Breast, colon, lung and hematological cancers “have high rates” of acquired resistance to chemotherapy drugs, including aromatase inhibitors for breast cancer. This phenomena, multiple drug resistance (MDR), is a major impediment to long-term cancer treatment.
That makes this research, published online December 6, 2017, groundbreaking.
[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 (emphasis added).
Metformin is a generic drug used to treat diabetes. It is already a promising treatment: for diabetic patients, metformin provides about a 30% reduction across the board in cancer risk. Even James Watson, the father of DNA, takes metformin as a preventative.
In addition, in vitro research shows metformin has an antiproliferative effect against multiple cancer cells lines.
Although researchers are still unclear on how metformin works, they know what it does: it improves the body’s sensitivity to insulin, the hormone that controls the level of sugar in your blood. Thus metformin helps control diabetes, a disease marked by excessive levels of blood glucose.
In 2010, researchers summarized the problem of MDR thusly:
Resistance exists against every effective anticancer drug and can develop by numerous mechanisms including decreased drug uptake, increased drug efflux, activation of detoxifying systems, activation of DNA repair mechanisms, evasion of drug-induced apoptosis.
Returning to the latest MDR research:
We demonstrate the effectiveness of metformin in resensitizing MDR breast cancer cell lines to their original treatment [not unlike its response in diabetes]… 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 (emphasis added).
This in vitro research showed that metformin was antiproliferative regardless of estrogen receptor status, but it was “noticeably” more effective with ER+ cancer than ER-. Prior research also demonstrated that metformin “has an anti-cancer effect on Tamoxifen resistant cells in vitro.”
Researchers wanted to determine if metformin could prevent the onset of MDR, not just reverse it. To do so, they adapted their in vitro process.
Here, we adapted our in vitro selection protocol by first pretreating cells with metformin, with a continued presence of metformin during the selection process… Using low doses of metformin before, and during, the selection process for treatment-resistant cell populations, we observed that this prevented or delayed the accumulation of multiple MDR markers (MDR-1, BCRP and TFPI1), reduced the expression of HIF1α (Fig 6A), and retained a high degree of drug sensitivity.
In contrast, rapid accumulation of MDR-protein markers and drug resistance was detected in the absence of metformin pretreatment (Fig 6A–6C). The correlation between lowered protein levels and decreased resistance supports the potential use of these proteins as biomarkers.
This research suggests a clinical role for metformin in the long-term management of cancer “to extend remission times or prevent drug resistance from developing.”
See also, The metabolic theory of cancer, October 31, 2017.
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Citation: Davies G, Lobanova L, Dawicki W, Groot G, Gordon JR, Bowen M, et al. (2017) Metformin inhibits the development, and promotes the resensitization, of treatment-resistant breast cancer. PLoS ONE 12(12): e0187191. https://doi.org/10.1371/journal.pone.0187191
Funding: Funded by Canadian Breast Cancer Foundation (TH and TA), Saskatchewan Health Research Foundation (TH, TA, JRG, GG), Canadian Foundation for Innovation (TH and TA), and Department of Medicine, University of Saskatchewan (TA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.