3-Deoxyschweinfurthin B Lowers Cholesterol Levels by Decreasing Synthesis and Increasing Export in Cultured Cancer Cell Lines.

Abstract

The schweinfurthins have potent antiproliferative activity in multiple glioblastoma multiforme (GBM) cell lines; however, the mechanism by which growth is impeded is not fully understood. Previously, we demonstrated that the schweinfurthins reduce the level of key isoprenoid intermediates in the cholesterol biosynthetic pathway. Herein, we describe the effects of the schweinfurthins on cholesterol homeostasis. Intracellular cholesterol levels are greatly reduced in cells incubated with 3-deoxyschweinfurthin B (3dSB), an analog of the natural product schweinfurthin B. Decreased cholesterol levels are due to decreased cholesterol synthesis and increased cholesterol efflux; both of these cellular actions can be influenced by liver X-receptor (LXR) activation. The effects of 3dSB on ATP-binding cassette transporter 1 levels and other LXR targets are similar to that of 25-hydroxycholesterol, an LXR agonist. Unlike 25-hydroxycholesterol, 3dSB does not act as a direct agonist for LXR α or β. These data suggest that cholesterol homeostasis plays a significant role in the growth inhibitory activity of the schweinfurthins and may elucidate a mechanism that can be targeted in human cancers such as GBM.

• Authors: Craig H Kuder, Megan M Weivoda, Ying Zhang, Junjia Zhu, Jeffrey D Neighbors, David F Wiemer, Raymond J Hohl
• Journal: Lipids (Lipids) Vol. 50 Issue 12 Pg. 1195-207 (Dec 2015) ISSN: 1558-9307 [Electronic] United States
• PMID: 26494560 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• ABCA1 protein, human
• ATP Binding Cassette Transporter 1
• Anticholesteremic Agents
• Antineoplastic Agents, Phytogenic
• Hydroxycholesterols
• Liver X Receptors
• NR1H3 protein, human
• Neoplasm Proteins
• Orphan Nuclear Receptors
• Recombinant Fusion Proteins
• Stilbenes
• schweinfurthin B
• 25-hydroxycholesterol
• Cholesterol
• Glutathione Transferase

Topics

• ATP Binding Cassette Transporter 1 (agonists, genetics, metabolism)
• Anticholesteremic Agents (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Biological Transport (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cholesterol (metabolism)
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic (drug effects)
• Glioblastoma (drug therapy, metabolism)
• Glutathione Transferase (chemistry, genetics, metabolism)
• Humans
• Hydroxycholesterols (metabolism)
• Hydroxylation
• Kinetics
• Liver X Receptors
• Neoplasm Proteins (agonists, genetics, metabolism)
• Orphan Nuclear Receptors (agonists, chemistry, genetics, metabolism)
• Protein Interaction Domains and Motifs
• Recombinant Fusion Proteins (chemistry, metabolism)
• Stilbenes (pharmacology)