Aim: Transport experiments with 3H-DG, culture growth and proliferation rate assays were performed.This work aimed to investigate the possible interference of metformin with glucose uptake by MCF-7 and MDA-MB-231 human breast adenocarcinoma cell lines as a mechanism contributing to its anticarcinogenic effect.
Introduction: Breast cancer, the most common cancer among women, remains one of the leading causes of mortality among women worldwide.1 Metformin has been widely used as a treatment for type 2 diabetes for over 40 years.2 The first report of a reduced risk of developing cancer for diabetic patients treated with metformin was published in 2005.3 Several mechanisms of action of metformin appear to be implicated in this effect.2,4
Methods: Transport experiments with 3H-DG, culture growth and proliferation rate assays were performed.
Results: Acute (26min) exposure of MCF-7 cells to metformin significantly inhibited uptake of 3H-deoxy-D-glucose (3H-DG) (maximal inhibition found with metformin 0.5mM: 27±2% reduction). Chronically (24h), metformin induced a concentration-dependent increase in 3H-DG uptake (maximal increase observed with metformin 1mM: 81±15% increase). Acute (26min) exposure of MDA-MB-231 cells to metformin slightly inhibited uptake of 3H-DG (maximal inhibition found with metformin 1mM: 10±3% reduction). Chronic (24h) exposure to metformin significantly increased 3H-DG uptake by MDA-MB-231 cells (maximal increase observed with metformin 1mM: 30±8% increase).
Chronic (24h) exposure of both cell lines to metformin (1mM) decreased culture growth/cell mass; in contrast, it increased cell proliferation rates. Combination of metformin (1mM) with the facilitative glucose transporter (GLUT) inhibitor kaempferol (30μM) did not result in a more marked effect on culture growth and cell proliferation rates.
Conclusion: Summarizing, chronic exposure of MCF-7 and MDA-MB-231 cells to metformin induces a marked increase in glucose uptake, associated with an anticarcinogenic effect of the drug. We suggest that the increase in glucose uptake is a compensatory mechanism to cellular energy depletion induced by metformin.
Acknowledgements: This study was supported by Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal (Plano estratégico UID/BIM/04293/2013).
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