Metformin And Dichloroacetate Combination Exert A Synergistic Effect On Cell Viability Of Oral Squamous Cell Carcinoma

Year 2019, Volume: 9 Issue: 2, 68 - 73, 08.08.2019

Seniz Inanc Didem Keles Gorkem Eskiizmir Yasemin Basbinar Gulgun Oktay

https://doi.org/10.32448/entupdates.569464

Abstract

Objective: To assess the effects of Metformin, Dichloroacetate (DCA) and their combination on cell viability in oral squamous cell carcinoma, UPCI-SCC-131 cell line.

Methods: UPCI-SCC-131 cells were plated in 96 E-plate (1x104 cells/well) and were treated with Metformin (1-16mM) and/or DCA (15-120mM) for 24-48-72h. xCELLigence SP system was used to monitor real time cell viability. In addition, drug combination index was analyzed with CompuSyn software according to Chou-Talalay method.

Results: Half-maximal inhibitory concentrations (IC50) of Metformin and DCA were found to be 3mM and 23mM, respectively, for 72 hours. CI values (0.76-0.80) in all combination groups below 1 indicated that Metformin/DCA combination had a moderate synergistic effect on cell viability in UPCI-SCC-131 cells.

Discussion: Metformin/DCA combination synergistically decreased the cell viability of UPCI-SCC-131 cells. Therefore, a combined application of Metformin and DCA may be considered as a candidate therapy for the “drug repositioning” of the treatment of oral cavity cancer.

Keywords

Metformin , Dichloroacetate , Drug combination , Oral Cavity Cancer

Supporting Institution

Dokuz Eylul University Scientific Research Project Coordination Unit

Project Number

2017.KB.SAĞ.001

References

• 1. Zhang ZJ, Li S. The prognostic value of metformin for cancer patients with concurrent diabetes: a systematic review and meta-analysis. Diabetes Obes Metab 2014;16:707-10.
• 2. Hanna RK, Zhou C, Malloy KM, et al. Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. Gynecologic Oncology 2012;125:458-69.
• 3. 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 research 2011;71:3196-201.
• 4. Chen Y, Cairns R, Papandreou I, Koong A, Denko NC. Oxygen consumption can regulate the growth of tumors a new perspective on the Warburg effect. PLoS One 2009;4:e7033.
• 5. Rajeshkumar NV, Yabuuchi S, Pai SG, et al. Treatment of Pancreatic Cancer Patient-Derived Xenograft Panel with Metabolic Inhibitors Reveals Efficacy of Phenformin. Clin Cancer Res 2017;23:5639-47.
• 6. YW Choi, IK Lim. Sensitization of metformin-cytotoxicity by dichloroacetate via reprogramming glucose metabolism in cancer cells. Cancer Lett 2014;346:300-8.
• 7. Chou TC, Talalay P. Quantitative analysis of dose effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984;22:27-55.
• 8. Sasahira T, Kirita T. Hallmarks of Cancer-Related Newly Prognostic Factors of Oral Squamous Cell Carcinoma. Int J Mol Sci 2018;19 doi:10.3390/ijms19082413.
• 9. Feller L, Lemmer J. Oral Squamous Cell Carcinoma: Epidemiology,Clinical Presentation and Treatment. J Cancer Ther 2012;3:263-8.
• 10. Chen X, Li C, He T, et al. Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression. Cancer Biol Ther 2016;17:507-14.
• 11. Zhuang Y, Miskimins WK. Metformin induces both caspase-dependent and poly(ADP-ribose) polymerase-dependent cell death in breast cancer cells. Mol Cancer Res 2011;9:603-15.
• 12. Guimarães TA, Farias LC, Santos ES, et al. Metformin increases PDH and suppresses HIF-1α under hypoxic conditions and induces cell death in oral squamous cell carcinoma. Oncotarget 2016;7:55057-68.
• 13. Qi X, Xu W, Xie J, et al. Metformin sensitizes the response of oral squamous cell carcinoma to cisplatin treatment through inhibition of NF-κB/ HIF-1α signal axis. Scientific Reports 2016;6:35788.
• 14. Harada K, Ferdous T, Harada T, Ueyama Y. Metformin in combination with 5-fluorouracil suppresses tumor growth by inhibiting the Warburg effect in human oral squamous cell carcinoma. Int J Oncol 2016;49:276-84.
• 15. Hanna RK, Zhou C, Malloy KM, et al. Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. Gynecol Oncol 2012;125:458-69.
• 16. Li B, Zhu Y, Sun Q, et al. Reversal of the Warburg effect with DCA in PDGF-treated human PASMC is potentiated by pyruvate dehydrogenase kinase-1 inhibition mediated through blocking Akt/GSK-3β signalling. Int J Mol Med 2018;42:1391-400.
• 17. Li B, Li X, Ni Z, et al. Dichloroacetate and metformin synergistically suppress the growth of ovarian cancer cells. Oncotarget 2016;7:59458-70.
• 18. Haugrud AB, Zhuang Y, Coppock JD, Miskimins WK. Dichloroacetate enhances apoptotic cell death via oxidative damage and attenuates lactate production in metformin-treated breast cancer cells. Breast Cancer Res Treat 2014;147:539-50.
• 19. Hong SE, Jin HO, Kim HA, et al. Targeting HIF-1alpha is a prerequisite for cell sensitivity to dichloroacetate (DCA) and metformin. Biochem Biophys Res Commun 2016;469:164-70.
• 20. Florio R, De Lellis L, Veschi S, et al. Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells. Sci Rep 2018;8:13610.