Table 1.

Metformin pathways/targets identified by in vitro studies.

References	Pathways/Target	Effect
Mitochondrial action
Thakur et al. [29]	Inhibition of mitochondrial complex 1 and mitochondrial glycerophosphate dehydrogenase (mGPDH)	Reduction in oxidative phosphorylation, decreased energy production, cell stress, and tumor cell apoptosis
Mechanisms involved in the inflammatory state
Rotondi et al. [33] Bauerle [31]	Inhibits interleukin 8 (CXCL8) stimulated by tumor necrosis factor alpha (TNF-α) which decrease nuclear factor κB (NF-κB)	Reduced growth and progression of thyroid cancer
AMPK-dependent
Chen et al. [17] Cho et al. [18] Hanly et al. [19]	Activation of AMPK triggers tuberous sclerosis complex 2 (TSC2), which inhibits the mTOR signaling pathway and hampers the activation of ribosomal protein S6 kinase beta-1 (p70S6K/pS6) and reduction in cyclin D1	Inhibition of protein synthesis and cell cycle arrest
Pierotti et al. [22]	AMPK activation phosphorylates an inhibitory serine residue in the insulin receptor substrate-1 (IRS-1), leading to downregulation of insulin-like growth factor 1 receptor (IGF-1R), which decreases the signaling of phosphatidylinositol 3-kinase/protein kinase pathway (PI3K/AKT), leading to the reduction in mTOR pathway activation	Inhibition of protein synthesis and cell cycle arrest
AMPK-independent
Hadad et al. [23]	Tumor necrosis factor receptor 1 (TNFR1) and G1/S checkpoint regulation	Reduction in cancer cell growth
Kourelis et al. [24]	Inhibition of unfolded protein response (UPR)	Apoptosis, prevents angiogenesis, and induces toxicity on cancer stem cells