Fig. 1

Hypotheses for metformin’s cancer prevention properties. Left-hand panel: Here, metformin directly inhibits Complex 1 of the electron transport chain. The function of Complex 1 is to accept electrons from NADH before donating them to Coenzyme Q for further shuttling down the electron transport chain (ETC). Along with other members of the ETC, the energy released by electron transfer facilitates the pumping of protons across the inner mitochondrial membrane to create an electrochemical gradient that allows ATP synthase to catalyse the conversion of ADP to ATP. Hence, metformin reduces oxidative phosphorylation (OXPHOS) disrupting cellular energy homeostasis and leading to activation of AMPK kinase. AMPK, a key regulator of energy balance, inhibits several anabolic pathways critical for cell proliferation. Additionally, interference with the ETC and tricarboxylic acid (TCA) cycle disrupts carbon metabolism and the supply of macromolecules required for cell proliferation [15]. Right hand panel: Metformin inhibits Complex 1 in hepatocytes activating AMPK and suppressing hepatic gluconeogenesis. It indirectly lowers circulating glucose and insulin levels, downregulating PI3K/AKT/mTOR signalling and suppressing cell proliferation, motility and anabolic metabolism