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.
Highlights
Team #4: Leukemia: Molecular Addictions, Resistances & Leukemic Stem Cells, Université Nice Côte d’Azur, C3M-Inserm U1065, Paris, France
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
Tumor cells from a mouse T-acute lymphoblastic leukemia (ALL) model generated by the T-cell specific deletion of PTEN display a constitutive activation of PI3K/Akt/mTOR that could be inhibited by metformin through AMPK activation and by torkinibs [80]
Summary
Numerous investigations worldwide rapidly demonstrated direct anti-cancer effects of metformin on various models [10,11,12]. Metformin exhibits a strong anti-proliferative action on cancer cell lines derived from breast, colon, ovaries, pancreas, lung, and prostate [13,14,15]. These results were strengthened by pre-clinical in vivo experiments using xenografts or transgenic mice and chemically-induced cancers. Metformin reduces hyperglycemia through different mechanisms: by enhancing insulin-stimulated glucose uptake and reducing hepatic glucose output [21] It lowers the production of glucose by the liver, and increases glucose utilization by muscles and adipocytes. If insulin/IGF-1 do not appear to be strong oncogenic drivers for acute leukemias, they are likely trophic factors, supporting the rational use of metformin to decrease hyperinsulinemia and to indirectly affect leukemic cells. New therapeutic strategies should be identified to eradicate leukemia
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