Isabella Dos Santos Guimarães1, Taciane Ladislau-Magescky2, Nayara Gusmão Tessarollo3, Diandra Zipinotti Dos Santos4, Etel Rodrigues Pereira Gimba5, Cinthya Sternberg6, Ian Victor Silva7, Leticia Batista Azevedo Rangel8. 1. Biotechnology Program/RENORBIO, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil; Clinical Research Division, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil. 2. Pitágoras University, Linhares, ES, Brazil. 3. Biotechnology Program/RENORBIO, Health Sciences Center, Federal University of Espirito Santo, Vitoria, 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; Research Coordination, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil. 6. Brazilian Society of Clinical Oncology, Belo Horizonte, Minas Gerais, Brazil; Post-Graduate Program of Anatomic Pathology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 7. Biotechnology Program/RENORBIO, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil; Department of Morphology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil. 8. Biotechnology Program/RENORBIO, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil; Post-Graduate Program of Biochemistry and Pharmacology, Federal University of Espirito Santo, Vitoria, ES, Brazil; Department of Pharmaceutical Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil. Electronic address: lbarangel@yahoo.com.
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.
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.
Authors: Bastian Czogalla; Maja Kahaly; Doris Mayr; Elisa Schmoeckel; Beate Niesler; Anna Hester; Christine Zeder-Göß; Thomas Kolben; Alexander Burges; Sven Mahner; Udo Jeschke; Fabian Trillsch Journal: Cancer Manag Res Date: 2019-08-14 Impact factor: 3.989
Authors: Vanessa Rosse de Souza; Mariana Concentino Menezes Brum; Isabella Dos Santos Guimarães; Paula de Freitas Dos Santos; Thuane Oliveira do Amaral; Joel Pimentel Abreu; Thuane Passos; Otniel Freitas-Silva; Etel Rodrigues Pereira Gimba; Anderson Junger Teodoro Journal: Biomolecules Date: 2019-11-06
Authors: Marta Mascaraque; Pablo Delgado-Wicke; Cristina Nuevo-Tapioles; Tamara Gracia-Cazaña; Edgar Abarca-Lachen; Salvador González; José M Cuezva; Yolanda Gilaberte; Ángeles Juarranz Journal: Cancers (Basel) Date: 2020-03-13 Impact factor: 6.639