Metformin, an Anti-diabetic Drug to Target Leukemia

Abstract

Metformin, a widely used anti-diabetic molecule, has attracted a strong interest in the last 10 years as a possible new anti-cancer molecule. Metformin acts by interfering with mitochondrial respiration, leading to an activation of the AMPK tumor-suppressive pathway to promote catabolic-energy saving reactions and block anabolic ones that are associated with abnormal cell proliferation. Metformin also acts at the organism level. In type 2 diabetes patients, metformin reduces hyperglycemia and increases insulin sensitivity by enhancing insulin-stimulated glucose uptake in muscles, liver, and adipose tissue and by reducing glucose output by the liver. Lowering insulin and insulin-like growth factor 1 (IGF-1) levels that stimulate cancer growth could be important features of metformin's mode of action. Despite continuous progress in treatments with the use of targeted therapies and now immunotherapies, acute leukemias are still of very poor prognosis for relapse patients, demonstrating an important need for new treatments deriving from the identification of their pathological supportive mechanisms. In the last decade, it has been realized that if cancer cells modify and reprogram their metabolism to feed their intense biochemical needs associated with their runaway proliferation, they develop metabolic addictions that could represent attractive targets for new therapeutic strategies that intend to starve and kill cancer cells. This Mini Review explores the anti-leukemic potential of metformin and its mode of action on leukemia metabolism.

Diabetes mellitus among adult survivors of childhood acute lymphoblastic leukemia: A report from the St. Jude Lifetime Cohort Study

“…These data are consistent with previous reports from the CCSS and the Bone Marrow Transplant Survivor Study. 33,34 Early reports from the NCT03118128 study have demonstrated that among patients with ALL who express high levels of the ABCB1 gene, those who receive metformin in combination with conventional chemotherapy had higher survival compared with those who Cancer February 15, 2020 only received conventional chemotherapy (83.33% vs 26.47%; P = .025). 6 This increased risk was associated with receipt of total body irradiation in both the CCSS (OR, 12.6; 95% CI, 6.2-25.3) and the Bone Marrow Transplant Survivor Study (OR, 3.42; 95% CI, 1.55-7.52) cohorts.…”

“…Several ongoing clinical trials currently are investigating the clinical and biological effects (antitumor) of metformin within the setting of high-risk and refractory and/or recurrent ALL (ClinicalTrials.gov identifiers NCT01324180 and NCT03118128). 33,34 Early reports from the NCT03118128 study have demonstrated that among patients with ALL who express high levels of the ABCB1 gene, those who receive metformin in combination with conventional chemotherapy had higher survival compared with those who Cancer February 15, 2020 only received conventional chemotherapy (83.33% vs 26.47%; P = .025). 33 These studies are relevant because they may provide safety data for the potential administration of metformin in children with ALL during therapy.…”

Mitochondrial targets of metformin—Are they physiologically relevant?

“…Since upstream AMPK activator liver kinase B1 (LKB1) is known to act as potent tumor suppressor, possible link between metformin administration and reduced cancer incidence has been suggested and indeed proven by the first epidemiological study . Since then, anticancer effect of metformin has been demonstrated in various models in vivo as well as in vitro …”

“…5 Since then, anticancer effect of metformin has been demonstrated in various models in vivo as well as in vitro. 6,7 Although metformin belongs to widely prescribed drugs, its mechanism of action in both type II diabetes and cancer is still under investigation. Based on epidemiological studies, association between adiposity and increased risk of cancer has been proposed via deregulation of key pathways including insulin resistance, but the direct connection is missing.…”

Metabolic reprogramming in childhood acute lymphoblastic leukemia

“…Even though the molecular mechanisms of death induction by metformin are believed to be via endoplasmic reticulum stress, the antidiabetic drug is another chemotherapeutic capable of inhibiting the ETC and the TCA cycle 95 . In a mouse model of PTEN ‐deficient T‐ALL, metformin inhibits leukemia progression and synergizes with 2‐DG 96,97 . A combination of metformin with anthracyclins and daunorubicin in cALL cell lines and patient samples also shows synergistic effect in vitro 98 .…”