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Antitumor effect of metformin is mediated by AMPK and FOXO3a
Author(s) -
Fonseca Eveline Aparecida Isquierdo,
Oliveira Maria A.,
Eichler Rosangela,
Akamine Eliana H.,
Carvalho Maria Helena C.,
Tostes Rita C.,
Barbosa Aneli M.,
Dekker Robert F.H.,
Khaper Neelam,
Fortes Zuleica B.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1038.10
Subject(s) - metformin , ampk , apoptosis , flow cytometry , oxidative stress , medicine , mtt assay , western blot , cell cycle , chemistry , endocrinology , pharmacology , cancer , diabetes mellitus , immunology , kinase , protein kinase a , biochemistry , gene
The objective of this study was to analyze the antitumor effect of metformin in‐vitro and in‐vivo. Breast cancer MCF‐7 cells were treated with metformin for 24, 48 and 72h. Antiproliferative activity was analyzed by the MTT assay. Oxidative stress was measured by the CM‐H 2 DCFDA assay. Apoptosis and cell cycle were analyzed by flow cytometry. mRNA expression was determined by RT‐PCR and protein expression by Western Blot. Metformin demonstrated an time‐ and dose‐dependent antiproliferative effect. This effect was associated with an increase in oxidative stress, apoptosis and cell cycle arrest. And, an increase in AMPK and FOXO3a activity was observed. Control and obese rats of 16 weeks of age received Walker‐256 tumor cells(1×10 7 cells/mL, sc) and metformin(300mg/kg, by gavage, for 15d, CTM and OTM). Control rats received tap water (CT and OT). On the 18 th week the tumor development was analyzed. Tumor development was higher in OT rats than compared with CT. Metformin reduced it and increased the pRb and p27 mRNA expression. In conclusion, we demonstrated that metformin has an antitumor effect which was mediated by pRb, p27, AMPK and FOXO3a. Financial support: FAPESP(Brazil), NSERC‐RCD and NOSM(Canada)