The drug metformin, typically prescribed to treat type 2 diabetes, keeps breast cancer cells from developing multiple drug resistance (MDR) and can reverse MDR after it has appeared, according to a study by Terra Arnason from the University of Saskatchewan, Canada, and colleagues.
Previous studies have shown that metformin has some anti-proliferative activity against multiple types of cancer cells. Moreover, clinical meta-analysis studies on cancer patients who already take metformin to treat diabetes have hinted that the drug may boost their survival and prevent the emergence of new tumours.
Arnason and colleagues probed the effect of metformin on the widely studied breast cancer cell line MCF7. Metformin, they found, had an anti-proliferative effect on MCF7, including cells that were resistant to the common chemotherapeutic Doxorubicin. When cells were pre-treated with metformin, the development of drug resistance was prevented or delayed. In addition, experiments conducted in both cell cultures and mouse models of aggressive breast cancer revealed that metformin reversed protein markers associated with MDR after its onset.
These findings establish that metformin has the potential to both reverse MDR in cell lines and prevent its onset. Future research will need to extend the timeline of the study to follow cancer cells for many months and determine if the effect of metformin is permanent or short-lived.
Abstract
Multiple drug resistant (MDR) malignancy remains a predictable and often terminal event in cancer therapy, and affects individuals with many cancer types, regardless of the stage at which they were originally diagnosed or the interval from last treatment. Protein biomarkers of MDR are not globally used for clinical decision-making, but include the overexpression of drug-efflux pumps (ABC transporter family) such as MDR-1 and BCRP, as well as HIF1α, a stress responsive transcription factor found elevated within many MDR tumors. Here, we present the important in vitro discovery that the development of MDR (in breast cancer cells) can be prevented, and that established MDR could be resensitized to therapy, by adjunct treatment with metformin. Metformin is prescribed globally to improve insulin sensitivity, including in those individuals with Type 2 Diabetes Mellitus (DM2). We demonstrate the effectiveness of metformin in resensitizing MDR breast cancer cell lines to their original treatment, and provide evidence that metformin may function through a mechanism involving post-translational histone modifications via an indirect histone deacetylase inhibitor (HDACi) activity. We find that metformin, at low physiological concentrations, reduces the expression of multiple classic protein markers of MDR in vitro and in preliminary in vivo models. Our demonstration that metformin can prevent MDR development and resensitize MDR cells to chemotherapy in vitro, provides important medical relevance towards metformin’s potential clinical use against MDR cancers.
Authors
Gerald Davies, Liubov Lobanova, Wojciech Dawicki, Gary Groot, John R Gordon, Matthew Bowen, Troy Harkness, Terra Arnason
[link url="http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187191"]PLOS One abstract[/link]