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.
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Abbreviations
- 3dSB:
-
3-Deoxyschweinfurthin B
- LXR:
-
Liver X receptor
- NCI60:
-
National Cancer Institute 60 cell cancer screen
- CNS:
-
Central nervous system
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Financial Support Statement
This project was supported in part by the Roy J. Carver Charitable Trust, the Roland W. Holden Family Program for Experimental Therapeutics, and the National Institutes of Health (5R42NS069272).
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Kuder, C.H., Weivoda, M.M., Zhang, Y. et al. 3-Deoxyschweinfurthin B Lowers Cholesterol Levels by Decreasing Synthesis and Increasing Export in Cultured Cancer Cell Lines. Lipids 50, 1195–1207 (2015). https://doi.org/10.1007/s11745-015-4083-z
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DOI: https://doi.org/10.1007/s11745-015-4083-z