**1. Introduction**

Metformin is derived from the French lilac (also known as goat's rue or *Gallega Officinalis*), a medieval European medicinal herb that was first described as a diabetes treatment in a mid-17th century English treatise called *Culperper's Complete Herbal*, but it was not until 1957 that the French physician Jean Sterne formally patented metformin as a drug treatment for diabetes. The efficacy of metformin for type 2 diabetes mellitus (T2DM) has since been established and it was approved by the US FDA in 1995 as a treatment for T2DM. Meanwhile by the late 1980's, studies on the effects of metformin on insulin receptor binding on tumor cells led researchers to conceive that metformin's effect may potentially be applied for cancer management [1]. Separately, it has long been suspected that T2DM may be a risk for cancer with its cancer promoting effects believed due to hyperinsulinemia in T2DM, since insulin was believed to exert a mitogenic effect [2], thus it was simply logical to investigate the potential

*Drug Repurposing - Molecular Aspects and Therapeutic Applications*

#### **Figure 1.**

*Research development of metformin as anticancer agent: Since early epidemiologic reports suggesting metformin use in type 2 diabetes was associated with reduced cancer incidence, research evidence that metformin may be preventive and/or therapeutic for human cancers has expanded, with most of the molecular and clinical breakthroughs in metformin and cancer have taken place during the past decades, and hundreds of clinical trials are currently exploring metformin's potential in cancer. Source: [5], Licensed under CC BY 3.0.*

benefits of an insulin lowering and hence counter-mitogenic anti-diabetic agent for its possible anti-cancer effects. By the early 2000's, studies have already established the potential benefits of metformin on hyperinsulinemia, obesity, hyperlipemia, hypertension, fibrinolysis, and endothelial dysfunction, with the expansion of the drug's potential applicability beyond T2DM to address weight gain, acanthosis nigricans, infertility and polycystic ovary syndrome [3]. In 2005, a landmark retrospective case control study by Evans et al. demonstrated that metformin exposure in T2DM was associated with the reduced risk of cancers [4] and further epidemiological studies

*Repurposing of Metformin as a Multifaceted and Multitasking Preventative and Treatment… DOI: http://dx.doi.org/10.5772/intechopen.96101*

also corroborated that diabetics treated with metformin have a lowered incidence of cancer than those treated with other agents, leading to increasing calls for the use of metformin to reduce the risk of cancer. In the past decade, metformin has seen over 50 million prescriptions per year in the US alone and there has been a concurrent explosion of interest in metformin's anticancer effects with dozens of systematic reviews and meta-analyses performed and published on hundreds of cancer studies involving hundreds of thousands of patients and with hundreds of clinical trials on metformin and cancer currently actively recruiting. The development and expansion of research into metformin's anticancer activities in the past two decades from the bench to the clinic is illustrated below in **Figure 1**.

Given that this review is intended as a summary of current clinical evidence for the potential uses of metformin in the prevention and treatment of cancer, we will provide only a succinct synthesis of the thousands of preclinical studies on the biological mechanisms and molecular pathways that has been performed in the past two decades and focus our attention mostly on recent clinical evidence of metformin's efficacy as demonstrated by clinical studies.
