Class-specific pro-apoptotic effect of statins on human vascular endothelial cells.
Neonangiogenesis represents an important step in tumor development and propagation. Statins may have anticancerogenic potential by blocking vascular endothelial cell growth. The antiproliferative effect of four statins on human endothelial cells was compared, concomitantly delineating a possible pro-apoptotic process. All four statins tested, i. e. atorvastatin, fluvastatin, lovastatin, and simvastatin inhibited cell proliferation. Nearly complete blocking of cell proliferation was achieved at a concentration of 10 microM. We were able to demonstrate that the antiproliferative effect of the statins is not due to cytotoxicity but rather to an apoptotic effect as demonstrated by comparison of cytotoxicity assay and apoptosis assay. The apoptotic mechanism seems to involve caspases, since the statins significantly enhanced caspase activity at dosages of 10 and 20 microM. Further experiments revealed a downregulation of the pro-apoptotic protein Bcl-2. Our data indicate that statins may class-specific inhibit angiogenesis at high dosages which can contribute to prevention of tumor development and progression.
Mück
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Section of Endocrinology and Menopause, University Women's Hospital, Calwerstrasse 7, 72076 Tuebingen, Germany. endo.meno@med.uni-tuebingen.de
Seeger
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Wallwiener
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D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D000069059:Atorvastatin; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D053222:Fas Ligand Protein; D005229:Fatty Acids, Monounsaturated / Q000145:classification / Q000494:pharmacology; D000077340:Fluvastatin; D006538:Heptanoic Acids / Q000145:classification / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000145:classification* / Q000494:pharmacology*; D007211:Indoles / Q000145:classification / Q000494:pharmacology; D008148:Lovastatin / Q000145:classification / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008657:Metabolic Clearance Rate; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011758:Pyrroles / Q000145:classification / Q000494:pharmacology; D019821:Simvastatin / Q000145:classification / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000502:physiology
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D000077340:Fluvastatin; D008148:Lovastatin; D000069059:Atorvastatin; D019821:Simvastatin