DOI QR코드

DOI QR Code

Lack of Metformin Effects on Different Molecular Subtypes of Breast Cancer under Normoglycemic Conditions: An in vitro Study

  • Sadighi, Sanambar ;
  • Amanpour, Saeid ;
  • Behrouzi, Bita ;
  • Khorgami, Zhinoos ;
  • Muhammadnejad, Samad
  • Published : 2014.03.01

Abstract

Background: In the past few years, a considerable number of preclinical studies have been proposed metformin as a potential anticancer agent, but some of these studies suffer from a number of methodological limitations such as assessment of cytotoxicity in the presence of supraphysiological glucose concentrations or applying suprapharmacological levels of the drug. These objections have limited the translation of published preclinical data to the clinical setting. The present study aimed to investigate direct anticancer effects of metformin on different molecular subtypes of breast cancer with pharmacological concentrations and under normoglycemic conditions in vitro. Materials and Methods: Breast cancer cell lines from luminal A, luminal B, ErbB2 and triple-negative molecular subtypes were treated with a pharmacological concentration of metformin (2mM) at a glucose concentration of 5.5mM. Time-dependant cell viability was assessed by dye exclusion assay. MTTbased cytotoxicity assays were also performed with metformin alone or in combination with paclitaxel. Results: Metformin did not show any growth inhibitory effects or time-dependant cytotoxicity on breast cancer cell lines in the presence of normal glucose concentrations at the therapeutic plasma level. No augmentation of the antineoplastic properties of paclitaxel was apparent under the tested conditions. Conclusions: Metformin is probably unable to exert cytotoxic or cytostatic effects on breast cancer subtypes at pharmacological concentrations and normal plasma glucose levels. These results highlight the importance of establishing a higher steady-state plasma concentration of metformin in the clinical setting for assessment of anticancer effects in normoglycemic patients.

Keywords

Breast cancer;metformin;cytotoxicity;in vitro;normoglycemia

References

  1. Szewczyk M, Richter C, Briese V, et al (2012). A retrospective in vitro study of the impact of anti-diabetics and cardioselective pharmaceuticals on breast cancer. Anticancer Res, 32, 2133-8.
  2. Liu H, Scholz C, Zang C, et al (2012). Metformin and the mTOR inhibitor everolimus (RAD001) sensitize breast cancer cells to the cytotoxic effect of chemotherapeutic drugs in vitro. Anticancer Res, 32, 1627-37.
  3. Peairs KS, Barone BB, Snyder CF, et al (2011). Diabetes mellitus and breast cancer outcomes: a systematic review and metaanalysis. J Clin Oncol, 29, 40-6. https://doi.org/10.1200/JCO.2009.27.3011
  4. Plumb JA, Milroy R, Kaye SB (1989). Effects of the pH dependence of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide-formazan absorption on chemosensitivity determined by a novel tetrazolium-based assay. Cancer Res, 49, 4435-40.
  5. Scarpello JH, Howlett HC (2008). Mettformin therapy and clinical uses. Diab Vasc Dis Res, 5, 157-67. https://doi.org/10.3132/dvdr.2008.027
  6. Viollet B, Guigas B, Sanz Garcia N, et al (2012). Cellular and molecular mechanisms of metformin: an overview. Clin Sci, 122, 253-70. https://doi.org/10.1042/CS20110386
  7. Wang Y, Zhang MX, Duan XY, et al (2011). Effects of antidiabetic drug metformin on human breast carcinoma cells with different estrogen receptor expressing in vitro. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, 27, 253-6.
  8. Wild S, Roglic G, Green A, et al (2004). Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care, 27, 1047-53. https://doi.org/10.2337/diacare.27.5.1047
  9. Wolf I, Sadetzki S, Catane R, et al (2005). Diabetes mellitus and breast cancer. Lancet Oncol, 6, 103-11. https://doi.org/10.1016/S1470-2045(05)01736-5
  10. Zakikhani M, Dowling R, Fantus IG, et al (2006). Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res, 66, 10269-73. https://doi.org/10.1158/0008-5472.CAN-06-1500
  11. Evans JM, Donnelly LA, Emslie-Smith AM, et al (2005). Metformin and reduced risk of cancer in diabetic patients. BMJ, 330, 1304-5. https://doi.org/10.1136/bmj.38415.708634.F7
  12. Cufi S, Corominas-Faja B, Vazquez-Martin A, et al (2012). Metformin-induced preferential killing of breast cancer initiating CD44+CD24-/low cells is sufficient to overcome primary resistance to trastuzumab in HER2+ human breast cancer xenografts. Oncotarget, 3, 395-8.
  13. Del Barco S, Vazquez-Martin A, Cufi S, et al (2011). Metformin: multi-faceted protection againist cancer. Oncotarget, 2, 896-917.
  14. Dowling RJ, Zakikhani M, Fantus IG, et al (2007) Metformin inhibits mammalian target of rapamycin-dependent translation inhibition in breast cancer cells. Cancer Res, 67, 10804-12. https://doi.org/10.1158/0008-5472.CAN-07-2310
  15. Goodwin PJ, Stambolic V, Lemieux J, et al (2011). Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents. Breast Cancer Res Treat, 126, 215-20. https://doi.org/10.1007/s10549-010-1224-1
  16. Goodwin PJ, Stambolic V (2011). Metformin, cancer risk, and prognosis. In "ASCO Educational Book". ASCO University, pp 42-5.
  17. Goodwin PJ, Ligibel JA, Stambolic V (2009). Metformin in breast cancer: time for action. J Clin Oncol, 27, 3271-3. https://doi.org/10.1200/JCO.2009.22.1630
  18. Hirsch HA, Iliopoulos D, Struhl K (2013). Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci USA, 110, 972-7. https://doi.org/10.1073/pnas.1221055110
  19. Lipscombe LL, Goodwin PJ, Zinman B, et al (2008). The impact of diabetes on survival following breast cancer. Breast Cancer Res Treat, 109, 389-95. https://doi.org/10.1007/s10549-007-9654-0
  20. Liu B, Fan Z, Edgerton SM, et al (2011). Potent anti-proliferative effects of metformin on trastuzumab-resistant breast cancer cells via inhibition of erbB2/IGF-1 receptor interactions. Cell Cycle, 10, 2959-66. https://doi.org/10.4161/cc.10.17.16359
  21. Bowker SL, Majumdar SR, Veugelers P, et al (2006). Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care, 29, 254-8. https://doi.org/10.2337/diacare.29.02.06.dc05-1558
  22. Chen TW, Liang YN, Feng D, et al (2013). Metformin inhibits proliferation and promotes apoptosis of HER2 positive breast cancer cells by downregulating HSP90. J BUON, 18, 51-6.

Cited by

  1. Medium Renewal Blocks Anti-Proliferative Effects of Metformin in Cultured MDA-MB-231 Breast Cancer Cells vol.11, pp.5, 2016, https://doi.org/10.1371/journal.pone.0154747
  2. Green synthesis of silver nanoparticles using Zingiber officinale and Thymus vulgaris extracts: characterisation, cell cytotoxicity, and its antifungal activity against Candida albicans in comparison to fluconazole pp.1751-875X, 2018, https://doi.org/10.1049/iet-nbt.2018.5146