Metformin inhibits the development and metastasis of ovarian cancer

  • Authors:
    • Buchu Wu
    • Shu Li
    • Lili Sheng
    • Jing Zhu
    • Liying Gu
    • Haoran Shen
    • Duanduan La
    • Brett D. Hambly
    • Shisan Bao
    • Wen Di
  • View Affiliations

  • Published online on: June 29, 2012     https://doi.org/10.3892/or.2012.1890
  • Pages: 903-908
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The aim of this study was to investigate the role of metformin in the regulation of development and metastasis of ovarian carcinoma cell lines in vitro and ovarian cancer in a nude mouse model in vivo. The effects of metformin on the ability of two high-metastatic potential human ovarian cancer cell lines (SKOV3 and HO8910-PM) to adhere, invade and migrate in vitro were observed by means of a cell adhesion test, cell invasion test and cell migration test. The size and number of the inoculated and metastatic tumours in vivo in a nude mouse were determined following intraperitoneal injection of metformin. Furthermore, the extent of angiogenesis (vWF) and macrophage infiltration in the tumour were determined. Proliferation, migration, invasion and adhesion of ovarian cancer cells were significantly inhibited (P<0.05) in a dose-dependent manner in vitro. In addition, metformin inhibited hepatic, intestinal and lung metastasis (P<0.05), with no weight loss in vivo, consistent with decreased expression of vWF and macrophage infiltration. Our data suggest that metformin inhibits the development and metastasis of ovarian cancer by reducing cellular-ECM interactions, neovascularisation and macrophage infiltration.

References

1 

Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 59:225–249. 2009. View Article : Google Scholar

2 

Zhang J and Wang B: Arsenic trioxide (As(2)O(3)) inhibits peritoneal invasion of ovarian carcinoma cells in vitro and in vivo. Gynecol Oncol. 103:199–206. 2006. View Article : Google Scholar : PubMed/NCBI

3 

Gubbels JA, Claussen N, Kapur AK, Connor JP and Patankar MS: The detection, treatment, and biology of epithelial ovarian cancer. J Ovarian Res. 3:82010. View Article : Google Scholar : PubMed/NCBI

4 

Bailey CJ and Turner RC: Metformin. N Engl J Med. 334:574–579. 1996. View Article : Google Scholar : PubMed/NCBI

5 

Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR and Morris AD: Metformin and reduced risk of cancer in diabetic patients. BMJ. 330:1304–1305. 2005. View Article : Google Scholar : PubMed/NCBI

6 

Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD and Evans JM: New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care. 32:1620–1625. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Zhuang Y and Miskimins WK: Cell cycle arrest in Metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1. J Mol Signal. 3:182008. View Article : Google Scholar : PubMed/NCBI

8 

Ben Sahra I, Laurent K, Loubat A, et al: The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene. 27:3576–3586. 2008.PubMed/NCBI

9 

Gotlieb WH, Saumet J, Beauchamp MC, et al: In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecol Oncol. 110:246–250. 2008. View Article : Google Scholar : PubMed/NCBI

10 

Cantrell LA, Zhou C, Mendivil A, Malloy KM, Gehrig PA and Bae-Jump VL: Metformin is a potent inhibitor of endometrial cancer cell proliferation - implications for a novel treatment strategy. Gynecol Oncol. 116:92–98. 2010. View Article : Google Scholar : PubMed/NCBI

11 

Zakikhani M, Dowling R, Fantus IG, Sonenberg N and Pollak M: Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 66:10269–10273. 2006. View Article : Google Scholar : PubMed/NCBI

12 

Buzzai M, Jones RG, Amaravadi RK, et al: Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 67:6745–6752. 2007. View Article : Google Scholar : PubMed/NCBI

13 

Hirsch HA, Iliopoulos D, Tsichlis PN and Struhl K: Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 69:7507–7511. 2009. View Article : Google Scholar : PubMed/NCBI

14 

Shenhua X, Lijuan Q, Hanzhou N, et al: Establishment of a highly metastatic human ovarian cancer cell line (HO-8910PM) and its characterization. J Exp Clin Cancer Res. 18:233–239. 1999.PubMed/NCBI

15 

Zhang S, Lin QD and Di W: Suppression of human ovarian carcinoma metastasis by the metastasis-suppressor gene, BRMS1. Int J Gynecol Cancer. 16:522–531. 2006. View Article : Google Scholar : PubMed/NCBI

16 

Bao S, Carr ED, Xu YH and Hunt NH: Gp91(phox) contributes to the development of experimental inflammatory bowel disease. Immunol Cell Biol. 89:853–860. 2011. View Article : Google Scholar : PubMed/NCBI

17 

Xu Y, Hunt NH and Bao S: The role of granulocyte macrophage-colony-stimulating factor in acute intestinal inflammation. Cell Res. 18:1220–1229. 2008. View Article : Google Scholar : PubMed/NCBI

18 

Phoenix KN, Vumbaca F and Claffey KP: Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERalpha negative MDA-MB-435 breast cancer model. Breast Cancer Res Treat. 113:101–111. 2009. View Article : Google Scholar

19 

Brem S, Cotran R and Folkman J: Tumor angiogenesis: a quantitative method for histologic grading. J Natl Cancer Inst. 48:347–356. 1972.PubMed/NCBI

20 

Jonjic N, Peri G, Bernasconi S, et al: Expression of adhesion molecules and chemotactic cytokines in cultured human mesothelial cells. J Exp Med. 176:1165–1174. 1992. View Article : Google Scholar : PubMed/NCBI

21 

Coussens LM and Werb Z: Inflammation and cancer. Nature. 420:860–867. 2002. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

September 2012
Volume 28 Issue 3

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Wu, B., Li, S., Sheng, L., Zhu, J., Gu, L., Shen, H. ... Di, W. (2012). Metformin inhibits the development and metastasis of ovarian cancer. Oncology Reports, 28, 903-908. https://doi.org/10.3892/or.2012.1890
MLA
Wu, B., Li, S., Sheng, L., Zhu, J., Gu, L., Shen, H., La, D., Hambly, B. D., Bao, S., Di, W."Metformin inhibits the development and metastasis of ovarian cancer". Oncology Reports 28.3 (2012): 903-908.
Chicago
Wu, B., Li, S., Sheng, L., Zhu, J., Gu, L., Shen, H., La, D., Hambly, B. D., Bao, S., Di, W."Metformin inhibits the development and metastasis of ovarian cancer". Oncology Reports 28, no. 3 (2012): 903-908. https://doi.org/10.3892/or.2012.1890