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

• Published in: Scientific reports 2019-04, Vol.9 (1), p.5864-5864, Article 5864
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 13/106; 38/39; 38/47; 38/90; 45/77; 631/67/1347; 631/80/86/2366; 96/1; 96/106; Antibiotics, Antineoplastic - pharmacology; Antidiabetics; Apoptosis; Apoptosis - drug effects; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Line, Tumor; Chemoresistance; DNA microarrays; Doxorubicin; Doxorubicin - pharmacology; Drug Resistance, Neoplasm - drug effects; Female; Gene expression; Humanities and Social Sciences; Humans; Inflammation; Interferon-alpha - metabolism; Labeling; Lipid Peroxidation - drug effects; MCF-7 Cells; Metformin; Metformin - pharmacology; multidisciplinary; Multidrug resistance; NF-κB protein; Nitric oxide; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - genetics; p53 Protein; Polymerase chain reaction; Prevention; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; Thiols; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; α-Interferon
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-42357-w

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.