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Review
. 2023 Jan 29;13(2):250.
doi: 10.3390/biom13020250.

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

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Review

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

Yi Zhang et al. Biomolecules. .

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.

Keywords: AMPK; leukemia; lymphoma; metformin; myeloma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The main systemic effects of metformin to lower blood sugar. GLP1: glucagon-like peptide-1; GDF15: growth differentiation factor 15.
Figure 2
Figure 2
The main cellular actions of metformin to lower blood sugar. OCT1: organic cation trans porter 1; FBP1: fructose-1,6-bisphosphatase; IRS1: insulin receptor substrate 1; GLUT1: glucose transporter protein 1; mGPD: mitochondrial glycerophosphate dehydrogenase; OXPHOS: oxidative phosphorylation; ATP: adenosine triphosphate; AMP: adenosine monophosphate; cAMP: cyclic adenosine monophosphate; IR: insulin receptor; PKA: protein kinase A; ACC: acetyl coenzyme A carboxylase; mTOR: mammalian target of rapamycin; AMPK: adenosine monophosphate-activated protein kinase; CaMKKβ: calcium/calmodulin-dependent protein kinaseβ; LKB1: liver kinase B1; AXIN: axis inhibitor; SIRT1: Sirtuin1; v-ATPase: vacuolar ATP hydrolase.
Figure 3
Figure 3
The main cellular anti-cancer actions of metformin. OCT1: organic cation transporter 1; AMP: adenosine monophosphate; ATP: adenosine triphosphate; OXPHOS: oxidative phosphorylation; REDD1: deoxyribonucleic acid (DNA) damage response 1; TNFα: tumor necrosis factor α; PTEN: phosphatase and tensin homolog; STAT3: transcription 3; IGF-1: insulin growth factor-1; YAP: yes-associated protein; TAZ: tea domain transcription factor; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; mTOR: mammalian target of rapamycin; COX-2: cyclooxygenase-2; Bcl-2: B-cell lymphoma-2; Bax: Bcl-2 associated x; NF-κB: nuclear factor kappa B; AMPK: adenosine monophosphate-activated protein kinase; ROS: reactive oxygen species; LKB1: liver kinase B1; FOXO3: forkhead box O3; HATs: histone acetyl-transferases; HDACs: histone deacetylases; DNMT: deoxyribonucleic acid (DNA) methyltransferase; ACC: acetyl coenzyme A carboxylase; HIF-1α: hypoxia-inducible factor-1α; Cyclin D1: cell cycle protein D1; EMT: mesenchymal transition; FASN: fatty acid synthase; UPR: unfolded protein response; MEK: mitogen-activated protein kinase; MRK: extracellular-related kinase; FasL: Fas ligand.

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