title: Metformin, at concentrations corresponding to the treatment of diabetes, potentiates the cytotoxic effects of carboplatin in cultures of ovarian cancer cells.
abstract: The use of the type 2 diabetics drug metformin has been correlated with enhanced progression-free survival in ovarian cancer. The literature has speculated that this enhancement is due to the high concentration of metformin directly causing cancer cell death. However, this explanation does not fit with clinical data reporting that the women exposed to constant micromolar concentrations of metformin, as present in the treatment of diabetes, respond better to chemotherapy. Herein, our aim was to examine whether micromolar concentrations of metformin alone could bring about cancer cell death and whether micromolar metformin could increase the cytotoxic effect of commonly used chemotherapies in A2780 and SKOV3 cell lines and primary cultured cancer cells isolated from the peritoneal fluid of patients with advanced ovarian cancer. Our results in cell lines demonstrate that no significant loss of viability or change in cell cycle was observed with micromolar metformin alone; however, we observed cytotoxicity with micromolar metformin in combination with chemotherapy at concentrations where the chemotherapy alone produced no loss in viability. We demonstrate that previous exposure and maintenance of metformin in conjunction with carboplatin produces a synergistic enhancement in cytotoxicity of A2780 and SKOV3 cells (55% and 43%, respectively). Furthermore, in 5 (44%) of the 11 ovarian cancer primary cultures, micromolar metformin improved the cytotoxic response to carboplatin but not paclitaxel or doxorubicin. In conclusion, we present data that support the need for a clinical study to evaluate the adjuvant maintenance or prescription of currently approved doses of metformin during the chemotherapeutic treatment of ovarian cancer.
authors: 1Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Rafaela
authors: R
authors: Erices
authors: Maria Loreto
authors: ML
authors: Bravo
authors: Pamela
authors: P
authors: Gonzalez
authors: Bárbara
authors: B
authors: Oliva
authors: Dusan
authors: D
authors: Racordon
authors: Marcelo
authors: M
authors: Garrido
authors: Carolina
authors: C
authors: Ibañez
authors: Sumie
authors: S
authors: Kato
authors: Jorge
authors: J
authors: Brañes
authors: Javier
authors: J
authors: Pizarro
authors: Maria Isabel
authors: MI
authors: Barriga
authors: Alejandro
authors: A
authors: Barra
authors: Erasmo
authors: E
authors: Bravo
authors: Catalina
authors: C
authors: Alonso
authors: Eva
authors: E
authors: Bustamente
authors: Mauricio A
authors: MA
authors: Cuello
authors: Gareth I
authors: GI
authors: Owen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D008687:Metformin; D016190:Carboplatin
keywords: chemotherapy; doxorubicin; paclitaxel
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