title: Phenformin as prophylaxis and therapy in breast cancer xenografts.
abstract: BACKGROUND
  Observations that diabetics treated with biguanide drugs have a reduced risk of developing cancer have prompted an enthusiasm for these agents as anti-cancer therapies. We sought to determine the efficacy of the biguanide phenformin in the chemoprophylaxis and in the treatment of oestrogen receptor (ER)-positive MCF7 and receptor triple-negative MDAMB231 xenografts in immunocompromised mice. We also compared the efficacy of phenformin and metformin in the treatment of MDAMB231.
  
  
  METHODS
  Immunocompromised mice were divided into groups: (1) phenformin administered for 2 weeks prior to cell injection; (2) established tumours treated with phenformin; (3) established tumours treated with metformin (only for MDAMB231 tumours); (4) untreated controls. Post-treatment tumours, liver and spleen were harvested for further analysis.
  
  
  RESULTS
  Phenformin significantly inhibited both the development and growth of MCF7 and MDAMB231 tumours, and for MDAMB231 at greater efficacy than metformin without murine toxicity. The number of mitotic figures was significantly fewer in xenografts treated with phenformin compared with controls. Results suggested that the mechanism of action of phenformin in vivo is consistent with AMPK activation.
  
  
  CONCLUSIONS
  Phenformin has clinical potential as an antineoplastic agent and should be considered for clinical trials both in ER-positive and triple-negative breast cancer.
authors.affiliation: Centre for Oncology and Molecular Medicine, University of Dundee, Dundee DD1 9SY, UK. m.v.c.l.appleyard@dundee.ac.uk
authors.forename: M V C L
authors.initials: MV
authors.lastname: Appleyard
authors.forename: K E
authors.initials: KE
authors.lastname: Murray
authors.forename: P J
authors.initials: PJ
authors.lastname: Coates
authors.forename: S
authors.initials: S
authors.lastname: Wullschleger
authors.forename: S E
authors.initials: SE
authors.lastname: Bray
authors.forename: N M
authors.initials: NM
authors.lastname: Kernohan
authors.forename: S
authors.initials: S
authors.lastname: Fleming
authors.forename: D R
authors.initials: DR
authors.lastname: Alessi
authors.forename: A M
authors.initials: AM
authors.lastname: Thompson
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D010629:Phenformin / Q000494:pharmacology / Q000627:therapeutic use*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013154:Spleen / Q000201:enzymology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D006657:Histones; D019394:Ki-67 Antigen; D008687:Metformin; D010629:Phenformin; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D000263:Adenylate Kinase