More metformin may be needed for breast cancer patients with high glucose levels
Breast cancer cell growth, motility, and aggression is promoted by excess glucose, as experienced by patients with diabetes and metabolic syndrome, reports a new study. In addition, the study showed that patients with high glucose may require higher doses of the drug metformin to achieve the same anticancer activity as patients with normal glucose levels.
Metformin, the most common first-line drug in the treatment of type 2 diabetes, has been shown in previous studies to reduce breast cancer risk, improve survival, and increase the effectiveness of chemotherapy. Numerous phase III clinical trials are currently evaluating the benefits and best uses of metformin in breast cancer patients.
Principal investigator Ann Thor, MD, of the University of Colorado Cancer Center in Denver, explained that their findings demonstrate that metformin works differently in high-glucose conditions compared with low-glucose conditions, but reported that the drug regulates different genes within cancer cells at high levels compared with normal glucose levels.
The study evaluated the effects of metformin on 17 breast cancer cell lines representing each of the molecular subtypes of the disease, at varying glucose levels. The study was published in Cell Cycle (2013;12).
"Commonly, lab studies of metformin are performed with very high glucose concentrations—about 17 Mmol of glucose per liter. But the average glucose level in healthy humans is only about one third of that dose—about 5 Mmol/L. And [persons] with diabetes may have glucose at 10 Mmol/L. We wanted to study metformin activity under these conditions," explained Thor.
So the question was this: how would metformin perform in breast cancer cells grown at more realistic, human levels of glucose? The researchers found that when glucose levels were dropped down to those in humans, metformin has an even bigger effect at standard doses. When glucose is high, more metformin is needed to achieve the same results.
Thor also pointed out that skeptics of metformin treatment for cancer in general or breast cancer in particular frequently point to the high concentrations of metformin needed to create results in the laboratory.
"Our data helps to explain why higher doses of metformin are required to obtain anticancer effects when cancer cells are grown in the lab, as compared to its use in humans," Thor said. She explained that entirely new mechanisms of action were present at lower glucose levels.
At high glucose concentrations, metformin primarily affected genes involved in metabolic processes and cell proliferation; at low glucose concentrations, metformin affected genes controlling cellular process and programmed cell death.
"An extension of this data implies that in breast cancer patients with diabetes or metabolic syndrome, metformin may be less effective at the standard dose. To be effective, doctors may have to first explore glucose control or may have to use a higher dose of metformin," Thor said.