Metformin and cancer: from the old medicine cabinet to pharmacological pitfalls and prospects.

Metformin is a biguanide derivative used in the treatment of type II diabetes (T2D) and one of the world's most widely prescribed drugs. Owing to its safety profile, it has been recently promoted for a range of other indications, particularly for its role in cancer prevention. There is evidence from studies in diabetic cohorts, as well as laboratory studies, that the action of metformin depends on a balance between the concentration and duration of exposure, which depends crucially on cell- and tissue-specific pharmacological factors. Mechanistic studies have revealed the involvement of increasingly complex pathways. Yet, there are several missing links regarding the role of drug transporters and drug-drug interactions, as well as the expression levels of transporters in normal versus tumor tissues, which may affect patient exposure and dosing when metformin is used in cancer prevention. This review highlights the current knowledge on metformin action and pharmacology, including novel insights into genomic factors, with a specific focus on cancer prevention. Furthermore, future challenges that may influence therapeutic outcome will be discussed.