Skip to main content

Chemosensitizing effects of metformin on cisplatin- and paclitaxel-resistant ovarian cancer cell lines



Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy. Primary cytoreductive surgery with adjuvant taxane-platinum chemotherapy is the standard treatment to fight ovarian cancer, however, their side effects are severe, and chemoresistance emerges at high rates. Therefore, EOC clinic urges for novel treatment strategies to reverse chemoresistance and to improve the survival rates. Metformin has been shown to act in synergy with certain anti-cancer agents, overcoming chemoresistance in various types of tumors. This paper aims to investigate the use of metformin as a new treatment option for cisplatin- and paclitaxel-resistant ovarian cancer.


The effects of metformin alone or in combination with conventional drugs on resistant EOC cell lines were investigated using the MTT assay for cell proliferation; Flow Cytometry analysis for cell cycle and the mRNA expression was analyzed using the real-time PCR technique.


We found that metformin exhibited antiproliferative effects in paclitaxel-resistant A2780-PR, and in cisplatin-resistant ACRP cell lines. The combined therapy containing conventional drugs and metformin improved the effect of the treatment in cell proliferation rate, especially in the resistant cells. We found that metformin, in clinical relevant doses, could significantly reduce the mRNA expression of inflammatory cytokines and NF-κB signaling pathway.


Taken together, our observations suggest that metformin inhibits the inflammatory pathway induced by paclitaxel and cisplatin treatment. Furthermore, metformin in combination with paclitaxel or cisplatin improved the sensitivity in drug-resistant ovarian cancer cells. Therefore, metformin may be beneficial treatment strategy, particularly in patients with tumors refractory to platinum and taxanes.

This is a preview of subscription content, access via your institution.


  1. Soslow R.A. Histologic subtypes of ovarian carcinoma: an overview. Int J Gynecol Pathol 2008;27(2):161–74.

    PubMed  Google Scholar 

  2. Yeung T, Leung CS, Yip KP, Yeung CLA, Wong STC, Mok SC. Cellular and molecular processes in ovarian cancer metastasis. A Review in the theme: cell and molecular processes in cancer metastasis. Am J Physiol Cell Physiol 2015;309(7):444–56.

    Article  Google Scholar 

  3. Chang SJ, Hodeib M, Chang J, Bristow RE. Survival impact of complete cytoreduction to no gross residual disease for advanced-stage ovarian cancer: a meta-analysis. Gynecol Oncol 2013;130(3):493–8.

    Article  PubMed  Google Scholar 

  4. Uno M, Saitoh Y, Mochida K, Tsuruyama E, Kiyono T, Imoto I, et al. NF-κB inducing kinase, a central signaling component of the non-canonical pathway of NF-κB, contributes to ovarian cancer progression. PLoS One 2014;9(2):e88347.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Mabuchi S, Ohmichi M, Nishio Y, Hayasaka T, Kimura A, Ohta T, et al. Inhibition of NFkappa B increases the efficacy of cisplatin in vitro and in vivo ovarian cancer models. J Biol Chem 2004;279(22):23477–85.

    Article  CAS  PubMed  Google Scholar 

  6. Yang YI, Ahn JH, Lee KT, Shih IeM, Choi JH. RSF1 is a positive regulator of NF-κB-induced gene expression required for ovarian cancer chemoresistance. Cancer Res 2014;74(8):2258–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol 1994;10:405–55.

    Article  CAS  PubMed  Google Scholar 

  8. Aggarwal BB. Nuclear factor-kappaB: the enemy within. Cancer Cell 2004;6(3):203–8.

    Article  CAS  PubMed  Google Scholar 

  9. Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, et al. NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 2004;431:461–6.

    Article  CAS  PubMed  Google Scholar 

  10. Holohan C, Van SS, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 2013;13(10):714–26.

    Article  CAS  PubMed  Google Scholar 

  11. Hoesel B, Schmid JA. The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer 2013;12:86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rattan R, Graham R, Maguire J, Giri S, Shridhar V. Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia 2011;13(5):483–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Erices R, Bravo M, Gonzalez P, Oliva B, Racordon D, Garrido M, et al. Metformin, at concentrations corresponding to the treatment of diabetes, potentiates the cytotoxic effects of carboplatin in cultures of ovarian cancer cells. Reprod Sci 2013;20(12):1433–46.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lengyel E, Litchfield LM, Mitra AK, Nieman KM, Mukherjee A, Zhang Y, et al. Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models. Am J Obstet Gynecol 2015;212(4):1–18.

    Article  Google Scholar 

  15. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005;330(7503):1304–5.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 2009;27(20):3297–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Romero IL, McCormick A, McEwen KA, Park S, Karrison T, Yamada SD, et al. Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity. Obstet Gynecol 2012;119(1):61–7.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Kumar S, Meuter A, Thapa P, Langstraat C, Giri S, Chien J, et al. Metformin intake is associated with better survival in ovarian cancer: a case-control study. Cancer 2013;119(3):555–62.

    Article  CAS  PubMed  Google Scholar 

  19. Kim HG, Hien TT, Han EH, Hwang YP, Choi JH, Kang KW, et al. Metformin inhibits P-glycoprotein expression via the NF-kappaB pathway and CRE transcriptional activity through AMPK activation. Br J Pharmacol 2011;162(5):1096–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wu B, Li S, Sheng L, Zhu J, Gu L, Shen H, et al. Metformin inhibits the development and metastasis of ovarian cancer. Oncol Rep 2012;28(3):903–8.

    Article  CAS  PubMed  Google Scholar 

  21. Sherman-Baust CA, Weeraratna AT, Rangel LB, Pizer ES, Cho KR, Schwartz DR. Remodeling of the extracellular matrix through overexpression of collagen VI contributes to cisplatin resistance in ovarian cancer cells. Cancer Cell 2003;3(4):377–86.

    Article  CAS  PubMed  Google Scholar 

  22. Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 1991;139(2):271–9.

    Article  CAS  PubMed  Google Scholar 

  23. Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 2009;69(19):7507–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rocha GZ, Dias MM, Ropelle ER, Osório-Costa F, Rossato FA, Vercesi AE, et al. Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth. Clin Cancer Res 2011;17(12):3993–4005.

    Article  CAS  PubMed  Google Scholar 

  25. Dowling RJ, Lam S, Bassi C, Mouaaz S, Aman A, Kiyota T, et al. Metformin pharmacokinetics in mouse tumors: implications for human therapy. Cell Metab 2016;23(4):567–8.

    Article  CAS  PubMed  Google Scholar 

  26. McDermott M, Eustace AJ, Busschots S, Breen L, Crown J, Clynes M, et al. In vitro development of chemotherapy and targeted therapy drug-resistant cancer cell lines: a practical guide with case studies. Front Oncol 2014;4(40):1–16.

    Google Scholar 

  27. Zhang R, Zhang P, Wang H, Hou D, Li W, Xiao G, et al. Inhibitory effects of metformin at low concentration on epithelial-mesenchymal transition of CD44(+) CD117(+) ovarian cancer stem cells. Stem Cell Res Ther 2015;6(262):1–12.

    Google Scholar 

  28. Shuang T, Wang M, Zhou Y, Shi C. Over-expression of nuclear NF-κB1 and c-Rel correlates with chemoresistance and prognosis of serous epithelial ovarian cancer. Exp Mol Pathol 2016;100(1):139–44.

    Article  CAS  PubMed  Google Scholar 

  29. Shuang T, Wang M, Zhou Y, Shi C, Wang D. NF-κB1, c-Rel, and ELK1 inhibit miR-134 expression leading to TAB1 upregulation in paclitaxel-resistant human ovarian cancer. Oncotarget 2017;8(15):24853–68.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci U S A 2013;110(3):972–7.

    Article  CAS  PubMed  Google Scholar 

  31. Ho EA, Piquette-Miller M. Regulation of multidrug resistance by pro-inflammatory cytokines. Curr Cancer Drug Targets 2006;6(4):295–311.

    Article  CAS  PubMed  Google Scholar 

  32. Lane D, Matte I, Garde-Granger P, Laplante C, Carignan A, Rancourt C, et al. Inflammation-regulating factors in ascites as predictive biomarkers of drug resistance and progression-free survival in serous epithelial ovarian cancers. BMC Cancer 2015;15(492):1–11.

    CAS  Google Scholar 

  33. Cohen S, Bruchim I, Graiver D, Evron Z, Oron-Karni V, Pasmanik-Chor M, et al. Platinum-resistance in ovarian cancer cells is mediated by IL-6 secretion via the increased expression of its target cIAP-2. J Mol Med 2013;91(3):357–68.

    Article  CAS  PubMed  Google Scholar 

  34. Dinarello CA. The biological properties of interleukin-1. Eur Cytokine Netw 1994;5(6):517–31.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Leticia Batista Azevedo Rangel.

Supplementary data

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

dos Santos Guimarães, I., Ladislau-Magescky, T., Tessarollo, N.G. et al. Chemosensitizing effects of metformin on cisplatin- and paclitaxel-resistant ovarian cancer cell lines. Pharmacol. Rep 70, 409–417 (2018).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Ovarian cancer
  • Metformin
  • Chemoresistance
  • Inflammatory cytokines