Figure 7. Possible mechanism of action of metformin in lymphoma cells.

Metformin blocks mitochondrial complex I leading to activation of AMPK via reduction in ATP production. This in turn, leads to activation and inactivation of several pathways dependent on AMPK. Only some of the relevant molecules are shown. In addition, metformin blocks or activates several pathways independent of AMPK. Some of them include inactivating PI3K/AKT pathway, activating DNA damage response (ATM/Chk2 and p53) pathways, inhibiting Rag-GTPases that activate mTOR. Venetoclax, a bcl-2 inhibitor is potentiated by metformin likely via it's role in blocking Stat3 pathway independent of AMPK and BAY-1143572 is likely potentiated by metformin via it's role in reducing cyclin D1 independent of AMPK. Though, involvement of other pathways in the potentiation of these drugs can't be ignored. All these signaling changes with metformin treatment eventually lead to increase in apoptosis-mediated cell death and reduction in cell proliferation of lymphoma cells. However, it should be noted that depending on the lymphoma cell type, some of these pathways may be more active and some pathways may be missing or dysregulated altogether.