title: Effect of metformin on the proliferation, migration, and MMP-2 and -9             expression of human umbilical vein endothelial cells.
abstract: Recent epidemiological studies have demonstrated that metformin lowers the risk of several types of cancer in diabetic patients. Matrix metalloproteinases (MMPs) play a crucial role in the degradation of the vascular basement membrane extracellular matrix proteins, thereby promoting endothelial cell invasion, migration and angiogenesis in the incidence and progression of tumors. The aim of this study was to investigate the effects of metformin on human umbilical vein endothelial cell (HUVEC) proliferation and migration, as well as on MMP-2 and MMP-9 expression. Cell proliferation was determined by cell counting and MTT colorimetric assays. Cell migration was assessed by the wound repair method. Quantitative real-time reverse transcription PCR was performed to quantify the mRNA expression of MMPs. Metformin at concentrations of 0.5-3.0 mM effectively reduced the number of endothelial cells by 5.5-55%, without being cytotoxic to the cells. Similarly, cell proliferation and migration were markedly inhibited by metformin. In addition, treatment with metformin demonstrated a strong (P<0.001) suppressive effect on the mRNA levels of MMP-2 and -9 in the endothelial cells. The inhibitory effects of metformin on endothelial cell number, migration, and MMP expression were reversed partially by compound C, which is an inhibitor of AMP-activated protein kinase (AMPK). The present study reports that metformin considerably inhibited the proliferation, migration, and MMP-2 and -9 expression of HUVECs, and the effect was partially AMPK-dependent. The obtained findings provide a molecular rationale, whereby metformin can exert anticancer effects.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy,                     Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Nilufar
authors.initials: N
authors.lastname: Esfahanian
authors.forename: Yadollah
authors.initials: Y
authors.lastname: Shakiba
authors.forename: Behroz
authors.initials: B
authors.lastname: Nikbin
authors.forename: Hamid
authors.initials: H
authors.lastname: Soraya
authors.forename: Nasrin
authors.initials: N
authors.lastname: Maleki-Dizaji
authors.forename: Mahmood
authors.initials: M
authors.lastname: Ghazi-Khansari
authors.forename: Alireza
authors.initials: A
authors.lastname: Garjani
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D011720:Pyrazoles; D011743:Pyrimidines; C516138:dorsomorphin; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9