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.

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Ovarian cancer patients respond well to first line chemotherapy but present high incidences of toxicity followed by consistent relapse within 18 months. Despite every cancer and patient being unique, generally all cancers are treated by the same chemotherapy regimes and patient metabolism is not considered in treatment selection. Differing metabolism may account for unacceptable toxicity or failures in chemotherapy treatment. It is becoming accepted that the metastatic cell is distinct to those found in the primary tumor and is thus the true target of chemotherapy. Our objectives were to isolate these potential ovarian metastatic cells from patients and correlate their in vitro response to the chemotherapy with clinical response. The single nucleotide polymorphism (SNP) distribution of genes related to chemotherapy metabolism was also analyzed in each patient. Primary cultures and blood samples of ovarian patients were obtained with signed informed consent from a network of Chilean and Peruvian hospitals. Chemotherapy response was assessed by MTS and data correlated with medical follow-up. SNPs were detected using commercial taqman probes from Applied Biosystem. Results. Ovarian cancer patients with clinical follow-up demonstrated a marked separation of progression free survival (PFS) curves according to classification within our in vitro assay. Analysis of exclusively first line patients demonstrated a median PFS of 17 months for patients predicted to respond to treatment showed by our assay, but only an average of 2 months of PFS in patients that the assay predicted no response. Initial analysis of 14 SNPs related to paclitaxel-platinum based chemotherapy demonstrates marked differences in Chilean patients. Conclusion. We demonstrate a clear distinction in time to relapse between the patients predicted or not to respond to treatment by our assay. Ovarian cancer patients demonstrate notably different distributions in SNPs previously correlated with platinum metabolism. Our results highlight the requirement of the medical community to take this research to the stage of randomized clinical trials. CORFO 13CTI21526-P6 & 13IDL2-18608, FONDECYT 1140960, 1140657 & 1120292. Citation Format: Maria Loreto Bravo, Pamela Gonzalez, Sumie Kato, Carolina Ibañez, Marcelo Garrido, Jorge Brañes, Maria Isabel Barriga, Eva Bustamante, Nicanor Barrena, Catalina Alonso, Leonel Muñoz, Erasmo Bravo, Clemente Arab, Alejandro Barra, Paula Jimenez, Patricio Gayan, Fernando Gonzalez, Ignacio Chavez, Alfredo Aguilar, Joseph Pinto, Mauricio Cuello, Gareth Owen, Jaime Cartagena. Prediction of chemotherapy response and metabolism for the tailoring of ovarian cancer treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4314. doi:10.1158/1538-7445.AM2015-4314

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