Pleiotropic Effects of a Schweinfurthin on Isoprenoid Homeostasis.
Summary of "Pleiotropic Effects of a Schweinfurthin on Isoprenoid Homeostasis."
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.
Affiliation
Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA.
Journal Details
This article was published in the following journal.
Name: Lipids
ISSN: 1558-9307
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/21633866
- DOI: http://dx.doi.org/10.1007/s11745-011-3572-y
Medical and Biotech [MESH] Definitions
Receptors, Interferon
Specific molecular sites or structures on or in cells with which interferons react or to which they bind in order to modify the function of the cells. Interferons exert their pleiotropic effects through two different receptors. alpha- and beta-interferon crossreact with common receptors, while gamma-interferon initiates its biological effects through its own specific receptor system.
Tocotrienols
Natural analogs of TOCOPHEROLS exhibiting antioxidant activity. These tocol derivatives and isomers contain a benzopyran ring and an unsaturated isoprenoid side chain.
Parasympathetic Nervous System
The craniosacral division of the autonomic nervous system. The cell bodies of the parasympathetic preganglionic fibers are in brain stem nuclei and in the sacral spinal cord. They synapse in cranial autonomic ganglia or in terminal ganglia near target organs. The parasympathetic nervous system generally acts to conserve resources and restore homeostasis, often with effects reciprocal to the sympathetic nervous system.
Regulon
In eukaryotes, a genetic unit consisting of a noncontiguous group of genes under the control of a single regulator gene. In bacteria, regulons are global regulatory systems involved in the interplay of pleiotropic regulatory domains and consist of several OPERONS.
Vitamin K 3
A synthetic naphthoquinone without the isoprenoid side chain and biological activity, but can be converted to active vitamin K2, menaquinone, after alkylation in vivo.
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