Metformin, a safe and inexpensive drug widely used to lower blood glucose in type 2 diabetics, is the most popular anti-diabetic drug in the United States with more than 42 million prescriptions in 2009. It was developed from the French lilac plant (
Galega officinalis) in the 1950s and was approved by the FDA in the mid-1990s as Glucophage. It is also increasingly being used in the treatment of various diseases not directly related to diabetes, such as polycystic ovarian syndrome (PCOS), non-alcoholic fatty liver disease (NAFLD), premature puberty [
1], and cardiovascular diseases [
2]. Recently, metformin has been attracting much attention as a potential anti-cancer agent to act across a broad spectrum of cancers [
3].
In the past few years, several population-based studies have indicated that metformin decreases the incidence of cancer and cancer-related mortality in diabetic patients. The reduction in risk ranges from 30% to 70%, depending on the type of cancer.
The population-based study conducted by the University of Dundee in 2005 [
4] triggered intense research interest in metformin. The observational results show a decrease of 25%–37% in cancer cases in diabetics taking metformin, compared with those taking other diabetes drugs, suggesting that diabetics receiving metformin are less prone to developing cancer.
A meta-analysis conducted at the Anderson Cancer Center [
5] revealed that metformin may offer protection against pancreatic cancer. The risk of pancreatic cancer in diabetics who took metformin was 62% lower than that in diabetics who never used it. Moreover, this effect appeared to be related to breast, liver, and colon cancers [
6,
7].
Results from above studies are in accordance with the hypothesis that increased insulin levels might promote cancer. In patients with type 2 diabetes, metformin decreases levels of insulin-like growth factor-1 (IGF-1) and circulating insulin, through which promote the activity of AMPK (AMP-activated protein kinase), a liver enzyme that plays an important role in insulin signaling. Consequently, the inhibition of IGF-1 by metformin explains its anti-diabetic activity. However, IGF-1 also plays a crucial role in cancer development.
Protein kinase LKB1, a well-recognized tumor suppressor, is the upstream regulator of AMPK. The activation of AMPK by metformin requires LKB1. This can partly explain the apparent anti-cancer effects of metformin. In addition, emerging research suggests that a possible mechanism by which metformin activates AMPK may also influence cancer cells directly. A series of
in vivo and
in vitro studies have provided evidence that directs LKB1/STK11 activation of AMPK by metformin resulting in the downstream inhibition of the mammalian target of rapamycin (mTOR) signaling, and leading to reduced protein synthesis and cell proliferation in tumor cells [
4,
8,
9]. This observation has been confirmed in a mouse model of smoking-related lung cancer [
10]. Metformin was given to mice exposed to nicotine-derived nitrosamine (known as NNK), which normally induces tumors in experimental animals easily. All the mice given only NNK without metformin developed lung cancer. Metformin reduced tumor burden by 40%–50% when given orally and 72% when given by injection. These latest findings are certainly plausible in the prevention of tobacco-induced lung cancer.
The chemopreventive potential of metformin may also be helpful in preventing tumors in non-diabetic patients. Using a genetic cancer model and a chemically induced cancer model in non-diabetic mice, scientists in Japan found that metformin suppressed the development of intestinal polyps (a murine model of familial adenomatous polyposis) and the azoxymethane-induced formation of colorectal aberrant crypt foci (ACF) by activating AMPK [
11,
12]. These observations suggest that metformin may be useful as an anti-cancer drug in non-diabetic contexts.
A small clinical trial reported by the same research team in Japan suggests that metformin may suppress pre-cancerous colorectal lesion development in humans [
12]. The scientists randomly assigned 12 non-diabetic patients with rectal ACF to low-dose metformin treatment (250 mg/day) and the others to placebo treatment. After one month, the number of foci in treated patients decreased significantly compared with the 14 patients who did not take the drug (Fig. 1). This is the first human trial of metformin as a cancer-preventing agent.
Pre-clinical study and clinical evidence have magnified interest in metformin that it may play a part as an adjunct to other conventional cancer therapies. It sensitizes cancer cells to well-defined chemotherapeutic drugs, such as doxorubicin and cisplatin [
13,
14]. Moreover, metformin is likely to function synergistically with chemotherapeutic drugs to block tumor growth and prolong remission through its ability to selectively kill cancer stem cells. It works more effectively than either drug alone.
Taken together, accumulating evidences support that the off-patent drug may play a new role in preventing cancer and could provide significant benefits for cancer patients.
With a long history as an anti-diabetic drug with few side effects, metformin seems likely to be safe and promising in cancer prevention and even treatment. However, its use for clinical treatment is still premature. Like all medicines, metformin can have side effects which so far, we do not recognize. mTOR is quite a popular target for various diseases, and drugs that downregulate mTOR may cause depression and mood problems, along with other side effects. For example, a harmful consequence of metformin is revealed last year to be a potential promotion of Alzheimer's when used as a monotherapy [
15]. Hence, further studies are essential to clarify the most promising settings for the development of metformin as an anti-cancer agent.
Higher Education Press and Springer-Verlag Berlin Heidelberg
PDF
(70KB)
