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. Here in, 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 (ABCA1) 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.

Schweinfurthins: Lipid Modulators with Promising Anticancer Activity

“…For instance, cytotoxicity of the 3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGCR) inhibitor, lovastatin, is enhanced when coincubated with the schweinfurthin analog 3dSB. This synergy is increased in the presence of lipid‐depleted serum, suggesting that the cytotoxicity of schweinfurthins is lipid‐dependent (Holstein et al, ; Kuder et al, ). However, schweinfurthins do not demonstrate a combined effect with the farnesyl diphosphate synthase (FDPS) inhibitor zoledronic acid (ZA), the geranylgeranyl diphosphate synthase (GGDPS) inhibitor digeranyl bisphosphonate (DGBP), or the squalene synthase (SS) inhibitor zaragozic acid (Zara).…”

Schweinfurthin natural products induce regression of murine melanoma and pair with anti-PD-1 therapy to facilitate durable tumor immunity

“…44,45 We have demonstrated that schweinfurthins induce tumor cells to behave as if they have a surfeit of cholesterol, even when this critical metabolite is limiting. 31 Treatment of glioblastoma cells with 3-deoxyschweinfurthin B led to reduction in HMG-CoA reductase but also promoted increased cholesterol efflux and reduced cholesterol import. Thus, schweinfurthins have a broader impact on cholesterol regulatory mechanisms than some of the more well-characterized cholesterol inhibitors.…”

“…Schweinfurthins are known to modulate several aspects of cholesterol metabolism, 31 but their anti-tumor properties are only partially defined. While lovastatin directly inhibits the first enzyme of cholesterol synthesis, β-Hydroxy β-methylglutaryl-conenzyme A (HMG-CoA) reductase, schweinfurthins indirectly reduce the synthesis of cholesterol while also increasing cholesterol export.…”

“…This type of activity, with little or no overlap with the pattern displayed by known agents, indicates a novel mechanism. 30 Schwienfurthins impact cholesterol metabolism through their effects on the mevalonate pathway 31 , which supplies isoprenoid intermediates for the synthesis of cholesterol. Since targeting the mevalonate pathway can influence the immune response, 32,33 we hypothesized that schweinfurthins may improve existing immunotherapies used to treat cancer.…”

Synthesis of amide isosteres of schweinfurthin-based stilbenes

“…Mechanistic investigations from several groups have suggested that the schweinfurthins may engage several different targets, including oxysterol binding proteins, 10 trans-Golgi-network trafficking, 11 and cholesterol biosynthesis and its cellular export. 12 The combination of a unique profile of activity with the limited success of efforts to obtain more of the schweinfurthins by isolation from the plant source, has led us to an extended effort to prepare these natural products by chemical synthesis. Our efforts to date have afforded seven of the natural products (schweinfurthins A, 13 B, 14 C, 15 E, 14 F, 16 G 16 and vedelianin 17 ), as well as 3-deoxyschweinfurthin B 18 ( 10 ) which we have used as a lead for a number of structure-activity studies.…”