By itself, metformin was ineffective in treating tumors. In a one-two punch, metformin reduced tumors faster and prolonged remission in mice longer than chemotherapy alone, apparently by targeting cancer stem cells, report Harvard Medical School researchers in the Sept. 14 advance online Cancer Research.

Metformin is the most popular anti-diabetic drug in the United States and one of the most prescribed drugs in the country overall, with more than 40 million prescriptions filled in 2008 for generic metformin alone. It originates from the French lilac (Galega officinalis), a plant known for several centuries to reduce the symptoms of diabetes mellitus.
When prescribed appropriately, metformin causes few adverse effects-the most common is gastrointestinal upset-and, unlike many other anti-diabetic drugs, does not cause hypoglycemia if used alone. It also helps reduce LDL cholesterol and triglyceride levels, and may aid weight loss.
Metformin improves hyperglycemia primarily through its suppression of hepatic glucose production (hepatic gluconeogenesis). Metformin activates AMP-activated protein kinase (AMPK), a liver enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats; activation of AMPK is required for metformin's inhibitory effect on the production of glucose by liver cells.
Some metabolic actions of metformin do appear to occur by AMPK-independent mechanisms.
In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake, increases fatty acid oxidation, and decreases absorption of glucose from the gastrointestinal tract.

By itself, metformin was ineffective in treating tumors. In a one-two punch, metformin reduced tumors faster and prolonged remission in mice longer than chemotherapy alone, apparently by targeting cancer stem cells, report Harvard Medical School researchers in the Sept. 14 advance online Cancer Research. ("Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth Q2 and Prolong Remission" Heather A. Hirsch et al. Cancer Research, Sept. 14 advance online publication).

In this study, the diabetes drug seemed to work independently of its ability to improve insulin sensitivity and lower blood sugar and insulin levels, all of which are also associated with better breast cancer outcomes.

The results fit within the cancer stem cell hypothesis, an intensely studied idea that a small subset of cancer cells has a special power to initiate tumors, fuel tumor growth, and promote recurrence of cancer. Cancer stem cells appear to resist conventional chemotherapies, which kill the bulk of the tumor.

In experiments led by postdoctoral fellows Heather Hirsch and Dimitrios Iliopoulos, the combination of metformin and the cancer drug doxorubicin killed human cancer stem cells and non-stem cancer cells in culture.

In mice, pretreatment with the diabetes drug prevented the otherwise dramatic ability of human breast cancer stem cells to form tumors. In other mice where tumors were allowed to take hold for 10 days, the dual therapy also reduced tumor mass more quickly and prevented relapse for longer than doxorubicin alone. In the two months between the end of treatment and the end of the experiment, tumors regrew in mice treated with chemotherapy alone, but not in mice that had received both drugs.

The team was further encouraged by the low dose of metformin needed for the effect in the laboratory, compared to the amount needed for analogous molecular experiments in basic diabetes research. The relative dosage in people for treating or preventing cancer is unknown and untested.

Apart from this interesting effect on cancer stem cells, the ability of metformin to enhance peripheral glucose uptake and increase fatty acid oxidation could be synergistic with the DCA ability to increase the intracellular metabolism of glucose, causing cancer cell apoptosis. Metaphorically, adding more fuel to the already accelerated engine of cancer cells would lead them to break down. Experiments are needed to verify this hypothesis.