Figure 7.

Working model of the multifacted mechanism of action of metformin in leukemic cells. In vitro metformin induces early energetic changes through the inhibition of ETCI, mitochondrial oxygen consumption (OCR) and mitochondrial ATP production (mtATP). The resulting metabolic response in all cells is an increase in glutamine consumption, fatty acid (FA) shuttling (acetylcarnitine), purines (PRPP, IMP, AMP) and amino acids (methionine), as well as a decrease in glycolytic intermediates. For cells that are sensitive to metformin-induced apoptosis, including HL60 and MOLM14, the specific metabolic response includes a strong increase in the Pasteur effect (for example, increased glycolytic ATP production, glucose consumption and lactate production), as well as an increase in tricarboxylic acids (fumarate and malate) which leads to activation of the mitochondrial apoptotic pathway. Cells that are insensitive to metformin-induced apoptosis, such as U937 cells, block this sensitive cell-specific metabolic response and apoptosis due to high AKT phosphorylation, high glucose consumption and low mitochondrial ATP production in the basal state.