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Article

Direct effects of phenformin on metabolism/bioenergetics and viability of SH‑SY5Y neuroblastoma cells

  • Authors:
    • Fintan Geoghegan
    • Naomi Chadderton
    • G. Jane Farrar
    • Daniela M. Zisterer
    • Richard K. Porter
  • View Affiliations / Copyright

    Affiliations: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 R590, Republic of Ireland, Ocular Genetics Unit, Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, D02 R590, Republic of Ireland
  • Pages: 6298-6306
    |
    Published online on: September 14, 2017
       https://doi.org/10.3892/ol.2017.6929
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Abstract

Phenformin, a member of the biguanides class of drugs, has been reported to be efficacious in cancer treatment. The focus of the current study was to establish whether there were direct effects of phenformin on the metabolism and bioenergetics of neuroblastoma SH‑SY5Y cancer cells. Cell viability was assessed using the alamar blue assay, flow cytometry analysis using propidium iodide and annexin V stain and poly (ADP‑ribose) polymerase analysis. Cellular and mitochondrial oxygen consumption was determined using a Seahorse Bioscience Flux analyser and an Oroboros Oxygraph respirometer. Cells were transfected using electroporation and permeabilized for in situ mitochondrial functional analysis using digitonin. Standard protocols were used for immunoblotting and proteins were separated on denaturing gels. Phenformin was effective in reducing the viability of SH‑SY5Y cells, causing G1 cell cycle arrest and inducing apoptosis. Bioenergetic analysis demonstrated that phenformin significantly decreased oxygen consumption in a dose‑ and time‑dependent manner. The sensitivity of oxygen consumption in SH‑SY5Y cells to phenformin was circumvented by the expression of NADH‑quinone oxidoreductase 1, a ubiquinone oxidoreductase, suggesting that complex I may be a target of phenformin. As a result of this inhibition, adenosine monophosphate protein kinase is activated and acetyl‑coenzyme A carboxylase is inhibited. To the best of our knowledge, the current study is the first to demonstrate the efficacy and underlying mechanism by which phenformin directly effects the survival of neuroblastoma cancer cells.
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1 

Galenkamp K, Carriba P, Urresti J, Planells-Ferrer L, Coccia E, Lopez-Soriano J, Barneda-Zahonero B, Moubarak RS, Segura MF and Comella JX: TNFα sensitizes neuroblastoma cells to FasL-, cisplatin- and etoposide-induced cell death by NF-κB-mediated expression of Fas. Mol Cancer. 14:622015. View Article : Google Scholar : PubMed/NCBI

2 

Amoroso F, Capece M, Rotondo A, Cangelosi D, Ferracin M, Franceschini A, Raffaghello L, Pistoia V, Varesio L and Adinolfi E: The P2X7 receptor is a key modulator of the PI3K/GSK3β/VEGF signaling network: Evidence in experimental neuroblastoma. Oncogene. 34:5240–5251. 2015. View Article : Google Scholar : PubMed/NCBI

3 

Cheung NK and Dyer MA: Neuroblastoma: Developmental biology, cancer genomics and immunotherapy. Nat Rev Cancer. 13:397–411. 2013. View Article : Google Scholar : PubMed/NCBI

4 

Dowling RJ, Goodwin PJ and Stambolic V: Understanding the benefit of metformin use in cancer treatment. BMC Med. 9:332011. View Article : Google Scholar : PubMed/NCBI

5 

Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR and Morris AD: Metformin and reduced risk of cancer in diabetic patients. BMJ. 330:1304–1305. 2005. View Article : Google Scholar : PubMed/NCBI

6 

Kwong SC and Brubacher J: Phenformin and lactic acidosis: A case report and review. J Emerg Med. 16:881–886. 1998. View Article : Google Scholar : PubMed/NCBI

7 

Huang X, Wullschleger S, Shapiro N, McGuire VA, Sakamoto K, Woods YL, McBurnie W, Fleming S and Alessi DR: Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J. 412:211–221. 2008. View Article : Google Scholar : PubMed/NCBI

8 

Appleyard MV, Murray KE, Coates PJ, Wullschleger S, Bray SE, Kernohan NM, Fleming S, Alessi DR and Thompson AM: Phenformin as prophylaxis and therapy in breast cancer xenografts. Br J Cancer. 106:1117–1122. 2012. View Article : Google Scholar : PubMed/NCBI

9 

Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, Glasauer A, Dufour E, Mutlu GM, Budigner GS and Chandel NS: Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife. 3:e022422014. View Article : Google Scholar : PubMed/NCBI

10 

Caraci F, Chisari M, Frasca G, Chiechio S, Salomone S, Pinto A, Sortino MA and Bianchi A: Effects of phenformin on the proliferation of human tumor cell lines. Life Sci. 74:643–650. 2003. View Article : Google Scholar : PubMed/NCBI

11 

Martin M and Marais R: Metformin: A diabetes drug for cancer, or a cancer drug for diabetics? J Clin Oncol. 30:2698–2700. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Carling D: The AMP-activated protein kinase cascade-a unifying system for energy control. Trends Biochem Sci. 29:18–24. 2004. View Article : Google Scholar : PubMed/NCBI

13 

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

14 

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 Pt. 3:607–614. 2000. View Article : Google Scholar

15 

Miskimins WK, Ahn HJ, Kim JY, Ryu S, Jung YS and Choi JY: Synergistic anti-cancer effect of phenformin and oxamate. PLoS ONE. 9:e855762014. View Article : Google Scholar : PubMed/NCBI

16 

Bailey CJ and Turner RC: Metformin. N Engl J Med. 334:574–579. 1996. View Article : Google Scholar : PubMed/NCBI

17 

Birsoy K, Possemato R, Lorbeer FK, Bayraktar EC, Thiru P, Yucel B, Wang T, Chen WW, Clish CB and Sabatini DM: Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature. 508:108–112. 2014. View Article : Google Scholar : PubMed/NCBI

18 

Zhang X, Wang H, Zhang S, Song J, Zhang Y, Wei X and Feng Z: MiR-134 functions as a regulator of cell proliferation, apoptosis, and migration involving lung septation. In Vitro Cell Dev Biol Anim. 48:131–136. 2012. View Article : Google Scholar : PubMed/NCBI

19 

Divakaruni AS, Rogers GW and Murphy AN: Measuring mitochondrial function in permeabilized cells using the seahorse XF analyzer or a clark-type oxygen electrode. Curr Protoc Toxicol. 60(25.2): 1–16. 2014.

20 

Hardie DG, Salt IP and Davies SP: Analysis of the role of the AMP-activated protein kinase in the response to cellular stress. Methods Mol Biol. 99:63–74. 2000.PubMed/NCBI

21 

Seo BB, Kitajima-Ihara T, Chan EK, Scheffler IE, Matsuno-Yagi A and Yagi T: Molecular remedy of complex I defects: Rotenone-insensitive internal NADH-quinone oxidoreductase of Saccharomyces cerevisiae mitochondria restores the NADH oxidase activity of complex I-deficient mammalian cells. Proc Natl Acad Sci USA. 95:9167–9171. 1998. View Article : Google Scholar : PubMed/NCBI

22 

Seeger RC and Reynolds CP: Treatment of high-risk solid tumors of childhood with intensive therapy and autologous bone marrow transplantation. Pediatr Clin North Am. 38:393–424. 1991. View Article : Google Scholar : PubMed/NCBI

23 

Keshelava N, Seeger RC, Groshen S and Reynolds CP: Drug resistance patterns of human neuroblastoma cell lines derived from patients at different phases of therapy. Cancer Res. 58:5396–5405. 1998.PubMed/NCBI

24 

Lennon JC, Bright SA, Carroll E, Butini S, Campiani G, O'Meara A, Williams DC and Zisterer DM: The novel pyrrolo-1,5-benzoxazepine, PBOX-6, synergistically enhances the apoptotic effects of carboplatin in drug sensitive and multidrug resistant neuroblastoma cells. Biochem Pharmacol. 87:611–624. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Balayssac D, Cayre A, Authier N, Bourdu S, Penault-Llorca F, Gillet JP, Maublant J, Eschalier A and Coudore F: Patterns of P-glycoprotein activity in the nervous system during vincristine-induced neuropathy in rats. J Peripher Nerv Syst. 10:301–310. 2005. View Article : Google Scholar : PubMed/NCBI

26 

Shackelford DB and Shaw RJ: The LKB1-AMPK pathway: Metabolism and growth control in tumour suppression. Nat Rev Cancer. 9:563–575. 2009. View Article : Google Scholar : PubMed/NCBI

27 

Goodarzi MO and Bryer-Ash M: Metformin revisited: Re-evaluation of its properties and role in the pharmacopoeia of modern antidiabetic agents. Diabetes Obes Metab. 7:654–665. 2005. View Article : Google Scholar : PubMed/NCBI

28 

Rizos CV and Elisaf MS: Metformin and cancer. Eur J Pharmacol. 705:96–108. 2013. View Article : Google Scholar : PubMed/NCBI

29 

Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG and Hardie DG: Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2:9–19. 2005. View Article : Google Scholar : PubMed/NCBI

30 

Jackson AL, Kilgore JE, Qiu H, Zhou C, Gehrig PA and Victoria L: Abstract 2442: Antitumorigenic effects of phenformin in human ovarian cancer cell lines. Cancer Res. 73:24422013. View Article : Google Scholar

31 

Yuan P, Ito K, Perez-Lorenzo R, Del Guzzo C, Lee JH, Shen CH, Bosenberg MW, McMahon M, Cantley LC and Zheng B: Phenformin enhances the therapeutic benefit of BRAF(V600E) inhibition in melanoma. Proc Natl Acad Sci USA. 110:18226–18231. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Guo Z, Chavez KJ, Alvarez J, Zhang X, Norris B, Maher M, Morgan M, Schumacher RJ, Cuellar R, Sevrioukova IF, et al: Abstract 2689: Breast cancer inhibition by a novel and potent biguanide, N1-hexyl-N5-benzyl-biguanide. Cancer Res. 74:26892014. View Article : Google Scholar

33 

Shackelford DB, Abt E, Gerken L, Vasquez DS, Seki A, Leblanc M, Wei L, Fishbein MC, Czernin J, Mischel PS and Shaw RJ: LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell. 23:143–158. 2013. View Article : Google Scholar : PubMed/NCBI

34 

Davidoff F: Effects of guanidine derivatives on mitochondrial function: III. The mechanism of phenethylbiguanide accumulation and its relationship to in vitro respiratory inhibition. J Biol Chem. 246:4017–4027. 1971.PubMed/NCBI

35 

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

36 

Hardie DG: AMPK: A target for drugs and natural products with effects on both diabetes and cancer. Diabetes. 62:164–2172. 2013. View Article : Google Scholar

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Copy and paste a formatted citation
Spandidos Publications style
Geoghegan F, Chadderton N, Farrar GJ, Zisterer DM and Porter RK: Direct effects of phenformin on metabolism/bioenergetics and viability of SH‑SY5Y neuroblastoma cells. Oncol Lett 14: 6298-6306, 2017.
APA
Geoghegan, F., Chadderton, N., Farrar, G.J., Zisterer, D.M., & Porter, R.K. (2017). Direct effects of phenformin on metabolism/bioenergetics and viability of SH‑SY5Y neuroblastoma cells. Oncology Letters, 14, 6298-6306. https://doi.org/10.3892/ol.2017.6929
MLA
Geoghegan, F., Chadderton, N., Farrar, G. J., Zisterer, D. M., Porter, R. K."Direct effects of phenformin on metabolism/bioenergetics and viability of SH‑SY5Y neuroblastoma cells". Oncology Letters 14.5 (2017): 6298-6306.
Chicago
Geoghegan, F., Chadderton, N., Farrar, G. J., Zisterer, D. M., Porter, R. K."Direct effects of phenformin on metabolism/bioenergetics and viability of SH‑SY5Y neuroblastoma cells". Oncology Letters 14, no. 5 (2017): 6298-6306. https://doi.org/10.3892/ol.2017.6929
Copy and paste a formatted citation
x
Spandidos Publications style
Geoghegan F, Chadderton N, Farrar GJ, Zisterer DM and Porter RK: Direct effects of phenformin on metabolism/bioenergetics and viability of SH‑SY5Y neuroblastoma cells. Oncol Lett 14: 6298-6306, 2017.
APA
Geoghegan, F., Chadderton, N., Farrar, G.J., Zisterer, D.M., & Porter, R.K. (2017). Direct effects of phenformin on metabolism/bioenergetics and viability of SH‑SY5Y neuroblastoma cells. Oncology Letters, 14, 6298-6306. https://doi.org/10.3892/ol.2017.6929
MLA
Geoghegan, F., Chadderton, N., Farrar, G. J., Zisterer, D. M., Porter, R. K."Direct effects of phenformin on metabolism/bioenergetics and viability of SH‑SY5Y neuroblastoma cells". Oncology Letters 14.5 (2017): 6298-6306.
Chicago
Geoghegan, F., Chadderton, N., Farrar, G. J., Zisterer, D. M., Porter, R. K."Direct effects of phenformin on metabolism/bioenergetics and viability of SH‑SY5Y neuroblastoma cells". Oncology Letters 14, no. 5 (2017): 6298-6306. https://doi.org/10.3892/ol.2017.6929
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