Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing

Abstract

Metformin is a well-known anti-diabetic drug that has been repurposed for several emerging applications, including as an anti-cancer agent. It boasts the distinct advantages of an excellent safety and tolerability profile and high cost-effectiveness at less than one US dollar per daily dose. Epidemiological evidence reveals that metformin reduces the risk of cancer and decreases cancer-related mortality in patients with diabetes; however, the exact mechanisms are not well understood. Energy metabolism may be central to the mechanism of action. Based on altering whole-body energy metabolism or cellular state, metformin's modes of action can be divided into two broad, non-mutually exclusive categories: "direct effects", which induce a direct effect on cancer cells, independent of blood glucose and insulin levels, and "indirect effects" that arise from systemic metabolic changes depending on blood glucose and insulin levels. In this review, we summarize an updated account of the current knowledge on metformin antitumor action, elaborate on the underlying mechanisms in terms of the hallmarks of cancer, and propose potential applications for repurposing metformin for cancer therapeutics.

Keywords: Cancer; Hallmarks; Mechanisms; Metformin.

Fig. 1

Main anticancer mechanisms of action of metformin based on hallmarks of cancer. Metformin can combat cancer by affecting metabolism, epigenetics, cell cycle, migration, metastasis, cell death, cell senescence, cancer stem cells, immunity, and gut microbes

Fig. 2

Main molecular anticancer mechanism of action of metformin. The pathways associated with anticancer action may be dependent on AMPK or independent of AMPK

Fig. 3

The primary site that at which metformin exerts its effects is the mitochondria. Metformin inhibits complex 1 in the respiratory chain and induces an elevation of AMP/ATP or ADP/ATP and subsequently activates AMPK. The indirect effects of metformin primarily rely on liver cells, where metformin decreases gluconeogenesis and fatty acid synthesis, thus influencing systemic metabolism. The direct effects of metabolism mainly involve the energy consumption of cancer cells

Fig. 4

Metformin regulates diverse factors to modulate immune cells in the tumor microenvironment to inspire immunity in cancer. Metformin can modulate tumor infiltrating lymphocytes (TIL), tumor-associated macrophages (TAMs), Treg, myeloid-derived suppressor cells (MDSCs), and PDL1 to increase the number and function of T cells and decrease T cell surveillance escape. Metformin can also downregulate PDL1 to increase cytotoxic T cells