Metformin as an adjuvant drug against pediatric sarcomas: hypoxia limits therapeutic effects of the drug

PLoS One. 2013 Dec 31;8(12):e83832. doi: 10.1371/journal.pone.0083832. eCollection 2013.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis / drug effects
  • Blotting, Western
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Child
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Hypoxia / physiopathology*
  • Immunoenzyme Techniques
  • Metformin / pharmacology*
  • Mice
  • Mice, Nude
  • Osteosarcoma / drug therapy*
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology
  • Pediatrics
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rhabdomyosarcoma / drug therapy*
  • Rhabdomyosarcoma / metabolism
  • Rhabdomyosarcoma / pathology
  • Sarcoma, Ewing / drug therapy*
  • Sarcoma, Ewing / metabolism
  • Sarcoma, Ewing / pathology
  • Tumor Cells, Cultured
  • Vincristine / pharmacology
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents, Phytogenic
  • Hypoglycemic Agents
  • RNA, Messenger
  • Vincristine
  • Metformin

Grants and funding

This work was funded by: Italian Association for Cancer Research grant (MFAG 11584 to CG; IG 10452 to KS; IG 10353 to PLL); The Italian Ministry of Health (Ricerca Finalizzata 2009 to KS 1628/2010); The Italian Ministry of Research and Instruction grant PRIN2009 cod. SFC2EK to KS. PRIN2009 to PLL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.