Despite significant advancements in the treatment of cancer and emergence of immunotherapies, the prognosis of acute leukemia remains poor and warrants the need for introduction of novel therapies. Over the past decade, metformin has garnered significant attention as a potential anti-cancer agent and appears to be an enticing option for managing patients with leukemia. Metformin is known to display its effects at the organism level. In patients with type 2 diabetes, it decreases hyperglycemia and increases insulin sensitivity by enhancing insulin-stimulated glucose uptake in muscles, adipose tissue, and liver, and by reducing glucose output by the liver. Lowering levels of insulin and insulin-like growth factor-1 that trigger cancer growth are likely to be key traits of metformins mechanism of action.

The investigators have demonstrated that metformin may be a beneficial agent for treating leukemia due to its action on mitochondrial respiration. It interferes with mitochondrial respiration, which causes activation of the 5-AMP-activated protein kinase (AMPK)tumor-suppressive pathway. This, in turn, promotes catabolic-energy saving reactions and inhibits anabolic ones that are related to abnormal cell proliferation. Furthermore, it inhibits constitutive mammalian target of rapamycin (mTOR), a pathological hallmark in leukemogenesis. Studies in the past showed that italso interferes with acute myeloid leukemia proliferation and displays clonogenic activity. Moreover, it induces apoptosis in human immortalized cell lines and primary samples. After blocking activation of mTORC1,it prevents initiation of translation, particularly of cyclin D1, cellular-Myc, and B-cell lymphoma-extra-large that are important for cancer proliferation. It also induces apoptosis of leukemic megakaryoblasts from acute megakaryoblasticleukemia, a rare type of leukemia with poor prognosis. Considering the aforementioned beneficial actions of metformin, it could be a promising adjuvant agent for leukemia.

Reference

1. Biondani G, Peyron JF. Metformin, an Anti-diabetic Drug to Target Leukemia. Front Endocrinol (Lausanne). 2018;9:446.