title: Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells.
abstract: The anti-cancer effects of metformin, the most widely used drug for type 2 diabetes, alone or in combination with ionizing radiation were studied with MCF-7 human breast cancer cells and FSaII mouse fibrosarcoma cells. Clinically achievable concentrations of metformin caused significant clonogenic death in cancer cells. Importantly, metformin was preferentially cytotoxic to cancer stem cells relative to non-cancer stem cells. Metformin increased the radiosensitivity of cancer cells in vitro, and significantly enhanced the radiation-induced growth delay of FSaII tumors (s.c.) in the legs of C3H mice. Both metformin and ionizing radiation activated AMPK leading to inactivation of mTOR and suppression of its downstream effectors such as S6K1 and 4EBP1, a crucial signaling pathway for proliferation and survival of cancer cells, in vitro as well as in the in vivo tumors.
  
  
  CONCLUSIONS
  Metformin kills and radiosensitizes cancer cells and eradicates radioresistant cancer stem cells by activating AMPK and suppressing mTOR.
authors.affiliation: Radiobiology Laboratory, Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, MN, U.S.A.
authors.forename: Chang W
authors.initials: CW
authors.lastname: Song
authors.forename: Hyemi
authors.initials: H
authors.lastname: Lee
authors.forename: Ruud P M
authors.initials: RP
authors.lastname: Dings
authors.forename: Brent
authors.initials: B
authors.lastname: Williams
authors.forename: John
authors.initials: J
authors.lastname: Powers
authors.forename: Troy Dos
authors.initials: TD
authors.lastname: Santos
authors.forename: Bo-Hwa
authors.initials: BH
authors.lastname: Choi
authors.forename: Heon Joo
authors.initials: HJ
authors.lastname: Park
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D008687:Metformin; C546842:MTOR protein, human; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase