Cytotechnology

, Volume 70, Issue 1, pp 439–448 | Cite as

Metformin synergistically enhances antitumor activity of cisplatin in gallbladder cancer via the PI3K/AKT/ERK pathway

  • Tingting Bi
  • Ao Zhu
  • Xufeng Yang
  • Huiying Qiao
  • Jinmei Tang
  • Yan Liu
  • Rong Lv
Original Article

Abstract

Metformin (Met) is a widely used antidiabetic drug and has demonstrated interesting anticancer effects in various cancer models, alone or in combination with chemotherapeutic drugs. The aim of the present study is to investigate the synergistic effect of Met with cisplatin (Cis) on the tumor growth inhibition of gallbladder cancer cells (GBC-SD and SGC-996) and explore the underlying mechanism. Cells were treated with Met and/or Cis and subjected to cell viability, colony formation, apoptosis, cell cycle, western blotting, xenograft tumorigenicity assay and immunohistochemistry. The results demonstrated that Met and Cis inhibited the proliferation of gallbladder cancer cells, and combination treatment with Met and Cis resulted in a combination index < 1, indicating a synergistic effect. Co-treatment with Met and Cis caused G0/G1 phase arrest by upregulating P21, P27 and downregulating CyclinD1, and induced apoptosis through decreasing the expression of p-PI3K, p-AKT, and p-ERK. In addition, pretreatment with a specific AKT activator (IGF-1) significantly neutralized the pro-apoptotic activity of Met + Cis, suggesting the key role of AKT in this process. More importantly, in nude mice model, Met and Cis in combination displayed more efficient inhibition of tumor weight and volume in the SGC-996 xenograft mouse model than Met or Cis alone. Immunohistochemistry analysis suggests the combinations greatly suppressed tumor proliferation, which is consistent with our in vitro results. In conclusion, our findings indicate that the combination therapy with Met and Cis exerted synergistic antitumor effects in gallbladder cancer cells through PI3K/AKT/ERK pathway, and combination treatment with Met and Cis would be a promising therapeutic strategy for gallbladder cancer patients.

Keywords

Metformin Gallbladder cancer Cisplatin AKT ERK 

Notes

Acknowledgements

This study was supported by the Program for Young Scientist in Science and Education of Suzhou City (No. KJXW2014053), the Program for Young Scientist in Science and Education of Wujiang No. 1 People’s Hospital (No. 201724).

Complaince with ethical standards

Conflict of interest

The authors declare no conflict of interest.

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Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2017

Authors and Affiliations

  • Tingting Bi
    • 1
  • Ao Zhu
    • 1
  • Xufeng Yang
    • 1
  • Huiying Qiao
    • 1
  • Jinmei Tang
    • 1
  • Yan Liu
    • 2
  • Rong Lv
    • 1
  1. 1.Department of Geriatric WardWujiang No. 1 People’s HospitalSuzhouChina
  2. 2.Department of General SurgeryWujiang No. 1 People’s HospitalSuzhouChina

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