Previous studies have shown that metformin, a drug commonly used to treat Type 2 diabetes, seems to also inhibit growth of multiple types of cancer cells. Moreover, 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 tumors.
In a new PLOS ONE study, researchers probed the effects of metformin on the breast cancer cell line MCF7, which is commonly used for preclinical laboratory cancer research. They found that metformin may counteract drug resistance in cancer cells. Terra Arnason, a clinical endocrinologist from the University of Saskatchewan and a lead researcher on the study, told me more about what they found.
What drew you to cell biology research, specifically studying cancer cells?
TA: There is such an important potential societal impact to be made from advances in cancer research. Our team realized that there was a large population of cancer survivors who beat it once, only to have it come back years or decades later, without warning and without targeted therapy. Treatments then have to switch to less tolerable choices that have severe side effects and may not even be effective. Understanding the underpinnings of the cellular changes that cause this recurrence felt like an important area to study.
Metformin is typically prescribed to treat Type 2 diabetes. Why did you think that metformin might inhibit cancer cells that are resistant to multiple drugs?
TA: As a clinical endocrinologist, I use metformin to treat diabetes independently of cancer, but it was several large meta-analysis reports that led us down this path; people with Type 2 diabetes taking metformin were found to have lower rates of cancer, and were also found to do better with the cancers they had. We had already reported that an unrelated oral diabetes drug (troglitazone) sensitized cancer cells to therapy, so we asked if this also applied to metformin.
TA: You found that pretreating cancer cells with metformin reduced or prevented development of multidrug resistance. Over what period of time was this tested?
These are in vitro studies, done in human cell culture. In this paper, our selection for resistance was over 10 days, either with daily metformin exposure or not. We found that these cells retained sensitivity to the chemotherapy drug only when pretreated for two days, followed by daily metformin exposure throughout the drug-selection process. In contrast to this experiment, which tested our ability to interrupt the acquisition of resistance, we also demonstrated that metformin could reverse drug resistance even in established multidrug resistance cell populations selected over months.
TA: Was there anything that surprised you in this study?
We were surprised at the number of cellular pathways that metformin impacts, when considering drug resistance. Metformin decreases the abundance of proteins known as ABC transporters both in vitro and in patient-derived (PDX) tumors implanted in mice, has indirect activity on enzymes known as histone-deacetylase, and acted independently of the function of an enzyme known as AMPK. We were also excited to note that metformin behaves very differently between matched drug-sensitive and drug-resistant human cancer cell populations.
TA: Were there limitations to the study?
This is an in vitro study for the most part, such that the concentrations of metformin used in cell culture are very difficult to extrapolate to an in vivo tumor environment. However, our finding that the mouse drug-resistant PDX tumors showed similar decreases in ABC transporters with metformin treatment is exiting. Our short selection period for drug resistant cell populations is also a limiting factor, as this does not mimic the clinical timeline for breast cancer patients undergoing chemotherapy, where treatment can be daily or intermittent over weeks.
TA: What are the next steps for this research?
Our next steps are exciting and involve collaboration with veterinary oncologists, using companion canines with spontaneous lymphoma who are being randomly selected for treatment with metformin, as we prospectively look for an extension in the length of remission and a decrease in the incidence of acquired treatment resistance, which is a frequent occurrence both in dogs and humans.
Reference: 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
Image Credit: Victoria Cookson, Breast Cancer Research Image Competition 2016 winner; Terra Arnason; Davies et al (2017)