PMID- 35008275 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220114 IS - 2072-6694 (Print) IS - 2072-6694 (Electronic) IS - 2072-6694 (Linking) VI - 14 IP - 1 DP - 2021 Dec 27 TI - Frontiers in Anti-Cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-Angiogenic Add-On Therapy in Glioblastoma. LID - 10.3390/cancers14010112 [doi] LID - 112 AB - Glioblastoma is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. Glioblastoma shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), has demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including glioblastoma. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss metformin's potential antitumoral effects on glioblastoma, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of glioblastoma patients. FAU - Guarnaccia, Laura AU - Guarnaccia L AUID- ORCID: 0000-0002-5909-0165 AD - Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy. AD - Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy. FAU - Marfia, Giovanni AU - Marfia G AD - Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy. AD - Clinical Pathology Unit, Aerospace Medicine Institute "A. Mosso", Italian Air Force, 20138 Milan, Italy. FAU - Masseroli, Matteo Maria AU - Masseroli MM AD - Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy. FAU - Navone, Stefania Elena AU - Navone SE AUID- ORCID: 0000-0002-0097-9146 AD - Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy. FAU - Balsamo, Melissa AU - Balsamo M AUID- ORCID: 0000-0002-2046-6591 AD - Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy. FAU - Caroli, Manuela AU - Caroli M AD - Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy. FAU - Valtorta, Silvia AU - Valtorta S AUID- ORCID: 0000-0003-2871-6046 AD - Department of Medicine and Surgery and Tecnomed Foundation, University of Milan Bicocca, 20900 Milano, Italy. AD - Department of Nuclear Medicine, San Raffaele Scientific Institute, IRCCS, 20132 Milano, Italy. AD - Institute of Bioimaging and Molecular Physiology, National Research Council (IBFM-CNR), 20090 Segrate, Italy. FAU - Moresco, Rosa Maria AU - Moresco RM AUID- ORCID: 0000-0002-2771-9387 AD - Department of Medicine and Surgery and Tecnomed Foundation, University of Milan Bicocca, 20900 Milano, Italy. AD - Department of Nuclear Medicine, San Raffaele Scientific Institute, IRCCS, 20132 Milano, Italy. AD - Institute of Bioimaging and Molecular Physiology, National Research Council (IBFM-CNR), 20090 Segrate, Italy. FAU - Campanella, Rolando AU - Campanella R AD - Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy. FAU - Garzia, Emanuele AU - Garzia E AUID- ORCID: 0000-0002-4062-1114 AD - Aerospace Medicine Institute "A. Mosso", Italian Air Force, 20138 Milan, Italy. AD - Reproductive Medicine Unit, Department of Mother and Child, San Paolo Hospital Medical School, ASST Santi Paolo e Carlo, 20142 Milan, Italy. FAU - Riboni, Laura AU - Riboni L AUID- ORCID: 0000-0002-4149-8226 AD - Department of Medical Biotechnology and Translational Medicine, Laboratorio Interdisciplinare Tecnologie Avanzate (LITA)-Segrate, University of Milan, 20054 Milan, Italy. FAU - Locatelli, Marco AU - Locatelli M AD - Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy. AD - Department of Medical-Surgical Physiopathology and Transplantation, University of Milan, 20122 Milan, Italy. AD - "Aldo Ravelli" Research Center, 20142 Milan, Italy. LA - eng GR - RC2020/2021/Ministero della Salute/ GR - IG 718 2018 - ID. 21635/AIRC/ GR - 2019-1737/Fondazione Cariplo/ PT - Journal Article PT - Review DEP - 20211227 PL - Switzerland TA - Cancers (Basel) JT - Cancers JID - 101526829 PMC - PMC8749852 OTO - NOTNLM OT - angiogenesis OT - brain tumors OT - glioblastoma OT - metformin COIS- The authors declare no conflict of interest. EDAT- 2022/01/12 06:00 MHDA- 2022/01/12 06:01 PMCR- 2021/12/27 CRDT- 2022/01/11 01:01 PHST- 2021/12/01 00:00 [received] PHST- 2021/12/15 00:00 [revised] PHST- 2021/12/19 00:00 [accepted] PHST- 2022/01/11 01:01 [entrez] PHST- 2022/01/12 06:00 [pubmed] PHST- 2022/01/12 06:01 [medline] PHST- 2021/12/27 00:00 [pmc-release] AID - cancers14010112 [pii] AID - cancers-14-00112 [pii] AID - 10.3390/cancers14010112 [doi] PST - epublish SO - Cancers (Basel). 2021 Dec 27;14(1):112. doi: 10.3390/cancers14010112.