Potential Applications for Biguanides in Oncology

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2013 Sep 4

PMID 23999444

Citations 100

Authors

Michael Pollak

Affiliations

Soon will be listed here.

Abstract

Metformin is widely prescribed for the treatment of type II diabetes. Recently, it has been proposed that this compound or related biguanides may have antineoplastic activity. Biguanides may exploit specific metabolic vulnerabilities of transformed cells by acting on them directly, or may act by indirect mechanisms that involve alterations of the host environment. Preclinical data suggest that drug exposure levels are a key determinant of proposed direct actions. With respect to indirect mechanisms, it will be important to determine whether recently demonstrated metformin-induced changes in levels of candidate systemic mediators such as insulin or inflammatory cytokines are of sufficient magnitude to achieve therapeutic benefit. Results of the first generation of clinical trials now in progress are eagerly anticipated. Ongoing investigations may justify a second generation of trials that explore pharmacokinetic optimization, rational drug combinations, synthetic lethality strategies, novel biguanides, and the use of predictive biomarkers.

Citing Articles

The Role of HK2 in Tumorigenesis and Development: Potential for Targeted Therapy with Natural Products.

He K, Tao F, Lu Y, Fang M, Huang H, Zhou Y Int J Med Sci. 2025; 22(4):790-805.

PMID: 39991762 PMC: 11843137. DOI: 10.7150/ijms.105553.

Biguanides antithetically regulate tumor properties by the dose-dependent mitochondrial reprogramming-driven c-Src pathway.

Park J, Jung K, Jia D, Yang S, Attri K, Ahn S Cell Rep Med. 2025; 6(2):101941.

PMID: 39933530 PMC: 11866546. DOI: 10.1016/j.xcrm.2025.101941.

Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma.

Mbah N, Myers A, Sajjakulnukit P, Chung C, Thompson J, Hong H Nat Commun. 2024; 15(1):8983.

PMID: 39419964 PMC: 11487135. DOI: 10.1038/s41467-024-52973-4.

Cytidine deaminase-dependent mitochondrial biogenesis as a potential vulnerability in pancreatic cancer cells.

Frances A, Lumeau A, Bery N, Gayral M, Stuani L, Sorbara M Commun Biol. 2024; 7(1):1065.

PMID: 39215188 PMC: 11364846. DOI: 10.1038/s42003-024-06760-y.

Mito-LND and (E)-Akt inhibitor-IV: novel compounds inducing endoplasmic reticulum stress and ROS accumulation against hepatocellular carcinoma.

Liao S, Wang Q, Chen S, Huang Q, Zhou L, Liu H J Transl Med. 2024; 22(1):792.

PMID: 39198815 PMC: 11351498. DOI: 10.1186/s12967-024-05545-5.

References

Lega I, Austin P, Gruneir A, Goodwin P, Rochon P, Lipscombe L . Association between metformin therapy and mortality after breast cancer: a population-based study. Diabetes Care. 2013; 36(10):3018-26. PMC: 3781496. DOI: 10.2337/dc12-2535. View

Algire C, Amrein L, Zakikhani M, Panasci L, Pollak M . Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer. 2010; 17(2):351-60. DOI: 10.1677/ERC-09-0252. View

Pritchard K, Shepherd L, Chapman J, Norris B, Cantin J, Goss P . Randomized trial of tamoxifen versus combined tamoxifen and octreotide LAR Therapy in the adjuvant treatment of early-stage breast cancer in postmenopausal women: NCIC CTG MA.14. J Clin Oncol. 2011; 29(29):3869-76. DOI: 10.1200/JCO.2010.33.7006. View

Gong L, Goswami S, Giacomini K, Altman R, Klein T . Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2012; 22(11):820-7. PMC: 3651676. DOI: 10.1097/FPC.0b013e3283559b22. View

Hadad S, Baker L, Quinlan P, Robertson K, Bray S, Thomson G . Histological evaluation of AMPK signalling in primary breast cancer. BMC Cancer. 2009; 9:307. PMC: 2744705. DOI: 10.1186/1471-2407-9-307. View

Evia-Viscarra M, Rodea-Montero E, Apolinar-Jimenez E, Munoz-Noriega N, Garcia-Morales L, Leanos-Perez C . The effects of metformin on inflammatory mediators in obese adolescents with insulin resistance: controlled randomized clinical trial. J Pediatr Endocrinol Metab. 2012; 25(1-2):41-9. DOI: 10.1515/jpem-2011-0469. View

Ouyang J, Parakhia R, Ochs R . Metformin activates AMP kinase through inhibition of AMP deaminase. J Biol Chem. 2010; 286(1):1-11. PMC: 3012963. DOI: 10.1074/jbc.M110.121806. View

Singh S, Akhtar N, Ahmad J . Plasma adiponectin levels in women with polycystic ovary syndrome: impact of metformin treatment in a case-control study. Diabetes Metab Syndr. 2012; 6(4):207-11. DOI: 10.1016/j.dsx.2012.05.013. View

Hvid H, Fendt S, Blouin M, Birman E, Voisin G, Svendsen A . Stimulation of MC38 tumor growth by insulin analog X10 involves the serine synthesis pathway. Endocr Relat Cancer. 2012; 19(4):557-74. DOI: 10.1530/ERC-12-0125. View

10.

Hawley S, Fullerton M, Ross F, Schertzer J, Chevtzoff C, Walker K . The ancient drug salicylate directly activates AMP-activated protein kinase. Science. 2012; 336(6083):918-22. PMC: 3399766. DOI: 10.1126/science.1215327. View

11.

Zhang P, Li H, Tan X, Chen L, Wang S . Association of metformin use with cancer incidence and mortality: a meta-analysis. Cancer Epidemiol. 2013; 37(3):207-18. DOI: 10.1016/j.canep.2012.12.009. View

12.

Corominas-Faja B, Quirantes-Pine R, Oliveras-Ferraros C, Vazquez-Martin A, Cufi S, Martin-Castillo B . Metabolomic fingerprint reveals that metformin impairs one-carbon metabolism in a manner similar to the antifolate class of chemotherapy drugs. Aging (Albany NY). 2012; 4(7):480-98. PMC: 3433934. DOI: 10.18632/aging.100472. View

13.

Matoba S, Kang J, Patino W, Wragg A, Boehm M, Gavrilova O . p53 regulates mitochondrial respiration. Science. 2006; 312(5780):1650-3. DOI: 10.1126/science.1126863. View

14.

Suissa S . Immortal time bias in pharmaco-epidemiology. Am J Epidemiol. 2007; 167(4):492-9. DOI: 10.1093/aje/kwm324. View

15.

Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G . Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010; 120(7):2355-69. PMC: 2898585. DOI: 10.1172/JCI40671. View

16.

Nkontchou G, Cosson E, Aout M, Mahmoudi A, Bourcier V, Charif I . Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. J Clin Endocrinol Metab. 2011; 96(8):2601-8. DOI: 10.1210/jc.2010-2415. View

17.

Goodwin P, Ennis M, Pritchard K, Trudeau M, Koo J, Taylor S . Insulin- and obesity-related variables in early-stage breast cancer: correlations and time course of prognostic associations. J Clin Oncol. 2011; 30(2):164-71. DOI: 10.1200/JCO.2011.36.2723. View

18.

Algire C, Amrein L, Bazile M, David S, Zakikhani M, Pollak M . Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo. Oncogene. 2010; 30(10):1174-82. DOI: 10.1038/onc.2010.483. View

19.

Ota S, Horigome K, Ishii T, Nakai M, Hayashi K, Kawamura T . Metformin suppresses glucose-6-phosphatase expression by a complex I inhibition and AMPK activation-independent mechanism. Biochem Biophys Res Commun. 2009; 388(2):311-6. DOI: 10.1016/j.bbrc.2009.07.164. View

20.

Turner N, Li J, Gosby A, To S, Cheng Z, Miyoshi H . Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes. 2008; 57(5):1414-8. DOI: 10.2337/db07-1552. View