Action Mechanism of Metformin and Its Application in Hematological Malignancy Treatments: A Review

Abstract

Hematologic malignancies (HMs) mainly include acute and chronic leukemia, lymphoma, myeloma and other heterogeneous tumors that seriously threaten human life and health. The common effective treatments are radiotherapy, chemotherapy and hematopoietic stem cell transplantation (HSCT), which have limited options and are prone to tumor recurrence and (or) drug resistance. Metformin is the first-line drug for the treatment of type 2 diabetes (T2DM). Recently, studies identified the potential anti-cancer ability of metformin in both T2DM patients and patients that are non-diabetic. The latest epidemiological and preclinical studies suggested a potential benefit of metformin in the prevention and treatment of patients with HM. The mechanism may involve the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway by metformin as well as other AMPK-independent pathways to exert anti-cancer properties. In addition, combining current conventional anti-cancer drugs with metformin may improve the efficacy and reduce adverse drug reactions. Therefore, metformin can also be used as an adjuvant therapeutic agent for HM. This paper highlights the anti-hyperglycemic effects and potential anti-cancer effects of metformin, and also compiles the in vitro and clinical trials of metformin as an anti-cancer and chemosensitizing agent for the treatment of HM. The need for future research on the use of metformin in the treatment of HM is indicated.

Synergistic anticancer effects of doxorubicin and metformin combination therapy: A systematic review

“…Another significant reported finding is the selective eradication of cancer stem cells achieved through the metformin-doxorubicin combination. [ 31 , 35 , 74 ]. CSCs possess intrinsic abilities to resist traditional therapy, such as activation of drug-efflux processes by the ATP binding cassette (ABC) transporters, dormant state transition, and rapid DNA-repair mechanisms [75] .…”

“…metformin also demonstrates inhibitory properties against angiogenesis and tumor migration. It achieves this by downregulating the expression of vascular endothelial growth factor (VEGF), suppressing HIF-1α-induced expression of factors associated with angiogenesis, and reducing the signaling of platelet-derived growth factor-B (PDGF-B) and platelet-derived growth factor receptor-beta (PDGF-Rβ) [74] .…”

Metformin and risk of hematological cancers in patients with diabetes: a systematic review and meta-analysis

“…Metformin exerts its protective effect against HCs through multiple biological mechanisms, including the activation of AMP-activated protein kinase (AMPK), inhibition of mammalian target of rapamycin (mTOR) signaling pathway, the reduction of insulin resistance and glucose levels, anti-inflammatory effects, protection against oxidative stress, modulation of the tumor microenvironment, and regulation of DNA damage and repair. 2 , 38 One key mechanism is the activation of AMPK, a master regulator of cellular metabolism that helps to maintain cellular energy balance. 39 AMPK activation stimulates catabolic pathways and inhibits anabolic pathways, leading to the production of adenosine triphosphate and the suppression of energy-consuming processes like protein and lipid synthesis.…”

“…The ORs and its 95% CIs were used as effect sizes to calculate the pooled effect for the relationship between metformin use and HCs. Heterogeneity across publications was tested by the Q-test and I 2 . 24 , 25 Because of the significant heterogeneity, the random effects (Der-Simonian-Laird) model was applied to compute the pooled effect estimate.…”

“… 1 The mechanisms for these types of malignancies are abnormal immune or hematological cells with unlimited proliferation and blocked differentiation affecting the blood, bone marrow, and lymphatic system, which can be particularly challenging to treat. 2 , 3 While numerous risk factors for HCs have been identified, including advanced age, genetics, ionizing radiation, viral infections, exposure to occupational or environmental toxins, obesity, smoking, sedentary lifestyle, and some autoimmune disorders, 4 – 6 these recognized risk factors only justify a small proportion of the etiology of HCs. 6 Therefore, the pursuit of innovative preventative methods continues to be a crucial endeavor to improve the prognosis of HCs.…”