Decursin

Decursin prevents TPA-induced invasion through suppression of PKCα/p38/NF-κB-dependent MMP-9 expression in MCF-7 human breast carcinoma cells.[Pubmed: 24604087]

Int J Oncol. 2014 May;44(5):1607-13.

Decursin, a coumarin compound, was first isolated from the roots of Angelica gigas almost four decades ago. It was found to exhibit cytotoxicity against various human cancer cells and to possess anti-amnesic activity in vivo through the inhibition of AChE activity. However, the effect of Decursin on breast cancer invasion is unknown. Matrix metalloproteinase-9 (MMP-9) is known to be an important factor for cancer cell invasion.
METHODS AND RESULTS:
Therefore, in this study, we investigated the inhibitory effect of Decursin on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMP-9 expression and cell invasion, as well as the molecular mechanisms involved in MCF-7 cells. Our results showed that Decursin inhibits TPA-induced MMP-9 expression and cell invasion through the suppression of NF-κB. Furthermore, Decursin repressed the TPA-induced phosphorylation of p38 MAPK and inhibited TPA-induced translocation of PKCα from the cytosol to the membrane, but did not affect the translocation of PKCδ.
CONCLUSIONS:
These results indicate that Decursin-mediated inhibition of TPA-induced MMP-9 expression and cell invasion involves the suppression of the PKCα, MAPK and NF-κB pathways in MCF-7 cells. Thus, Decursin may have potential value in restricting breast cancer metastasis.

Decursin and decursinol angelate inhibit VEGF-induced angiogenesis via suppression of the VEGFR-2-signaling pathway.[Pubmed: 19228635 ]

Carcinogenesis. 2009 Apr;30(4):655-61.

Inhibition of angiogenesis is an attractive approach for the treatment of angiogenic diseases, such as cancer. Vascular endothelial growth factor (VEGF) is one of the most important activators of angiogenesis and interacts with the high-affinity tyrosine kinase receptors, VEGFR-1 and VEGFR-2. The pyranocoumarin compounds Decursin and Decursinol angelate isolated from the herb, Angelica gigas, are known to possess potent anti-inflammatory activities. However, little is known about their antiangiogenic activity or their underlying mechanisms.
METHODS AND RESULTS:
Here, we show the antiangiogenic effects of Decursin and Decursinol angelate using in vitro assays and in vivo animal experiments. Decursin and Decursinol angelate inhibited VEGF-induced angiogenic processes in vitro, including proliferation, migration and tube formation of human umbilical vein endothelial cells. Decursin and Decursinol angelate significantly suppressed neovessel formation in chick chorioallantoic membrane and tumor growth in a mouse model. The microvessel density in tumors treated with Decursin for 14 days was significantly decreased compared with a vehicle control group. Decursin and Decursinol angelate inhibited VEGF-induced phosphorylation of VEGFR-2, extracellular signal-regulated kinases and c-Jun N-terminal kinase mitogen-activated protein kinases.
CONCLUSIONS:
Taken together, these results demonstrate that Decursin and Decursinol angelate are novel candidates for inhibition of VEGF-induced angiogenesis.

Decursin attenuates hepatic fibrogenesis through interrupting TGF-beta-mediated NAD(P)H oxidase activation and Smad signaling in vivo and in vitro.[Pubmed: 24880074]

Life Sci. 2014 Jul 17;108(2):94-103.

We studied that a potent antifibrotic effect of Decursin on in vivo liver damage model and the mechanism in inhibiting which transforming growth factor (TGF)-β1-induced human hepatic stellate cells (HSCs) activation.
METHODS AND RESULTS:
Liver injury was induced in vivo by intraperitoneal injection of carbon tetrachloride (CCl4) with or without Decursin for 4weeks in mice. Human hepatic stellate cell line, an immortalized human HSC line, was used in in vitro assay system. The effects of Decursin on HSC activation were measured by analyzing the expression of α-smooth muscle actin (α-SMA) and collagen I in liver tissue and human HSCs. Decursin treatment significantly reduced the ratio of liver/body weight, α-SMA activation, and type I collagen overexpression in CCl4 treated mice liver. The elevated serum levels, including ALT, AST, and ALP, were also decreased by Decursin treatment. Treatment of Decursin markedly proved the generation of reactive oxygen species, NAD(P)H oxidase (NOX) protein (1, 2, and 4) upregulation, NOX activity, and superoxide anion production in HSCs by TGF-β1. It also significantly reduced TGF-β1-induced Smad 2/3 phosphorylation, nuclear translocation of Smad 4, and association of Smad 2/3-Smad 4 complex. Consistent with in vitro results, Decursin treatment effectively blocked the levels of NOX protein, and Smad 2/3 phosphorylation in injured mice liver.
CONCLUSIONS:
Decursin blocked CCl4-induced liver fibrosis and inhibited TGF-β1-mediated HSC activation in vitro. These data demonstrated that Decursin exhibited hepatoprotective effects on experimental fibrosis, potentially by inhibiting the TGF-β1 induced NOX activation and Smad signaling.

Decursin attenuates kainic acid-induced seizures in mice.[Pubmed: 25171200]

Neuroreport. 2014 Nov 12;25(16):1243-9.

Epilepsy is a neurological disorder with recurrent unprovoked seizures as the main symptom. Of the coumarin derivatives in Angelica gigas, Decursin, a major coumarin component, was reported to exhibit significant protective activity against glutamate-induced neurotoxicity when added to primary cultures of rat cortical cells. This study served to investigate the effects of Decursin on a kainic acid (KA)-induced status epilepticus model.
METHODS AND RESULTS:
Thirty minutes after intraperitoneal injections of Decursin (20 mg/kg) in male 7-week-old C57BL/6 mice, the animals were treated with KA (30 mg/kg, intraperitoneally) and then examined for behavioral seizure score, electroencephalogram, seizure-related expressed protein levels, neuronal cell loss, neurodegeneration, and astrogliosis. KA injections significantly enhanced neurodegenerative conditions but treatment with Decursin 30 min before KA injection reduced the detrimental effects of KA in mice. The Decursin-treated KA-injected group showed significantly decreased behavioral seizure activity and remarkably attenuated intense and high-frequency seizure discharges in the parietal cortex for 2 h compared with the group treated only with KA. Furthermore, in-vivo results indicated that Decursin strongly inhibits selective neuronal death, astrogliosis, and oxidative stress induced by KA administration.
CONCLUSIONS:
Therefore Decursin is able to attenuate KA-induced seizures and could have potential as an antiepileptic drug.

Potential of decursin to inhibit the human cytochrome P450 2J2 isoform.[Pubmed: 24788058]

Decursin exerts anti-cancer activity in MDA-MB-231 breast cancer cells via inhibition of the Pin1 activity and enhancement of the Pin1/p53 association.[Pubmed: 23580332]

Phytother Res. 2014 Feb;28(2):238-44.

The peptidyl-prolyl cis/trans isomerase Pin1 is overexpressed in a wide variety of cancer cells and thus considered as an important target molecule for cancer therapy.
METHODS AND RESULTS:
This study demonstrates that Decursin, a bioactive compound from Angelica gigas, exert the anti-cancer effect against breast cancer cells via regulation of Pin1 and its related signaling molecules. We observed that Decursin induced G1 arrest with decrease in cyclin D1 level in Pin1-expressing breast cancer cells MDA-MB-231, but not Pin1-non-expressing breast cancer cells MDA-MB-157. In addition, Decursin significantly reduced protein expression and enzymatic activity of Pin1 in MDA-MB-231 cells. Further, we found that Decursin treatment enhanced the p53 expression level and failed to down-regulate Pin1 in the cells transfected with p53 siRNA, indicating the importance of p53 in the Decursin-mediated Pin1 inhibition in MDA-MB-231 cells. Decursin stimulated association between Pin1 to p53. Moreover, Decursin facilitated p53 transcription in MDA-MB-231 cells.
CONCLUSIONS:
Overall, our current study suggests the potential of Decursin as an attractive cancer therapeutic agent for breast cancer by targeting Pin1 protein.

Food Chem Toxicol. 2014 Aug;70:94-9.

CYP2J2 enzyme is highly expressed in human tumors and carcinoma cell lines, and epoxyeicosatrienoic acids, CYP2J2-mediated metabolites, have been implicated in the pathologic development of human cancers.
METHODS AND RESULTS:
To identify a CYP2J2 inhibitor, 50 natural products obtained from plants were screened using astemizole as a CYP2J2 probe substrate in human liver microsomes. Of these, Decursin noncompetitively inhibited CYP2J2-mediated astemizole O-demethylation and terfenadine hydroxylation activities with Ki values of 8.34 and 15.8μM, respectively. It also showed cytotoxic effects against human hepatoma HepG2 cells in a dose-dependent manner while it did not show cytotoxicity against mouse hepatocytes.
CONCLUSIONS:
The present data suggest that Decursin is a potential candidate for further evaluation for its CYP2J2 targeting anti-cancer activities. Studies are currently underway to test Decursin as a potential therapeutic agent for cancer.

Decursin inhibits induction of inflammatory mediators by blocking nuclear factor-kappaB activation in macrophages.[Pubmed: 16510559 ]

Mol Pharmacol. 2006 Jun;69(6):1783-90.

In the course of screening inhibitors of matrix metalloproteinase (MMP)-9 induction in macrophages, we isolated Decursin, a coumarin compound, from the roots of Angelicae gigas. As a marker for the screening and isolation, we tested expression of MMP-9 in RAW264.7 cells and THP-1 cells after treatment with bacterial lipopolysaccharide (LPS), the TLR-4 ligand.
METHODS AND RESULTS:
Decursin suppressed MMP-9 expression in cells stimulated by LPS in a dose-dependent manner at concentrations below 60 microM with no sign of cytotoxicity. The suppressive effect of Decursin was observed not only in cells stimulated with ligands for TLR4, TLR2, TLR3, and TLR9 but also in cells stimulated with interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha, indicating that the molecular target of Decursin is common signaling molecules induced by these stimulants. In addition to the suppression of MMP-9 expression, Decursin blocked nitric oxide production and cytokine (IL-8, MCP-1, IL-1beta, and TNF-alpha) secretion induced by LPS. To find out the molecular mechanism responsible for the suppressive effect of Decursin, we analyzed signaling molecules involved in the TLR-mediated activation of MMP-9 and cytokines. Decursin blocked phosphorylation of IkappaB and nuclear translocation of NF-kappaB in THP-1 cells activated with LPS. Furthermore, expression of a luciferase reporter gene under the promoter containing NF-kappaB binding sites was blocked by Decursin.
CONCLUSIONS:
These data indicate that Decursin is a novel inhibitor of NF-kappaB activation in signaling induced by TLR ligands and cytokines.