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Article

Co-treatment of breast cancer cells with pharmacologic doses of 2-deoxy-D-glucose and metformin: Starving tumors

  • Authors:
    • Ulrike Wokoun
    • Martin Hellriegel
    • Günter Emons
    • Carsten Gründker
  • View Affiliations / Copyright

    Affiliations: Department of Gynecology and Obstetrics, Georg-August-University, D-37075 Göttingen, Germany
  • Pages: 2418-2424
    |
    Published online on: March 6, 2017
       https://doi.org/10.3892/or.2017.5491
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Abstract

A characteristic of tumor cells is the increased aerobic glycolysis for energy production. Thus, inhibition of glycolysis represents a selective therapeutic option. It has been shown that glycolysis inhibitor 2-deoxy-D-glucose (2DG) induces apoptotic cell death in different tumor entities. In addition, the antitumor activity of the anti-diabetic drug metformin has been demonstrated. In the present study, we aimed to ascertain whether the combination of pharmacologic doses of 2DG with metformin increases the antitumor efficacy. Cell viability of MDA-MB-231 and HCC1806 triple-negative breast cancer (TNBC) cells treated without or with 2DG or with metformin alone or with the combination of both agents was measured using Alamar Blue assay. Induction of apoptosis was quantified by measurement of the loss of mitochondrial membrane potential and cleavage of PARP. Treatment of breast cancer cells with glycolysis inhibitor 2DG or with the anti-diabetic drug metformin resulted in a significant decrease in cell viability and an increase in apoptosis. Treatment with 2DG in combination with metformin resulted in significantly reduced viability compared with the single agent treatments. The observed reduction in viability was due to induction of apoptosis. In addition, in regards to apoptosis induction a stronger effect in the case of co-treatment compared with single agent treatments was observed. The glycolytic phenotype of human breast cancer cells can be targeted for therapeutic intervention. Co-treatment with doses of the glycolysis inhibitor 2DG and anti-diabetic drug metformin is tolerable in humans and may be a suitable therapy for human breast cancers.
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View References

1 

Warburg O: The Metabolism of Tumors. Arnold Constable; London: pp. 254–270. 1930

2 

Yamamoto T, Seino Y, Fukumoto H, Koh G, Yano H, Inagaki N, Yamada Y, Inoue K, Manabe T and Imura H: Over-expression of facilitative glucose transporter genes in human cancer. Biochem Biophys Res Commun. 170:223–230. 1990. View Article : Google Scholar : PubMed/NCBI

3 

Pelicano H, Martin DS, Xu RH and Huang P: Glycolysis inhibition for anticancer treatment. Oncogene. 25:4633–4646. 2006. View Article : Google Scholar : PubMed/NCBI

4 

Kaplan O, Navon G, Lyon RC, Faustino PJ, Straka EJ and Cohen JS: Effects of 2-deoxyglucose on drug-sensitive and drug-resistant human breast cancer cells: Toxicity and magnetic resonance spectroscopy studies of metabolism. Cancer Res. 50:544–551. 1990.PubMed/NCBI

5 

Laszlo J, Humphreys SR and Goldin A: Effects of glucose analogues (2-deoxy-D-glucose, 2-deoxy-D-galactose) on experimental tumors. J Natl Cancer Inst. 24:267–281. 1960.PubMed/NCBI

6 

Aft RL, Zhang FW and Gius D: Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: Mechanism of cell death. Br J Cancer. 87:805–812. 2002. View Article : Google Scholar : PubMed/NCBI

7 

Bell SE, Quinn DM, Kellett GL and Warr JR: 2-Deoxy-D-glucose preferentially kills multidrug-resistant human KB carcinoma cell lines by apoptosis. Br J Cancer. 78:1464–1470. 1998. View Article : Google Scholar : PubMed/NCBI

8 

Lee YJ, Galoforo SS, Berns CM, Tong WP, Kim HR and Corry PM: Glucose deprivation-induced cytotoxicity in drug resistant human breast carcinoma MCF-7/ADR cells: Role of c-myc and bcl-2 in apoptotic cell death. J Cell Sci. 110:681–686. 1997.PubMed/NCBI

9 

Reutter M, Emons G and Gründker C: Starving tumors: Inhibition of glycolysis reduces viability of human endometrial and ovarian cancer cells and enhances antitumor efficacy of GnRH receptor-targeted therapies. Int J Gynecol Cancer. 23:34–40. 2013. View Article : Google Scholar : PubMed/NCBI

10 

Giannarelli R, Aragona M, Coppelli A and Del Prato S: Reducing insulin resistance with metformin: The evidence today. Diabetes Metab. 29:6S28–6S35. 2003. View Article : Google Scholar : PubMed/NCBI

11 

Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R and Zinman B: American Diabetes Association; European Association for Study of Diabetes: Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 32:193–203. 2009. View Article : Google Scholar : PubMed/NCBI

12 

Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Kovalenko IG, Poroshina TE, Semenchenko AV, Provinciali M, et al: Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol. 40:685–693. 2005. View Article : Google Scholar : PubMed/NCBI

13 

Anisimov VN, Egormin PA, Piskunova TS, Popovich IG, Tyndyk ML, Yurova MN, Zabezhinski MA, Anikin IV, Karkach AS and Romanyukha AA: metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo. Cell Cycle. 9:188–197. 2010. View Article : Google Scholar : PubMed/NCBI

14 

Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, Tanti JF, Le Marchand-Brustel Y and Bost F: The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene. 27:3576–3586. 2008. View Article : Google Scholar : PubMed/NCBI

15 

Janjetovic K, Harhaji-Trajkovic L, Misirkic-Marjanovic M, Vucicevic L, Stevanovic D, Zogovic N, Sumarac-Dumanovic M, Micic D and Trajkovic V: In vitro and in vivo anti-melanoma action of metformin. Eur J Pharmacol. 668:373–382. 2011. View Article : Google Scholar : PubMed/NCBI

16 

Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD and Dennis PA: Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Cancer Prev Res. 3:1066–1076. 2010. View Article : Google Scholar

17 

Rattan R, Graham RP, Maguire JL, Giri S and Shridhar V: Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia. 13:483–491. 2011. View Article : Google Scholar : PubMed/NCBI

18 

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, et al: Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 108:1167–1174. 2001. View Article : Google Scholar : PubMed/NCBI

19 

Camacho L, Dasgupta A and Jiralerspong S: Metformin in breast cancer - an evolving mystery. Breast Cancer Res. 17:882015. View Article : Google Scholar : PubMed/NCBI

20 

Emons G, Ortmann O, Becker M, Irmer G, Springer B, Laun R, Hölzel F, Schulz KD and Schally AV: High affinity binding and direct antiproliferative effects of LHRH analogues in human ovarian cancer cell lines. Cancer Res. 53:5439–5446. 1993.PubMed/NCBI

21 

Emons G, Schröder B, Ortmann O, Westphalen S, Schulz KD and Schally AV: High affinity binding and direct antiproliferative effects of luteinizing hormone-releasing hormone analogs in human endometrial cancer cell lines. J Clin Endocrinol. 77:1458–1464. 1993. View Article : Google Scholar

22 

Irmer G, Bürger C, Müller R, Ortmann O, Peter U, Kakar SS, Neill JD, Schulz KD and Emons G: Expression of the messenger RNAs for luteinizing hormone-releasing hormone (LHRH) and its receptor in human ovarian epithelial carcinoma. Cancer Res. 55:817–822. 1995.PubMed/NCBI

23 

Raez LE, Papadopoulos K, Ricart AD, Chiorean EG, Dipaola RS, Stein MN, Lima Rocha CM, Schlesselman JJ, Tolba K, Langmuir VK, et al: A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol. 71:523–530. 2013. View Article : Google Scholar : PubMed/NCBI

24 

FDA: Metformin: Official FDA Information. Side-Effects And Uses. 2011.https://www.fda.gov/ohrms/dockets/dailys/02/May02/053102/800471e6.pdfAccession date: October 25, 2016.

25 

Shank JJ, Yang K, Ghannam J, Cabrera L, Johnston CJ, Reynolds RK and Buckanovich RJ: Metformin targets ovarian cancer stem cells in vitro and in vivo. Gynecol Oncol. 127:390–397. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Zhang F and Aft RL: Chemosensitizing and cytotoxic effects of 2-deoxy-D-glucose on breast cancer cells. J Cancer Res Ther. 5:(Suppl 1). S41–S43. 2009. View Article : Google Scholar : PubMed/NCBI

27 

Cheong JH, Park ES, Liang J, Dennison JB, Tsavachidou D, Nguyen-Charles C, Cheng Wa K, Hall H, Zhang D, Lu Y, et al: Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Mol Cancer Ther. 10:2350–2362. 2011. View Article : Google Scholar : PubMed/NCBI

28 

Ben Sahra I, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, Le Marchand-Brustel Y, Giorgetti-Peraldi S, Cormont M, Bertolotto C, et al: Targeting cancer cell metabolism: The combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res. 70:2465–2475. 2010. View Article : Google Scholar : PubMed/NCBI

29 

Andrzejewski S, Gravel SP, Pollak M and St-Pierre J: Metformin directly acts on mitochondria to alter cellular bioenergetics. Cancer Metab. 2:122014. View Article : Google Scholar : PubMed/NCBI

30 

Bridges HR, Jones AJ, Pollak MN and Hirst J: Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J. 462:475–487. 2014. View Article : Google Scholar : PubMed/NCBI

31 

Drahota Z, Palenickova E, Endlicher R, Milerova M, Brejchova J, Vosahlikova M, Svoboda P, Kazdova L, Kalous M, Cervinkova Z, et al: Biguanides inhibit complex I, II and IV of rat liver mitochondria and modify their functional properties. Physiol Res. 63:1–11. 2014.PubMed/NCBI

32 

El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M and Leverve X: Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 275:223–228. 2000. View Article : Google Scholar : PubMed/NCBI

33 

Owen MR, Doran E and Halestrap AP: Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 348:607–614. 2000. View Article : Google Scholar : PubMed/NCBI

34 

He L and Wondisford FE: metformin action: Concentrations matter. Cell Metab. 21:159–162. 2015. View Article : Google Scholar : PubMed/NCBI

35 

Brown J: Effects of 2-deoxyglucose on carbohydrate metablism: Review of the literature and studies in the rat. Metabolism. 11:1098–1112. 1962.PubMed/NCBI

36 

DiPaola RS, Dvorzhinski D, Thalasila A, Garikapaty V, Doram D, May M, Bray K, Mathew R, Beaudoin B, Karp C, et al: Therapeutic starvation and autophagy in prostate cancer: A new paradigm for targeting metabolism in cancer therapy. Prostate. 68:1743–1752. 2008. View Article : Google Scholar : PubMed/NCBI

37 

McComb RB and Yushok WD: Metabolism of ascites tumor cells. Iv. Enzymatic reactions involved in adenosinetriphosphate degradation induced by 2-deoxyglucose. Cancer Res. 24:198–205. 1964.PubMed/NCBI

38 

Lalau JD and Race JM: Lactic acidosis in metformin therapy. Drugs. 58:(Suppl 1). 55–82. 1999. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Wokoun U, Hellriegel M, Emons G and Gründker C: Co-treatment of breast cancer cells with pharmacologic doses of 2-deoxy-D-glucose and metformin: Starving tumors. Oncol Rep 37: 2418-2424, 2017.
APA
Wokoun, U., Hellriegel, M., Emons, G., & Gründker, C. (2017). Co-treatment of breast cancer cells with pharmacologic doses of 2-deoxy-D-glucose and metformin: Starving tumors. Oncology Reports, 37, 2418-2424. https://doi.org/10.3892/or.2017.5491
MLA
Wokoun, U., Hellriegel, M., Emons, G., Gründker, C."Co-treatment of breast cancer cells with pharmacologic doses of 2-deoxy-D-glucose and metformin: Starving tumors". Oncology Reports 37.4 (2017): 2418-2424.
Chicago
Wokoun, U., Hellriegel, M., Emons, G., Gründker, C."Co-treatment of breast cancer cells with pharmacologic doses of 2-deoxy-D-glucose and metformin: Starving tumors". Oncology Reports 37, no. 4 (2017): 2418-2424. https://doi.org/10.3892/or.2017.5491
Copy and paste a formatted citation
x
Spandidos Publications style
Wokoun U, Hellriegel M, Emons G and Gründker C: Co-treatment of breast cancer cells with pharmacologic doses of 2-deoxy-D-glucose and metformin: Starving tumors. Oncol Rep 37: 2418-2424, 2017.
APA
Wokoun, U., Hellriegel, M., Emons, G., & Gründker, C. (2017). Co-treatment of breast cancer cells with pharmacologic doses of 2-deoxy-D-glucose and metformin: Starving tumors. Oncology Reports, 37, 2418-2424. https://doi.org/10.3892/or.2017.5491
MLA
Wokoun, U., Hellriegel, M., Emons, G., Gründker, C."Co-treatment of breast cancer cells with pharmacologic doses of 2-deoxy-D-glucose and metformin: Starving tumors". Oncology Reports 37.4 (2017): 2418-2424.
Chicago
Wokoun, U., Hellriegel, M., Emons, G., Gründker, C."Co-treatment of breast cancer cells with pharmacologic doses of 2-deoxy-D-glucose and metformin: Starving tumors". Oncology Reports 37, no. 4 (2017): 2418-2424. https://doi.org/10.3892/or.2017.5491
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