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  • Title: Effect of metformin on estrogen and progesterone receptor-positive (MCF-7) and triple-negative (MDA-MB-231) breast cancer cells.
    Author: Amaral I, Silva C, Correia-Branco A, Martel F.
    Journal: Biomed Pharmacother; 2018 Jun; 102():94-101. PubMed ID: 29550639.
    Abstract:
    This work aimed to investigate the effect of metformin on cellular glucose uptake and metabolism by breast cancer cells, as a mechanism contributing to its anticancer properties. Estrogen and progesterone receptor-positive (MCF-7) and triple-negative (MDA-MB-231) breast cancer cell lines were used as in vitro models of breast cancer. Short-term (26 min) exposure of MCF-7 and MDA-MB-231 cells to metformin inhibited uptake of 3H-deoxy-D-glucose (3H-DG). In contrast, long-term (24 h) exposure to metformin (5 μM-1 mM) concentration-dependently increased 3H-DG uptake in both cell lines. This effect was associated with an increase in lactate production but was not associated with changes in GLUT1 mRNA expression. Long-term exposure of MCF-7 and MDA-MB-231 cells to metformin (5 μM-1 mM) concentration-dependently reduced cell viability and culture mass and slightly increased cell proliferation rates. Combination of metformin (1 mM) with the facilitative glucose transporter (GLUT) inhibitor kaempferol (30 μM) did not change the effect of metformin on culture growth. In conclusion, short-term exposure to metformin reduces cellular glucose uptake, probably by direct inhibition of GLUT1. However, after long-term exposure to metformin, cellular uptake of glucose is significantly increased, not associated to changes in GLUT1 transcription rates. We suggest that, in the long-term, metformin induces a compensatory increase in glucose uptake in response to cellular energy depletion resulting from its inhibitory effect on mitochondrial oxidative phosphorylation machinery. Metformin-induced dependence of breast cancer cells on glycolytic pathway, associated with an anticarcinogenic effect of the drug, provides a biochemical basis for the design of new therapeutic strategies.
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