Chemosensitizing effects of metformin on cisplatin- and paclitaxel-resistant ovarian cancer cell lines |
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Authors: | Isabella dos Santos Guimarães Taciane Ladislau-Magescky Nayara Gusmão Tessarollo Diandra Zipinotti dos Santos Etel Rodrigues Pereira Gimba Cinthya Sternberg Ian Victor Silva Leticia Batista Azevedo Rangel |
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Institution: | 1. Biotechnology Program/RENORBIO, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil;2. Clinical Research Division, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil;3. Pitágoras University, Linhares, ES, Brazil;4. Post-Graduate Program of Biochemistry and Pharmacology, Federal University of Espirito Santo, Vitoria, ES, Brazil;5. Natural Sciences Department, Health and Humanities Institute, Fluminense Federal University, Rio das Ostras, RJ, Brazil;6. Research Coordination, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil;7. Brazilian Society of Clinical Oncology, Belo Horizonte, Minas Gerais, Brazil;8. Post-Graduate Program of Anatomic Pathology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;9. Department of Morphology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil;10. Department of Pharmaceutical Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil |
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Abstract: | BackgroundEpithelial 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.MethodsThe 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.ResultsWe 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.ConclusionsTaken 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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Keywords: | Ovarian cancer Metformin Chemoresistance Inflammatory cytokines |
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