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

Autor:	Marinello PC; Laboratory of Molecular Pathology, Department of Pathological Sciences, State University of Londrina, UEL, Londrina, PR, Brazil., Panis C; Laboratory of Tumor Biology, State University of West Parana, Unioeste, Francisco Beltrão, PR, Brazil., Silva TNX; Laboratory of Molecular Pathology, Department of Pathological Sciences, State University of Londrina, UEL, Londrina, PR, Brazil., Binato R; Stem Cell Laboratory, Bone Marrow Transplantation Unit, National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil., Abdelhay E; Stem Cell Laboratory, Bone Marrow Transplantation Unit, National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil., Rodrigues JA; Laboratory of Cancer Biology, Department of Biophysics and Biometrics, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil., Mencalha AL; Laboratory of Cancer Biology, Department of Biophysics and Biometrics, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil., Lopes NMD; Laboratory of Molecular Pathology, Department of Pathological Sciences, State University of Londrina, UEL, Londrina, PR, Brazil., Luiz RC; Laboratory of Molecular Pathology, Department of Pathological Sciences, State University of Londrina, UEL, Londrina, PR, Brazil., Cecchini R; Laboratory of Pathophysiology and Free radicals, Department of Pathological Sciences, State University of Londrina, UEL, Londrina, PR, Brazil., Cecchini AL; Laboratory of Molecular Pathology, Department of Pathological Sciences, State University of Londrina, UEL, Londrina, PR, Brazil. alcecchini@uel.br.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2019 Apr 10; Vol. 9 (1), pp. 5864. Date of Electronic Publication: 2019 Apr 10.
DOI:	10.1038/s41598-019-42357-w
Abstrakt:	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.
Databáze:	MEDLINE
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