Effect of metformin on the proliferation, migration, and MMP-2 and -9 expression of human umbilical vein endothelial cells
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.Molecular Medicine Reports (Impact Factor: 1.55). 04/2012; 5(4):1068-74. DOI: 10.3892/mmr.2012.753
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.
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ABSTRACT: Recently, epithelial-mesenchymal transition (EMT) has been implicated in human pathology, including fibrosis and cancer metastasis. In this study, we investigated the inhibitory effects of green tea seed (GTS) on the EMT process and migration using the human breast cancer cell line, MDA-MB231. Pretreatment with GTS significantly inhibited migration of breast cancer cells, as measured by monolayer scratch assay. GTS treatment clearly decreased vimentin (a mesenchymal marker) and focal adhesion kinase (FAK) mRNA expression, while E-cadherin (an epithelial marker) expression was significantly increased. Furthermore, GTS also reduced matrix metalloproteinase (MMP)-2 and -9. Taken together, our results demonstrated that GTS inhibits migration of breast cancer cells by suppressing the EMT process via reduction of MMP activities and FAK mRNA expression. Based on these findings, we speculate that GTS might be a potential agent for inhibition of breast cancer cell migration.Food science and biotechnology 08/2013; 22(4). DOI:10.1007/s10068-013-0193-7 · 0.65 Impact Factor
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ABSTRACT: AMP-activated protein kinase (AMPK) is an evolutionary conserved energy-sensing enzyme that regulates cell metabolism. Emerging evidence indicates that AMPK also plays an important role in modulating endothelial cell function. In the present study, we investigated whether AMPK modulates endothelial cell growth. Treatment of cultured human umbilical vein endothelial cells with the AMPK activators 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), 6,7-dihydro-4-hydroxy-3-(2'-hydroxy[1,1'-biphenyl]-4-yl)-6-oxo-thieno[2,3-b]pyridine-5-carbonitrile (A-769662), or metformin inhibited cell proliferation and DNA synthesis. The antiproliferative action of AICAR was largely prevented by the adenosine kinase inhibitor 5'-iodotubercidin and mimicked by infecting endothelial cells with an adenovirus expressing constitutively active AMPK. In contrast, pharmacological blockade of endothelial nitric oxide synthase or heme oxygenase-1 activity failed to reverse the inhibition of endothelial cell growth by AICAR. Flow cytometry experiments revealed that pharmacological activation of AMPK arrested endothelial cells in the G₀/G₁ phase of the cell cycle, and this was associated with increases in p53 phosphorylation and p53, p21, and p27 protein expression and decreases in cyclin A protein expression and retinoblastoma protein phosphorylation. In addition, silencing p21 and p27 expression partially restored the mitogenic response of AMPK-activated cells. Finally, activation of AMPK by AICAR blocked the migration of endothelial cells after scrape injury and stimulated tube formation by endothelial cells plated onto Matrigel-coated plates. In conclusion, these studies demonstrate that AMPK activation inhibits endothelial cell proliferation by elevating p21 and p27 expression. In addition, they show that AMPK regulates endothelial cell migration and differentiation and identify AMPK as an attractive therapeutic target in treating diseases associated with aberrant endothelial cell growth.Journal of Pharmacology and Experimental Therapeutics 06/2012; 342(3):827-34. DOI:10.1124/jpet.112.194712 · 3.97 Impact Factor
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ABSTRACT: Healthy individuals can harbour microscopic tumours and dysplastic foci in different organs in an undetectable and asymptomatic state for many years. These lesions do not progress in the absence of angiogenesis or inflammation. Targeting both processes before clinical manifestation can prevent tumour growth and progression. Angioprevention is a chemoprevention approach that interrupts the formation of new blood vessels when tumour cell foci are in an indolent state. Many efficacious chemopreventive drugs function by preventing angiogenesis in the tumour microenvironment. Blocking the vascularization of incipient tumours should maintain a dormancy state such that neoplasia or cancer exist without disease. The current limitations of antiangiogenic cancer therapy may well be related to the use of antiangiogenic agents too late in the disease course. In this Review, we suggest mechanisms and strategies for using antiangiogenesis agents in a safe, preventive clinical angioprevention setting, proposing different levels of clinical angioprevention according to risk, and indicate potential drugs to be employed at these levels. Finally, angioprevention may go well beyond cancer in the prevention of a range of chronic disorders where angiogenesis is crucial, including different forms of inflammatory or autoimmune diseases, ocular disorders, and neurodegeneration.Nature Reviews Clinical Oncology 07/2012; 9(9):498-509. DOI:10.1038/nrclinonc.2012.120 · 14.18 Impact Factor
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