A Natural Product That Lowers Cholesterol As an Antagonist Ligand for FXR

Urizar, Nancy L.; Liverman, Amy B.; Dodds, D'Nette T.; Silva, Frank Valentin; Ordentlich, Peter; Yan, Yingzhuo; Gonzalez, Frank J.; Heyman, Richard A.; Mangelsdorf, David J.; Moore, David D.

doi:10.1126/science.1072891

Cited by 478 publications

(381 citation statements)

References 35 publications

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“…Guggulsterone is an antagonist of the FXR, a key regulator of cholesterol homeostasis [33]. Recent studies demonstrate that FXR is expressed and functional in vascular endothelial cells indicating that FXR may play a role in endothelial homeostasis and serve as a novel molecular target for manipulating vascular inflammation [4,11,17].…”

Section: Discussionmentioning

confidence: 99%

Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis

et al. 2008

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Section: Discussionmentioning

confidence: 99%

Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis

et al. 2008

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“…Recent studies have shown that guggulsterone is an antagonist of farnesoid X receptor (12,13). In addition, guggulsterone has been shown to increase transcription of bile salt export pump (14).…”

Section: Introductionmentioning

confidence: 99%

Guggulsterone-Induced Apoptosis in Human Prostate Cancer Cells Is Caused by Reactive Oxygen Intermediate–Dependent Activation of c-Jun NH2-Terminal Kinase

et al. 2007

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Guggulsterone, a constituent of Indian Ayurvedic medicinal plant Commiphora mukul, causes apoptosis in cancer cells but the sequence of events leading to cell death is poorly understood. We now show that guggulsterone-induced cell death in human prostate cancer cells is caused by reactive oxygen intermediate (ROI)-dependent activation of c-Jun NH 2 -terminal kinase (JNK). Exposure of PC-3 and LNCaP cells to apoptosis inducing concentrations of guggulsterone resulted in activation of JNK and p38 mitogen-activated protein kinase (p38 MAPK) in both cell lines and activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in LNCaP cells. The guggulsterone-induced apoptosis in PC-3/LNCaP cells was partially but statistically significantly attenuated by pharmacologic inhibition (SP600125) as well as genetic suppression of JNK activation. On the other hand, pharmacologic inhibition of p38 MAPK activation in PC-3 or LNCaP cells (SB202190) and ERK1/2 activation in LNCaP cells (PD98059) did not protect against guggulsterone-induced cell death. The guggulsterone treatment caused generation of ROI in prostate cancer cells but not in a normal prostate epithelial cell line (PrEC), which was also resistant to guggulsteronemediated JNK activation. The guggulsterone-induced JNK activation as well as cell death in prostate cancer cells was significantly attenuated by overexpression of catalase and superoxide dismutase. In addition, guggulsterone treatment resulted in a decrease in protein level and promoter activity of androgen receptor in LNCaP cells. In conclusion, the present study reveals that the guggulsterone-induced cell death in human prostate cancer cells is regulated by ROI-dependent activation of JNK and guggulsterone inhibits promoter activity of androgen receptor. [Cancer Res 2007;67(15):7439-49]

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“…For thousands of years, guggulsterone has been used to treat various human diseases, including inflammation, arthritis and cardiovascular disease (9)(10)(11). The active components of this herbal extract are the trans Z-and cis E-isomers of guggulsterone (12).…”

Section: Introductionmentioning

confidence: 99%

Guggulsterone inhibits human cholangiocarcinoma Sk-ChA-1 and Mz-ChA-1 cell growth by inducing caspase-dependent apoptosis and downregulation of survivin and Bcl-2 expression

et al. 2015

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Abstract. Guggulsterone has recently been reported to demonstrate anti-tumor effects in a variety of cancers. The present study aims to investigate the biological roles and underlying mechanism of the action of guggulsterone in cholangiocarcinoma. The immortalized human cholangiocarcinoma Sk-ChA-1 and Mz-ChA-1 cell lines were treated with various concentrations of the trans isomer of guggulsterone, Z-guggulsterone. Cellular proliferation was determined using the XTT assay. The apoptotic status of cholangiocarcinoma cells was assessed by Hoechst 33258 staining, DNA fragmentation assay and flow cytometry. Specific caspase inhibitor was used to explore the role of caspase in guggulsterone-induced apoptosis. A colorimetric assay was performed to measure the alterations of the activities of caspase-3, -8 and -9. Western blot analysis was used to detect the protein expression of survivin, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein and cleaved poly (adenosine diphosphate-ribose) polymerase (PARP). As revealed by the present data, guggulsterone significantly inhibited the growth of the two human cholangiocarcinoma cell lines by inducing cellular apoptosis. In addition, guggulsterone-induced apoptosis of cholangiocarcinoma cells was demonstrated to be partially inhibited by the caspase inhibitors z-VAD-fmk, z-LEHD-fmk and z-IETD-fmk, accompanied by the activation of caspases-3, -8 and -9, accumulation of cleaved PARP and decreased expression of survivin and Bcl-2. In conclusion, the present study demonstrated that guggulsterone was able to suppress the proliferation of cholangiocarcinoma by inducing caspase-dependent apoptosis and downregulating survivin and Bcl-2.

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A Natural Product That Lowers Cholesterol As an Antagonist Ligand for FXR

Cited by 478 publications

References 35 publications

Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis

Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis

Guggulsterone-Induced Apoptosis in Human Prostate Cancer Cells Is Caused by Reactive Oxygen Intermediate–Dependent Activation of c-Jun NH2-Terminal Kinase

Guggulsterone inhibits human cholangiocarcinoma Sk-ChA-1 and Mz-ChA-1 cell growth by inducing caspase-dependent apoptosis and downregulation of survivin and Bcl-2 expression

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