Metformin inhibited esophageal squamous cell carcinoma proliferation in vitro and in vivo and enhanced the anti-cancer effect of cisplatin

PLoS One. 2017 Apr 13;12(4):e0174276. doi: 10.1371/journal.pone.0174276. eCollection 2017.


Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with poor prognosis in China. Chemotherapy now is one of the most frequently used treatments for patients with ESCC in middle or late stage, however the effects were often limited by increased chemoresistance or treatment toxicity. So it is urgent to find new drugs to treat ESCC patients. Metformin with low cost and toxicity has proved to have anti-cancer effects in a numerous cancers, while its role and mechanism in ESCC has seldom been studied. In the present study, we found that metformin exhibited not only an anti-proliferation ability in a dose and time dependent manner but also a proapoptosis effect in a dose dependent manner in ESCC cell line KYSE450. Our in vivo experiment also showed that metformin markedly inhibited KYSE450 xenograft tumors growth compared to those treated with normal saline. What's more, no obvious toxic reactions were observed. To further explore the underlying mechanism, we found that metformin treatment could significantly damp the expression of 4EBP1 and S6K1 in KYSE 450 cells in vitro and in vivo, furthermore, the p-4EBP1 and p-S6K1 expression in KYSE 450 cells were also inhibited greatly in vitro and in vivo. During the therapy of cancer, in order to overcome side effects, combination therapy was often used. In this paper, we demonstrated that metformin potentiated the effects of cisplatin via inhibiting cell proliferation and promoting cell apoptosis. Taken together, metformin owned the potential anti-cancer effect on ESCC in monotherapy or was combined with cisplatin and these results laid solid basis for the use of metformin in ESCC.

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Animals
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cisplatin / pharmacology*
  • Esophageal Neoplasms / drug therapy*
  • Esophageal Neoplasms / metabolism
  • Esophageal Neoplasms / pathology
  • Esophageal Squamous Cell Carcinoma
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Male
  • Metformin / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Proteins / biosynthesis
  • RNA-Binding Proteins / biosynthesis
  • Ribosomal Protein S6 Kinases, 70-kDa / biosynthesis
  • Xenograft Model Antitumor Assays


  • Adaptor Proteins, Signal Transducing
  • Neoplasm Proteins
  • PA2G4 protein, human
  • RNA-Binding Proteins
  • Metformin
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • Cisplatin

Grant support

This study was supported by Fundamental Research Program of Henan Education Department (No. 13A320638) and Fundamental and Advanced Technology Research Program of Henan Science and Technology Department (No. 132300410127). The funder did the study, analyzed the data, decided the publication and prepared the manuscript.