title: Metformin as an adjuvant drug against pediatric sarcomas: hypoxia limits therapeutic effects of the drug.
abstract: Metformin, a well-known insulin-sensitizer commonly used for type 2 diabetes therapy, has recently emerged as potentially very attractive drug also in oncology. It is cheap, it is relatively safe and many reports have indicated effects in cancer prevention and therapy. These desirable features are particularly interesting for pediatric sarcomas, a group of rare tumors that have been shown to be dependent on IGF and insulin system for pathogenesis and progression. Metformin exerts anti-mitogenic activity in several cancer histotypes through several molecular mechanisms. In this paper, we analyzed its effects against osteosarcoma, Ewing sarcoma and rhabdomyosarcoma, the three most common pediatric sarcomas. Despite in vitro metformin gave remarkable antiproliferative and chemosensitizing effects both in sensitive and chemoresistant cells, its efficacy was not confirmed against Ewing sarcoma xenografts neither as single agent nor in combination with vincristine. This discrepancy between in vitro and in vivo effects may be due to hypoxia, a common feature of solid tumors. We provide evidences that in hypoxia conditions metformin was not able to activate AMPK and inhibit mTOR signaling, which likely prevents the inhibitory effects of metformin on tumor growth. Thus, although metformin may be considered a useful complement of conventional chemotherapy in normoxia, its therapeutic value in highly hypoxic tumors may be more limited. The impact of hypoxia should be considered when novel therapies are planned for pediatric sarcomas.
authors.affiliation: CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garofalo
authors.affiliation: CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Mariantonietta
authors.initials: M
authors.lastname: Capristo
authors.affiliation: CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Manara
authors.affiliation: CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Mancarella
authors.affiliation: Experimental Oncology Laboratory, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Landuzzi
authors.affiliation: Department of Health, University of Catanzaro, Catanzaro, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Belfiore
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Pier-Luigi
authors.initials: PL
authors.lastname: Lollini
authors.affiliation: Experimental Oncology Laboratory, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.affiliation: CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Scotlandi
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000860:Hypoxia / Q000503:physiopathology*; D007124:Immunoenzyme Techniques; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010372:Pediatrics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D014750:Vincristine; D008687:Metformin