title: Anti-angiogenic Effects of Metformin, an AMPK Activator, on Human Umbilical Vein Endothelial Cells and on Granulation Tissue in Rat.
abstract: OBJECTIVE
  Metformin is well known for activation of AMP-activated protein kinase (AMPK). AMPK activation inhibits mammalian target of rapamycin (mTOR) as a key signaling process in cell proliferation. Recent epidemiological studies demonstrate that metformin lowers the risk for several types of cancer in diabetic patients. Concerning the critical role of angiogenesis in the incidence and progression of tumors, we investigated the effect of metformin on human umbilical vein endothelial cells migration, as well as on vascular endothelial growth factor (VEGF) expressions in the cells and also on angiogenesis in air pouch model in rats.
  
  
  METHODS
  A "wound" repair method was used to assess the cell migration (n=6). Real-time PCR was performed to quantify the mRNA expression of VEGF (n=5). In air pouch model, carrageenan was injected into the air pouches on the back of rats (n=6) and following an IV injection of carmine red dye granulomatous tissue was processed for the assessment of the dye content. An ordinary ANOVA with Student-Newman-Keuls post hoc test was used to compare groups.
  
  
  RESULTS
  Metformin (orally, 50mg/kg) significantly (P<0.01) decreased angiogenesis in granulomatous tissue by 34% in pouch-bearing rats. Metformin at concentrations of 0.5-3 mM significantly (P<0.001) inhibited VEGF mRNA expression and endothelial cell migration. The inhibitory effects of metformin on the endothelial cell migration were reversed partially by compound C (P<0.01), an inhibitor of AMPK.
  
  
  CONCLUSIONS
  The present study reported that metformin inhibited endothelial cell migration and angiogenesis in vitro and in vivo, and the effect was partially AMPK dependent.
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
authors: Hamid
authors: H
authors: Soraya
authors: Nilufar
authors: N
authors: Esfahanian
authors: Yadollah
authors: Y
authors: Shakiba
authors: Mahmood
authors: M
authors: Ghazi-Khansari
authors: Behroz
authors: B
authors: Nikbin
authors: Hasan
authors: H
authors: Hafezzadeh
authors: Nasrin
authors: N
authors: Maleki Dizaji
authors: Alireza
authors: A
authors: Garjani
keywords: Angiogenesis; Endothelial cells; Metformin; Migration; Proliferation
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