Evaluation of Cytotoxic Effects of the Combination of Metformin with Docetaxel and 5-Fluorouracil on the Gastric Cancer Cells

Document Type : Original Article (s)

Authors

1 MSc Student, Department of Anatomical Sciences and Pathology, School of Medicine and Paramedicine, Ardabil University of Medical Sciences, Ardabil, Iran

2 Associate Professor, Research Laboratory for Embryology and Stem Cells AND Department of Anatomical Sciences and Pathology, School of Medicine and Paramedicine, Ardabil University of Medical Sciences, Ardabil, Iran

Abstract

Background: In the present study, the cytotoxic effects of the combination of metformin with docetaxel and 5- fluorouracil were studied on AGS gastric cancer cell line.Methods: In this experimental study, the cells were exposed to different concentrations of metformin (1-80 mM), docetaxel (0.6-22.5 ng/ml), 5-fluorouracil (0.045-12 μg/ml), and combination of them. The cell proliferation was evaluated using MTT assay, and the cell apoptosis was evaluated by acridine orange/ethidium bromide assay.Findings: Metformin, docetaxel, and 5-fluorouracil inhibited cell viability of AGS gastric cancer cells in a concentration- and time-dependent manner. The half-maximal inhibitory concentration (IC50) values were decreased after treatment with metformin/docetaxel and metformin/5-fluorouracil (P < 0.050). Moreover, the combination treatments significantly increased apoptosis of gastric cancer cells (P < 0.050).Conclusion: Our results showed that the combination of metformin with docetaxel and 5-fluorouracil could be effective in the treatment of patients with gastric cancer.

Keywords

References

  1. Rahman R, Asombang AW, Ibdah JA. Characteristics of gastric cancer in Asia. World J Gastroenterol 2014; 20(16): 4483-90.
  2. Taghavi N, Nasrollahzadeh D, Merat S, Yazdanbod A, Hormazdi M, Sotoudeh M, et al. Epidemiology of upper gastrointestinal cancers in Iran: A sub site analysis of 761 cases. World J Gastroenterol 2007; 13(40): 5367-70.
  3. Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A, Fleig WE. Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol 2006; 24(18): 2903-9.
  4. Yu B, Gu D, Zhang X, Liu B, Xie J. The role of GLI2-ABCG2 signaling axis for 5Fu resistance in gastric cancer. J Genet Genomics 2017; 44(8): 375-83.
  5. Tamegai H, Kaiga T, Kochi M, Fujii M, Kanamori N, Mihara Y, et al. Pharmacokinetics of docetaxel in gastric cancer patients with malignant ascites. Cancer Chemother Pharmacol 2013; 71(3): 727-31.
  6. Micic D, Cvijovic G, Trajkovic V, Duntas LH, Polovina S. Metformin: Its emerging role in oncology. Hormones (Athens) 2011; 10(1): 5-15.
  7. Zheng J, Xie SH, Santoni G, Lagergren J. Metformin use and risk of gastric adenocarcinoma in a Swedish population-based cohort study. Br J Cancer 2019; 121(10): 877-82.
  8. Lacroix O, Couttenier A, Vaes E, Cardwell CR, De SH, Robert A. Impact of metformin on gastric adenocarcinoma survival: A Belgian population based study. Cancer Epidemiol 2018; 53: 149-55.
  9. Yu G, Fang W, Xia T, Chen Y, Gao Y, Jiao X, et al. Metformin potentiates rapamycin and cisplatin in gastric cancer in mice. Oncotarget 2015; 6(14): 12748-62.
  10. Lesan V, Ghaffari SH, Salaramoli J, Heidari M, Rostami M, Alimoghaddam K, et al. Evaluation of antagonistic effects of metformin with Cisplatin in gastric cancer cells. Int J Hematol Oncol Stem Cell Res 2014; 8(3): 12-9.
  11. Xiao P, Ma T, Zhou C, Xu Y, Liu Y, Zhang H. Anticancer effect of docetaxel induces apoptosis of prostate cancer via the cofilin-1 and paxillin signaling pathway. Mol Med Rep 2016; 13(5): 4079-84.
  12. Najafzadeh N, Mazani M, Abbasi A, Farassati F, Amani M. Low-dose all-trans retinoic acid enhances cytotoxicity of cisplatin and 5-fluorouracil on CD44(+) cancer stem cells. Biomed Pharmacother 2015; 74: 243-51.
  13. Han G, Gong H, Wang Y, Guo S, Liu K. AMPK/mTOR-mediated inhibition of survivin partly contributes to metformin-induced apoptosis in human gastric cancer cell. Cancer Biol Ther 2015; 16(1): 77-87.
  14. Kim SH, Kim SC, Ku JL. Metformin increases chemo-sensitivity via gene downregulation encoding DNA replication proteins in 5-Fu resistant colorectal cancer cells. Oncotarget 2017; 8(34): 56546-57.
  15. Soo JS, Ng CH, Tan SH, Malik RA, Teh YC, Tan BS, et al. Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells. Apoptosis 2015; 20(10): 1373-87.
  16. 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(1): 276-84.
  17. Lu R, Yang J, Wei R, Ke J, Tian Q, Yu F, et al. Synergistic anti-tumor effects of liraglutide with metformin on pancreatic cancer cells. PLoS One 2018; 13(6): e0198938.
  18. Janjetovic K, Vucicevic L, Misirkic M, Vilimanovich U, Tovilovic G, Zogovic N, et al. Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt. Eur J Pharmacol 2011; 651(1-3): 41-50.
Journal of Isfahan Medical School
Volume 38, Issue 567 - Serial Number 567
January and February 2020
Pages 139-146

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History

  • Receive Date: 16 October 2019
  • Revise Date: 01 November 2024
  • Accept Date: 06 April 2022

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