Metformin and temozolomide, a synergic option to overcome resistance in glioblastoma multiforme models

// Silvia Valtorta 1, 2, 3, 4, * , Alessia Lo Dico 5, * , Isabella Raccagni 1, 2, 3, 4 , Daniela Gaglio 2, 4 , Sara Belloli 2, 3, 4 , Letterio S. Politi 6, 7, 8 , Cristina Martelli 5 , Cecilia Diceglie 5, 1 , Marcella Bonanomi 4 , Giulia Ercoli 9 , Valentina Vaira 5, 9 , Luisa Ottobrini 2, 5, * and Rosa Maria Moresco 1, 2, 3, 4, * 1 Tecnomed Foundation and Medicine and Surgery Department, University of Milan-Bicocca, Monza, Italy 2 Institute of Molecular Bioimaging and Physiology (IBFM), CNR, Segrate, Italy 3 Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy 4 SYSBIO.IT, Centre of Systems Biology, Milan, Italy 5 Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan, Italy 6 Imaging Core, IRCCS San Raffaele Scientific Institute, Milan, Italy 7 University of Massachusetts Medical School, Worcester, MA, USA 8 Hematology/Oncology Division and Radiology Department, Boston Children’s Hospital, Boston, MA, USA 9 Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy * These authors contributed equally to this work Correspondence to: Rosa Maria Moresco, email: moresco.rosamaria@hsr.it Keywords: glioblastoma multiforme; metformin; temozolomide; glioma stem cells; metabolism Received: June 07, 2017 Accepted: November 14, 2017 Published: December 06, 2017 ABSTRACT Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor survival. Cytoreduction in association with radiotherapy and temozolomide (TMZ) is the standard therapy, but response is heterogeneous and life expectancy is limited. The combined use of chemotherapeutic agents with drugs targeting cell metabolism is becoming an interesting therapeutic option for cancer treatment. Here, we found that metformin (MET) enhances TMZ effect on TMZ-sensitive cell line (U251) and overcomes TMZ-resistance in T98G GBM cell line. In particular, combined-treatment modulated apoptosis by increasing Bax/Bcl-2 ratio, and reduced Reactive Oxygen Species (ROS) production. We also observed that MET associated with TMZ was able to reduce the expression of glioma stem cells (GSC) marker CD90 particularly in T98G cells but not that of CD133. In vivo experiments showed that combined treatment with TMZ and MET significantly slowed down growth of TMZ-resistant tumors but did not affect overall survival of TMZ-sensitive tumor bearing mice. In conclusion, our results showed that metformin is able to enhance TMZ effect in TMZ-resistant cell line suggesting its potential use in TMZ refractory GBM patients. However, the lack of effect on a GBM malignancy marker like CD133 requires further evaluation since it might influence response duration.