Metformin - its anti-cancer effects in hematologic malignancies

Abstract

The main anti-diabetic effect of metformin mediated through stimulation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) is the inhibition of hepatic gluconeogenesis and triggering glucose uptake in skeletal muscles. Additionally, some new pathways, besides the AMPK activation, were discovered, that can explain wide-range properties of metformin. All these properties are now attracting the attention of researchers in the fields other than diabetes and the drug has been reported to have anti-cancer, immunoregulatory and anti-aging effects. Among others, the beneficial effects of metformin in hematological disorders like leukemias, lymphomas, and multiple myeloma were reported. Despite a great progress in therapy, these diseases are still incurable in most cases. Thus, there is an urgent need to discover novel, less toxic and more effective drugs especially for older or chemotherapy-resistant patients. In this review article, the current findings on the anti-cancer effect of metformin together with underlying possible mechanisms in blood cancers are discussed. However. to evaluate precisely these promising effects of metformin, more studies are required, because many of the published results are preclinical.

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References

Cunha Jr AD, Pericole FV, Carvalheira JBC. Metformin and blood cancers. Clinics (Sao Paulo) 2018;73:e412s. DOI: https://doi.org/10.6061/clinics/2018/e412s

Bailey CJ. Metformin: its botanical background. Pract Diab Int 2004;21:115-7. DOI: https://doi.org/10.1002/pdi.606

Zhou J, Massey S, Story D, Li L. Metformin: an old drug with new applications. Int J Mol Sci 2018;19:28-63. DOI: https://doi.org/10.3390/ijms19102863

Paneni F, Lüscher TF. Cardiovascular protection in the treatment of type 2 diabetes: a review of clinical trial results across drug classes. Am J Cardiol 2017;120:17-27. DOI: https://doi.org/10.1016/j.amjcard.2017.05.015

UKPDS Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53. DOI: https://doi.org/10.1016/S0140-6736(98)07019-6

UKPDS Group. Effect of intensive blood-glucose control with metiormin on complication in overweight patients with type 2 diabetes (UKPDS34). Lancet 1998;352:854-65. DOI: https://doi.org/10.1016/S0140-6736(98)07037-8

UKPDS Group. Tight blood pressure control and risk of rnacrovascular and microvascular complications in type 2 diabetes (UKPDS 38).BMJ 1998;317:703-13. DOI: https://doi.org/10.1136/bmj.317.7160.703

Evans JM, Donnelly LA, Emslie-Smith AM et al. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005;330:1304-5. DOI: https://doi.org/10.1136/bmj.38415.708634.F7

Gong J, Kelekar G, Shen J, et al. The expanding role of metformin in cancer: an update on antitumor mechanisms and clinical development. Target Oncol 2016;11:447-67. DOI: https://doi.org/10.1007/s11523-016-0423-z

Papanagnou P, Stivarou T, Tsironi M. Unexploited antineoplastic effects of commercially available anti-diabetic drugs. Pharmaceuticals (Basel) 2016;9:E24. DOI: https://doi.org/10.3390/ph9020024

Deng D, Yang Y, Tang X, et al. Association between metformin therapy and incidence, recurrence and mortality of prostate cancer: evidence from a meta-analysis. Diabetes Metab Res Rev 2015;31:595-602. DOI: https://doi.org/10.1002/dmrr.2645

Raval AD, Thakker D, Vyas A, et al. Impact of metformin on clinical outcomes among men with prostatecancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis 2015;18:110-21. DOI: https://doi.org/10.1038/pcan.2014.52

Sakoda LC, Ferrara A, Achacoso NS, et al. Metformin use and lung cancer risk in patients with diabetes. Cancer Prev Res (Phila) 2015;8:174-9. DOI: https://doi.org/10.1158/1940-6207.CAPR-14-0291

Lin JJ, Gallagher EJ, Sigel K, et al. Survival of patients with stage IV lung cancer with diabetes treated with metformin. Am J Respir Crit Care Med 2015;191:448-54. DOI: https://doi.org/10.1164/rccm.201407-1395OC

Yen YC, Lin C, Lin SW, et al. Effect of metformin on the incidence of head and neck cancer in diabetics. Head Neck 2015;37:1268-73. DOI: https://doi.org/10.1002/hed.23743

Col NF, Ochs L, Springmann V, et al. Metformin and breast cancer risk: a meta-analysis and critical literature review. Breast Cancer Res Treat 2012;135:639-46. DOI: https://doi.org/10.1007/s10549-012-2170-x

Wang Z, Lai ST, Xie L, et al. Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Res Clin Pract 2014;106:19-26. DOI: https://doi.org/10.1016/j.diabres.2014.04.007

Lee DJ, Kim B, Lee JH, et al. The effect of metformin on responses to chemotherapy and survival in stage IV colorectal cancer with diabetes. Korean J Gastroenterol 2012;60:355-61. DOI: https://doi.org/10.4166/kjg.2012.60.6.355

Dilokthornsakul P, Chaiyakunapruk N, Termrungruanglert W, et al. The effects of metformin onovarian cancer: a systematic review. Int J Gynecol Cancer 2013;23:1544-51. DOI: https://doi.org/10.1097/IGC.0b013e3182a80a21

Zhang ZJ, Zheng ZJ, Shi R, et al. Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab 2012;97:2347-53. DOI: https://doi.org/10.1210/jc.2012-1267

Duncan BB, Schmidt MI. Metformin, cancer, alphabet soup, and the role of epidemiology in etiologic research. Diabetes Care 2009;32:1748-50. DOI: https://doi.org/10.2337/dc09-1183

Hundal RS, Krssak M Dufour S, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 2000;49:2063-9. DOI: https://doi.org/10.2337/diabetes.49.12.2063

Pryor R, Cabreiro F. Repurposing metformin: an old drug with new tricks in its binding pockets. Biochem J 2015;471:307-22. DOI: https://doi.org/10.1042/BJ20150497

Natali A, Ferrannini E. Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. Diabetologia 2006;49:434-41. DOI: https://doi.org/10.1007/s00125-006-0141-7

Wright AD, Cull CA, Macleod KM, Holman RR. Hypoglycemia in type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73. J Diabetes Complicat 2006;20:395-401. DOI: https://doi.org/10.1016/j.jdiacomp.2005.08.010

Hostalek U, Gwilt M, Hildemann S. Therapeutic use of metformin in prediabetes and diabetes prevention. Drugs 2015;75:1071-94. DOI: https://doi.org/10.1007/s40265-015-0416-8

Bailey CJ, Mynett KJ, Page T. Importance of the intestine as a site of metformin-stimulated glucose utilization. Br J Pharmacol 1994;112:671-5. DOI: https://doi.org/10.1111/j.1476-5381.1994.tb13128.x

Bailey CJ, Wilcock C, Day C. Effect of metformin on glucose metabolism in the splanchnic bed. Br J Pharmacol 1992;105:1009-13. DOI: https://doi.org/10.1111/j.1476-5381.1992.tb09093.x

Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167-74. DOI: https://doi.org/10.1172/JCI13505

Wiederkehr A, Wollheim C.B. Mini review: implication of mitochondria in insulin secretion and action. Endocrinology 2006;147:2643-9. DOI: https://doi.org/10.1210/en.2006-0057

Mcbride HM, Neuspiel M, Wasiak S. Mitochondria: more than just a powerhouse. Curr Biol 2006;16:551-60. DOI: https://doi.org/10.1016/j.cub.2006.06.054

Hu F, Liu F. Mitochondrial stress: A bridge between mitochondrial dysfunction and metabolic diseases? Cell Signal 2011;23:1528-33. DOI: https://doi.org/10.1016/j.cellsig.2011.05.008

Viollet B, Guigas B, Sanz Garcia N, et al. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 2012;122:253-70. DOI: https://doi.org/10.1042/CS20110386

Hardie DG. AMP-activated protein kinase as a drug target. Annu Rev Pharmacol Toxicol 2007;47:185-210. DOI: https://doi.org/10.1146/annurev.pharmtox.47.120505.105304

Buzzai M, Jones RG, Amaravadi RK, et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 2007;67:6745-52. DOI: https://doi.org/10.1158/0008-5472.CAN-06-4447

Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000;348:607-14. DOI: https://doi.org/10.1042/bj3480607

Hinke SA, Martens GA, Cai Y, et al. Methyl succinate antagonises biguanide-induced AMPK-activation and death of pancreatic beta-cells through restoration of mitochondrial electron transfer. Br J Pharmacol 2007;150:1031-43. DOI: https://doi.org/10.1038/sj.bjp.0707189

Foretz M, Hebrard S, Leclerc J, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 2010;120:2355-69. DOI: https://doi.org/10.1172/JCI40671

Fullerton MD, Galic S, Marcinko K, et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med 2013;19:1649-54. DOI: https://doi.org/10.1038/nm.3372

Burgess SC, He T, Yan Z, et al. Cytosolic phosphoenolpyruvate carboxykinase does not solely control the rate of hepatic gluconeogenesis in the intact mouse liver. Cell Metab 2007;5:313-20. DOI: https://doi.org/10.1016/j.cmet.2007.03.004

Miller RA, Chu Q, Xie J, et al. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 2013;494:256-60. DOI: https://doi.org/10.1038/nature11808

Samuel VT, Beddow SA, Iwasaki T, et al. Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with Type 2 Diabetes. Proc Natl Acad Sci U S A 2009;106:12121-6. DOI: https://doi.org/10.1073/pnas.0812547106

Liu Y, Hong T. Combination therapy of dipeptidyl peptidase-4 inhibitors and metformin in type 2 diabetes: rationale and evidence. Diabetes Obes Metab 2014;16:111-7. DOI: https://doi.org/10.1111/dom.12128

Wu T, Thazhath SS, Bound MJ, et al. Mechanism of increase in plasma intact GLP-1 by metformin in type 2 diabetes: stimulation of GLP-1 secretion or reduction in plasma DPP-4 activity? Diabetes Res Clin Pract 2014;106:e3-6. DOI: https://doi.org/10.1016/j.diabres.2014.08.004

Karmali R, Dalovisio A, Borgia JA, et al. All in the family: Clueing into the link between metabolic syndrome and hematologic malignancies. Blood Rev 2015;29:71-80. DOI: https://doi.org/10.1016/j.blre.2014.09.010

Nagel G, Stocks T, Spath D, et al. Metabolic factors and blood cancers among 578,000 adults in the metabolic syndrome and cancer project (Me-Can). Ann Hematol 2012;91:1519-31.

Birmann BM, Giovannucci E, Rosner B, et al. Body mass index, physical activity, and risk of multiple myeloma. Cancer Epidemiol Biomarkers Prev 2007;16:1474-8. DOI: https://doi.org/10.1158/1055-9965.EPI-07-0143

Larsson SC, Wolk A. Obesity and risk of non-Hodgkin's lymphoma: a meta-analysis. Int J Cancer 2007;121:1564-70. DOI: https://doi.org/10.1002/ijc.22762

Larsson SC, Wolk A. Overweight and obesity and incidence of leukemia: a meta-analysis of cohort studies. Int J Cancer 2008;122:1418-21. DOI: https://doi.org/10.1002/ijc.23176

Nagel G, Stocks T, Spath D, et al. Metabolic factors and blood cancers among 578,000 adults in the metabolic syndrome and cancer project (Me-Can). Ann Hematol 2012;91:1519-31. DOI: https://doi.org/10.1007/s00277-012-1489-z

Renehan AG, Tyson M, Egger M, et al. Body-mass index and incidence of cancer: a systematic review andmeta-analysis of prospective observational studies. Lancet 2008;371:569-78. DOI: https://doi.org/10.1016/S0140-6736(08)60269-X

Castillo JJ, Mull N, Reagan JL, et al. Increased incidence of non-Hodgkin lymphoma, leukemia, and myeloma in patients with diabetes mellitus type 2: a meta-analysis of observational studies. Blood 2012;119:4845-50. DOI: https://doi.org/10.1182/blood-2011-06-362830

Chiu BC, Gapstur SM, Greenland P, et al. Body mass index, abnormal glucose metabolism, and mortality from hematopoietic cancer. Cancer Epidemiol Biomarkers Prev 2006;15:2348-54. DOI: https://doi.org/10.1158/1055-9965.EPI-06-0007

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646-74. DOI: https://doi.org/10.1016/j.cell.2011.02.013

Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348:1625-38. DOI: https://doi.org/10.1056/NEJMoa021423

Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 2008;8:915-28. DOI: https://doi.org/10.1038/nrc2536

Hadad SM, Baker L, Quinlan PR, et al. Histological evaluation of AMPK signalling in primary breast cancer. BMC Cancer 2009;9:307-10. DOI: https://doi.org/10.1186/1471-2407-9-307

Wingo SN, Gallardo TD, Akbay EA, et al. Somatic LKB1 mutations promote cervical cancer progression. PLoS One 2009;4P:e5137. DOI: https://doi.org/10.1371/journal.pone.0005137

Salani B, Marini C, Rio AD, et al. Metformin impairs glucose consumption and survival in Calu-1 cells by direct inhibition of hexokinase-II. Sci Rep 2013;3:2070-9. DOI: https://doi.org/10.1038/srep02070

Salani B, Del Rio A, Marini C, et al. Metformin, cancer and glucose metabolism. Endocr Relat Cancer 2014;21:461-71. DOI: https://doi.org/10.1530/ERC-14-0284

Moiseeva O, Deschenes-Simard X, St-Germain E, et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell 2013;12:489-98. DOI: https://doi.org/10.1111/acel.12075

Pearce EL, Walsh MC, Cejas PJ, et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 2009;460:103-7. DOI: https://doi.org/10.1038/nature08097

Sui X, Xu Y, Wang X, et al. Metformin: a novel but controversial drug in cancer prevention and treatment. Mol Pharm 2015;12:3783-91. DOI: https://doi.org/10.1021/acs.molpharmaceut.5b00577

Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008;30:214-26. DOI: https://doi.org/10.1016/j.molcel.2008.03.003

Hawley SA, Gadalla AE, Olsen GS, Hardie DG. The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adeninenucleotide-independent mechanism. Diabetes 2002;51:2420-5. DOI: https://doi.org/10.2337/diabetes.51.8.2420

Blandino G, Valerio M, Cioce M. Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC. Nat Commun 2012;3:865-9. DOI: https://doi.org/10.1038/ncomms1859

Jones RG, Plas DR, Kubek S, et al. AMP-activated protein kinase induces a p53-dependentmetabolic checkpoint. Mol Cell 2005;18:283-93. DOI: https://doi.org/10.1016/j.molcel.2005.03.027

Cabreiro F, Au C, Leung KY, et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 2013;153:228-39. DOI: https://doi.org/10.1016/j.cell.2013.02.035

Corominas-Faja B, Quirantes-Pine R, Oliveras-Ferraros C, et al. Metabolomic fingerprint reveals that metformin impairs one-carbon metabolism in a manner similar to the antifolate class of chemotherapy drugs. Aging 2012;4:480-98. DOI: https://doi.org/10.18632/aging.100472

Algire C, Moiseeva O, Deschenes-Simard X, et al. Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res 2012;5:536-43. DOI: https://doi.org/10.1158/1940-6207.CAPR-11-0536

Kalender A, Selvaraj A, Kim SY, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 2010;11:390-401. DOI: https://doi.org/10.1016/j.cmet.2010.03.014

Ben Sahra I, Laurent K, Loubat A, et al. The antidiabetic drug metforminexerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 2008;27:3576-86. DOI: https://doi.org/10.1038/sj.onc.1211024

Ben Sahra I, Regazzetti C, Robert G, et al. Metformin, independent of AMPK,induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res 2011;71:4366-72. DOI: https://doi.org/10.1158/0008-5472.CAN-10-1769

Marini C, Salani B, Massollo M, et al. Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer. Cell Cycle 2013;12:3490-9. DOI: https://doi.org/10.4161/cc.26461

Feng Y, Ke C, Tang Q, et al. Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling. Cell Death Dis 2014;5:e1088. DOI: https://doi.org/10.1038/cddis.2014.59

Rosilio C, Ben-Sahra I, Bost F, Peyron JF. Metformin: A metabolic disruptor and anti-diabetic drug to target human leukemia Cancer Letters 2014;346:188-96. DOI: https://doi.org/10.1016/j.canlet.2014.01.006

Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res 2011;71:3196-201. DOI: https://doi.org/10.1158/0008-5472.CAN-10-3471

Hanna RK, Zhou C, Malloy KM, et al. Metformin potentiates the effects of paclitaxel in endometrium cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. Gynecol Oncol 2012;125:458-69. DOI: https://doi.org/10.1016/j.ygyno.2012.01.009

Green AS, Chapuis N, Lacombe C, et al. LKB1/AMPK/mTOR signaling pathway in hematological malignancies: from metabolism to cancer cell biology. Cell Cycle 2011;10:2115-20. DOI: https://doi.org/10.4161/cc.10.13.16244

Green AS, Chapuis N, Maciel TT, et al. The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation. Blood 2010;116:4262-73. DOI: https://doi.org/10.1182/blood-2010-02-269837

Vakana E, Platanias LC. AMPK in BCR-ABL expressing leukemias. Regulatory effects and therapeutic implications. Oncotarget 2011;2:1322-8. DOI: https://doi.org/10.18632/oncotarget.413

Vakana E, Altman JK, Glaser H, et al. Antileukemic effects of AMPK activators on BCR-ABL-expressing cells. Blood 2011;118: 6399-402. DOI: https://doi.org/10.1182/blood-2011-01-332783

Shi R, Lin J, Gong Y, et al. The antileukemia effect of metformin in the Philadelphia chromosome - positive leukemia cell line and patient primary leukemia cell. Anticancer Drugs 2015;29:913-22. DOI: https://doi.org/10.1097/CAD.0000000000000266

Rosilio C, Lounnas N, Nebout M, et al. The metabolic perturbators metformin, phenformin and AICAR interfere with the growth and survival of murine PTEN-deficient T cell lymphomas and human T-ALL/T-LL cancer cells. Cancer Lett 2013;336:114-26. DOI: https://doi.org/10.1016/j.canlet.2013.04.015

Ramos-Peñafiel C, Olarte-Carrillo I, Cerón-MaldonadoR, et al. Effect of metformin on the survival of patients with ALL who express high levels of the ABCB1 drug resistance gene. J Transl Med 2018;16:245-9. DOI: https://doi.org/10.1186/s12967-018-1620-6

Yuan F, Cheng C, Xiao F, et al. Inhibition of mTORC1/P70S6K pathway by metformin synergistically sensitizes acute myeloid leukemia to Ara-C. Life Sci 2020;243:1172-6. DOI: https://doi.org/10.1016/j.lfs.2020.117276

Sabnis H, Bradley HF, Tripathi S, et al. Synergistic cell death in FLT3-ITD positive acute myeloid leukemia by combined treatment with metformin and 6-benzylthioinosine. Leuk Res 2016;50:132-40. DOI: https://doi.org/10.1016/j.leukres.2016.10.004

Huai L, Wang C, Zhang C, et al. Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ ERK signaling pathway. Biochem Biophys Res Commun 2012;422:398-404. DOI: https://doi.org/10.1016/j.bbrc.2012.05.001

Asik A, Kayabasi C, Ozmen Yelken B, et al. Antileukemic effect of paclitaxel in combination with metformin in HL-60 cell line. Gene 2018;647:213-20. DOI: https://doi.org/10.1016/j.gene.2018.01.017

Bruno S, Ledda B, Tenca C, et al. Metformin inhibits cell cycle progression of B-cell chronic lymphocytic leukemia cells. Oncotarget 2015;6:22624-40. DOI: https://doi.org/10.18632/oncotarget.4168

Adekola KU, Dalva Aydemir S, Ma S, et al. Intigating and targeting chronic lymphocytic leukemia metabolism with the human immunodeficiency virus protease inhibitor ritonavir and metformin. Leuk Lymphoma 2015;56:450-9. DOI: https://doi.org/10.3109/10428194.2014.922180

Shi WY, Xiao D, Wang L, et al. Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy. Cell Death Dis 2012;3:e275. DOI: https://doi.org/10.1038/cddis.2012.13

Quesada AE, Nguyen ND, Rios A, Brown RE. Morphoproteomics identifies constitutive activation of the mTORC2/Akt and NF-kB pathways and expressions of IGF-1R, Sirt1, COX-2, and FASN in peripheral T-cell lymphomas: pathogenetic implications and therapeutic options. Int J Clin Exp Pathol 2014;7:8732-9.

Tseng CH. Metformin is associated with a lower risk of non-Hodgkin lymphoma in patients with type 2 diabetes. Diabetes Metab 2019;45:458-64. DOI: https://doi.org/10.1016/j.diabet.2019.05.002

Singh A, Gu J, Yanamadala V, et al. Metformin lowers the mitochondrial potential of lymphoma cells and its use during front- line rituximab-based chemo-immunotherapy improves the clinical outcome of diffuse Large B-cell lymphoma. Blood 2013;122:1825-9. DOI: https://doi.org/10.1182/blood.V122.21.1825.1825

Smyth L, Blunt DN, Gatov E, et al. Statin and cyclooxygenase-2 inhibitors improve survival in newly diagnosed diffuse large B-cell lymphoma: a large population-based study of 4913 subjects [published online ahead of print, 2020 Apr 17]. Br J Haematol 2020;10.1111/bjh.16635. DOI: https://doi.org/10.1111/bjh.16635

Wang Y, Maurer MJ, Larson MC, et al. Impact of metformin use on the outcomes of newly diagnosed diffuse large B-cell lymphoma and follicular lymphoma. Br J Haematol 2019;186:820-8. DOI: https://doi.org/10.1111/bjh.15997

Keane NA, Glavey SV, Krawczyk J, O’Dwyer M. AKT as a therapeutic target in multiple myeloma. Expert Opin Ther Targets 2014;18:897-915. DOI: https://doi.org/10.1517/14728222.2014.924507

Zi FM, He JS, Li Y, et al. Metformin displays antimyeloma activity and synergistic effect with dexamethasone in in vitro and in vivo xenograft models. Cancer Lett. 2015;356:443-53. DOI: https://doi.org/10.1016/j.canlet.2014.09.050

Jagannathan S, Abdel-Malek MA, Malek E, et al. Pharmacologic screens reveal metformin that suppresses GRP78- dependent autophagy to enhance the anti-myeloma effect of bortezomib. Leukemia 2015;29:2184-91. DOI: https://doi.org/10.1038/leu.2015.157

Mishra AK, Dingli D. Metformin inhibits IL-6 signaling by decreasing IL-6R expression on multiple myeloma cells. Leukemia 2019;33:2695-709. DOI: https://doi.org/10.1038/s41375-019-0470-4

Wu W, Merriman K, Nabaah A, et al. The association of diabetes and anti-diabetic medications with clinical outcomes in multiple myeloma. Br J Cancer 2014;111:628-36. DOI: https://doi.org/10.1038/bjc.2014.307

Chang SH, Luo S, O'Brian KK, et al. Association between metformin use and progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans with diabetes mellitus: a population-based retrospective cohort study [published correction appears in Lancet Haematol 2015;2:e54. DOI: https://doi.org/10.1016/S2352-3026(14)00037-4

Trucco M, Barredo JC, Goldberg J, et al. A phase I window, dose escalating and safety trial of metformin in combination with induction chemotherapy in relapsed refractory acute lymphoblastic leukemia: Metformin with induction chemotherapy of vincristine, dexamethasone, PEG-asparaginase, and doxorubicin. Pediatr Blood Cancer 2018;65:e27224. DOI: https://doi.org/10.1002/pbc.27224

MacKenzie MJ, Ernst S, Johnson C, Winquist E. A phase I study of temsirolimus and metformin in advanced solid tumours. Invest New Drugs 2012;30:647-52. DOI: https://doi.org/10.1007/s10637-010-9570-8

Published
2021-02-26
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Keywords:
Metformin, leukemia, lymphoma, multiple myeloma, AKT/mTOR signaling pathway.
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How to Cite
Podhorecka, M. (2021). Metformin - its anti-cancer effects in hematologic malignancies. Oncology Reviews, 15(1). https://doi.org/10.4081/oncol.2021.514