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

Craig H Kuder; Megan M Weivoda; Ying Zhang; Junjia Zhu; Jeffrey D Neighbors; David F Wiemer; Raymond J Hohl

doi:10.1007/s11745-015-4083-z

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

Journal article

Peer reviewed

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

Craig H Kuder, Megan M Weivoda, Ying Zhang, Junjia Zhu, Jeffrey D Neighbors, David F Wiemer and Raymond J Hohl

Lipids, Vol.50(12), pp.1195-1207

12/2015

DOI: 10.1007/s11745-015-4083-z

PMCID: PMC5238408

PMID: 26494560

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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.

Humans

Drug Resistance, Neoplasm

Stilbenes - pharmacology

Neoplasm Proteins - metabolism

Orphan Nuclear Receptors - metabolism

Recombinant Fusion Proteins - metabolism

ATP Binding Cassette Transporter 1 - metabolism

Glutathione Transferase - genetics

Liver X Receptors

ATP Binding Cassette Transporter 1 - agonists

Glioblastoma - metabolism

Biological Transport - drug effects

Protein Interaction Domains and Motifs

Gene Expression Regulation, Neoplastic - drug effects

Neoplasm Proteins - genetics

Cell Survival - drug effects

Hydroxylation

Orphan Nuclear Receptors - agonists

Glutathione Transferase - metabolism

Recombinant Fusion Proteins - chemistry

Cholesterol - metabolism

Glutathione Transferase - chemistry

Orphan Nuclear Receptors - genetics

Neoplasm Proteins - agonists

Orphan Nuclear Receptors - chemistry

Cell Line, Tumor

Hydroxycholesterols - metabolism

Kinetics

Antineoplastic Agents, Phytogenic - pharmacology

Glioblastoma - drug therapy

Anticholesteremic Agents - pharmacology

ATP Binding Cassette Transporter 1 - genetics

Details

Title: Subtitle: 3-Deoxyschweinfurthin B Lowers Cholesterol Levels by Decreasing Synthesis and Increasing Export in Cultured Cancer Cell Lines
Creators: Craig H Kuder - Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA
Megan M Weivoda - Department of Endocrinology, Mayo Clinic, Rochester, MN, USA
Ying Zhang - Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
Junjia Zhu - Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
Jeffrey D Neighbors - Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA
David F Wiemer - Department of Chemistry, University of Iowa, Iowa City, IA, 52242, USA
Raymond J Hohl - Departments of Medicine and Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA. rhohl@hmc.psu.edu
Resource Type: Journal article
Publication Details: Lipids, Vol.50(12), pp.1195-1207
DOI: 10.1007/s11745-015-4083-z
PMID: 26494560
PMCID: PMC5238408
NLM abbreviation: Lipids
ISSN: 1558-9307
eISSN: 1558-9307
Publisher: United States
Grant note: R42 NS069272 / NINDS NIH HHS 5R42NS069272 / NINDS NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 12/2015
Academic Unit: Neuroscience and Pharmacology; Chemistry; Internal Medicine
Record Identifier: 9983985965002771

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