Internal medicine

Biguanide

Sitagliptin

AMPK

Lactic acidosis

Diabetes mellitus

Bioinformatics

Biology

Cancer

Endocrinology

Kinase

Insulin resistance

Metformin

Phenformin

Type 2 Diabetes Mellitus

Hypoglycemia

Hyperinsulinemia

Protein kinase A

Cancer research

Biochemistry

Medicine

Pharmacology

International Journal of Molecular Sciences

Currently, there is increasing evidence linking diabetes mellitus (especially type 2 diabetes mellitus) with carcinogenesis through various biological processes, such as fat-induced chronic inflammation, hyperglycemia, hyperinsulinemia, and angiogenesis. Chemotherapeutic agents are used in the treatment of cancer, but in most cases, patients develop resistance. Phenformin, an oral biguanide drug used to treat type 2 diabetes mellitus, was removed from the market due to a high risk of fatal lactic acidosis. However, it has been shown that phenformin is, with other biguanides, an authentic tumor disruptor, not only by the production of hypoglycemia due to caloric restriction through AMP-activated protein kinase with energy detection (AMPK) but also as a blocker of the mTOR regulatory complex. Moreover, the addition of phenformin eliminates resistance to antiangiogenic tyrosine kinase inhibitors (TKI), which prevent the uncontrolled metabolism of glucose in tumor cells. In this review, we evidence the great potential of phenformin as an anticancer agent. We thoroughly review its mechanism of action and clinical trial assays, specially focusing on current challenges and future perspectives of this promising drug.

Phenformin as an Anticancer Agent: Challenges and Prospects