stilbenes and farnesyl-pyrophosphate

The schweinfurthins, a family of natural products derived from the isoprenoid biosynthetic pathway (IBP), have marked growth inhibitory activity. However, the biochemical basis for the schweinfurthins cellular effects has remained ill-defined. Here, the effects of the synthetic schweinfurthin, 3-deoxyschweinfurthin (3dSB) on multiple aspects of isoprenoid homeostasis are explored. Cytotoxicity assays demonstrate a synergistic interaction between 3dSB and the HMG-CoA reductase inhibitor lovastatin but not with other IBP inhibitors in a variety of human cancer cell lines. The cytotoxic effects of 3dSB were enhanced in cells incubated in lipid-depleted serum. 3dSB was found to enhance the lovastatin-induced decrease in protein prenylation. In addition, 3dSB decreases intracellular farnesyl pyrophosphate and geranylgeranyl pyrophosphate levels in both established cell lines and primary cells. To determine whether 3dSB alters the regulation of expression of genes involved in isoprenoid homeostasis, real-time PCR studies were performed in human cell lines cultured in either lipid-replete or -deplete conditions. These studies demonstrate that 3dSB abrogates lovastatin-induced upregulation of sterol regulatory element-containing genes and lovastatin-induced downregulation of ABCA1. In aggregate, these studies are the first to demonstrate that a schweinfurthin exerts pleiotropic effects on isoprenoid homeostasis.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Cell Line, Tumor; Cell Survival; Down-Regulation; Drug Synergism; Humans; Lovastatin; Neoplasms; Polyisoprenyl Phosphates; Prenylation; Sesquiterpenes; Stilbenes; Terpenes

To examine the mechanisms of action of resveratrol and its interaction with simvastatin on growth and the mevalonate pathway in rat theca-interstitial cells.. In vitro study.. Research laboratory.. Immature Sprague-Dawley female rats.. Theca-interstitial cells were cultured in the absence or presence of resveratrol, simvastatin, mevalonic acid, farnesyl pyrophosphate, and/or geranylgeranyl pyrophosphate.. 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.. 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.. 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.

Topics: Animals; Blotting, Western; Cell Proliferation; Cells, Cultured; Cholesterol; DNA Replication; Dose-Response Relationship, Drug; Drug Synergism; Female; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mevalonic Acid; Polyisoprenyl Phosphates; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Sesquiterpenes; Simvastatin; Stilbenes; Theca Cells