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

Pharmacological Reports volume 70, pages 409–417 (2018)Cite this article

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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Authors and Affiliations

  1. Biotechnology Program/RENORBIO, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil

    Isabella dos Santos Guimarães, Nayara Gusmão Tessarollo, Ian Victor Silva & Leticia Batista Azevedo Rangel

  2. Clinical Research Division, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil

    Isabella dos Santos Guimarães

  3. Pitágoras University, Linhares, ES, Brazil

    Taciane Ladislau-Magescky

  4. Post-Graduate Program of Biochemistry and Pharmacology, Federal University of Espirito Santo, Vitoria, ES, Brazil

    Diandra Zipinotti dos Santos & Leticia Batista Azevedo Rangel

  5. Natural Sciences Department, Health and Humanities Institute, Fluminense Federal University, Rio das Ostras, RJ, Brazil

    Etel Rodrigues Pereira Gimba

  6. Research Coordination, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil

    Etel Rodrigues Pereira Gimba

  7. Brazilian Society of Clinical Oncology, Belo Horizonte, Minas Gerais, Brazil

    Cinthya Sternberg

  8. Post-Graduate Program of Anatomic Pathology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

    Cinthya Sternberg

  9. Department of Morphology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil

    Ian Victor Silva

  10. Department of Pharmaceutical Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil

    Leticia Batista Azevedo Rangel

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  1. Isabella dos Santos Guimarães
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  2. Taciane Ladislau-Magescky
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Correspondence to Leticia Batista Azevedo Rangel.

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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). https://doi.org/10.1016/j.pharep.2017.11.007

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  • DOI: https://doi.org/10.1016/j.pharep.2017.11.007

Keywords

  • Ovarian cancer
  • Metformin
  • Chemoresistance
  • Inflammatory cytokines