title: Resveratrol inhibits the mevalonate pathway and potentiates the antiproliferative effects of simvastatin in rat theca-interstitial cells.
abstract: OBJECTIVE
  To examine the mechanisms of action of resveratrol and its interaction with simvastatin on growth and the mevalonate pathway in rat theca-interstitial cells.
  
  
  METHODS
  In vitro study.
  
  
  METHODS
  Research laboratory.
  
  
  METHODS
  Immature Sprague-Dawley female rats.
  
  
  METHODS
  Theca-interstitial cells were cultured in the absence or presence of resveratrol, simvastatin, mevalonic acid, farnesyl pyrophosphate, and/or geranylgeranyl pyrophosphate.
  
  
  METHODS
  DNA synthesis was assessed by thymidine incorporation assay; 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) expression and activity were evaluated with the use of quantitative real-time polymerase chain reaction, Western blot analysis, and HMGCR activity assay. Cholesterol synthesis was determined by the conversion of [(14)C]-acetate to [(14)C]-cholesterol.
  
  
  RESULTS
  Resveratrol potentiated the simvastatin-induced inhibition on cell proliferation in a concentration-dependent manner. Inhibitory effects of resveratrol were partly abrogated by the addition of mevalonic acid, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate. Resveratrol reduced HMGCR expression and activity, and decreased cholesterol synthesis. In contrast, simvastatin inhibited HMGCR activity with a compensatory increase in HMGCR expression. Resveratrol counteracted this effect of simvastatin on HMGCR expression but augmented the simvastatin-induced inhibition on HMGCR activity and cholesterol synthesis.
  
  
  CONCLUSIONS
  Resveratrol inhibits the mevalonate pathway via distinctly different mechanisms than statins. These observations demonstrate a novel mechanism of action of resveratrol and underscore the potential translational/clinical relevance of resveratrol interactions with simvastatin.
authors: Department of Obstetrics and Gynecology, School of Medicine, University of California Davis, Sacramento, California 95817, USA.
authors: Donna H
authors: DH
authors: Wong
authors: Jesus A
authors: JA
authors: Villanueva
authors: Amanda B
authors: AB
authors: Cress
authors: Anna
authors: A
authors: Sokalska
authors: Israel
authors: I
authors: Ortega
authors: Antoni J
authors: AJ
authors: Duleba
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism*; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology*; D013799:Theca Cells / Q000187:drug effects* / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; D013267:Stilbenes; C004808:farnesyl pyrophosphate; D002784:Cholesterol; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; C002963:geranylgeranyl pyrophosphate; D000077185:Resveratrol; D008798:Mevalonic Acid