Perillyl alcohol, an inhibitor of geranylgeranyl transferase, induces apoptosis of immortalized human vascular smooth muscle cells in vitro.
The isoprenoids geranylgeraniol and farnesol are required for lipid modification of several important cellular proteins. In this study the effect of perillyl alcohol (PA), an inhibitor of geranylgeranyl transferase, was examined on proliferation and apoptosis of immortalized human vascular smooth muscle cells (HVSMCs) derived from saphenous vein. PA induced a time- and concentration-dependent inhibition of cell proliferation over 3 days and 48 h exposure to PA inhibited [methyl-3H-thymidine incorporation induced by 10% fetal calf serum in a concentration-dependent manner. Flow cytometry analysis indicated that PA reduced the proportion of cells in S phase and increased apoptosis. PA-induced apoptosis was confirmed by terminal deoxynucleotidyl transferase (TdT) reagent-based immunocytochemistry. In contrast, the selective inhibitors of farnesyl transferase B581 and BZA-5B were without effect. In view of the proposed role of proliferation and apoptosis in myointimal hyperplasia, inhibitors of geranylgeranyl transferases may have therapeutic potential in cardiovascular disease.
Unlu
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Clinical Pharmacology, National Heart & Lung Institute, Imperial College of Science, Technology & Medicine, St. Mary's Hospital, London, England.
Mason
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Schachter
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Hughes
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D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D017209:Apoptosis / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004253:DNA Nucleotidylexotransferase / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D007120:Immunochemistry; D066298:In Vitro Techniques; D039821:Monoterpenes; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology; D012501:Saphenous Vein / Q000187:drug effects; D013729:Terpenes / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors
C090156:BZA 5B; D004791:Enzyme Inhibitors; D039821:Monoterpenes; D009842:Oligopeptides; D013729:Terpenes; D001569:Benzodiazepines; C088459:B 581; C032208:perillyl alcohol; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D004253:DNA Nucleotidylexotransferase; D013936:Thymidine