABSTRACT

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. More... »

PAGES

5864

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-019-42357-w

DOI

http://dx.doi.org/10.1038/s41598-019-42357-w

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1113356026

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30971831


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