title: Pleiotropic effects of a schweinfurthin on isoprenoid homeostasis.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Holstein
authors.forename: Craig H
authors.initials: CH
authors.lastname: Kuder
authors.forename: Huaxiang
authors.initials: H
authors.lastname: Tong
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Hohl
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D054876:Prenylation / Q000187:drug effects; D012717:Sesquiterpenes / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D013729:Terpenes / Q000378:metabolism*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; D013267:Stilbenes; D013729:Terpenes; C117233:schweinfurthin B; C004808:farnesyl pyrophosphate; D008148:Lovastatin; C002963:geranylgeranyl pyrophosphate