Metformin and temozolomide, a synergic option to overcome resistance in glioblastoma multiforme models
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Silvia Valtorta1,2,3,4,*, Alessia Lo Dico5,*, Isabella Raccagni1,2,3,4, Daniela Gaglio2,4, Sara Belloli2,3,4, Letterio S. Politi6,7,8, Cristina Martelli5, Cecilia Diceglie5,1, Marcella Bonanomi4, Giulia Ercoli9, Valentina Vaira5,9, Luisa Ottobrini2,5,* and Rosa Maria Moresco1,2,3,4,*
1Tecnomed Foundation and Medicine and Surgery Department, University of Milan-Bicocca, Monza, Italy
2Institute of Molecular Bioimaging and Physiology (IBFM), CNR, Segrate, Italy
3Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
4SYSBIO.IT, Centre of Systems Biology, Milan, Italy
5Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan, Italy
6Imaging Core, IRCCS San Raffaele Scientific Institute, Milan, Italy
7University of Massachusetts Medical School, Worcester, MA, USA
8Hematology/Oncology Division and Radiology Department, Boston Children’s Hospital, Boston, MA, USA
9Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
*These authors contributed equally to this work
Rosa Maria Moresco, email: firstname.lastname@example.org
Keywords: glioblastoma multiforme; metformin; temozolomide; glioma stem cells; metabolism
Received: June 07, 2017 Accepted: November 14, 2017 Published: December 06, 2017
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.
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