Dehydrocostus lactone

Phytother Res. 2015 May;29(5):680-6.

Inhibition of Wnt/β-Catenin Pathway by Dehydrocostus Lactone and Costunolide in Colon Cancer Cells.[Pubmed: 25625870]

Abnormal activation of β-catenin has been reported in 90% in the sporadic and hereditary colorectal cancer. The suppression of abnormally activated β-catenin is one of the good strategies for chemoprevention and treatment of colorectal cancer.
METHODS AND RESULTS:
In this study, we have isolated two main compounds from root of Saussurea lappa, Dehydrocostus lactone (DCL) and costunolide (CL), and investigated their anti-colorectal cancer activities. DCL and CL suppressed cyclin D1 and survivin through inhibiting nuclear translocation of β-catenin. They also suppressed the nuclear translocation of galectin-3 that is one of the coactivators of β-catenin in SW-480 colon cancer cells. Furthermore, DCL and CL suppressed proliferation and survival of SW-480 colon cancer cells through the induction of cell cycle arrest and cell death.
CONCLUSIONS:
Taken together, DCL and CL from root of S. lappa have anti-colorectal cancer activities through inhibiting Wnt/β-catenin pathway.

Planta Med. 2012 Nov;78(16):1749-56.

Effect of costunolide and dehydrocostus lactone on cell cycle, apoptosis, and ABC transporter expression in human soft tissue sarcoma cells.[Pubmed: 23047249]

Human soft tissue sarcomas represent a rare group of malignant tumours that frequently exhibit chemotherapeutic resistance and increased metastatic potential following unsuccessful treatment.
METHODS AND RESULTS:
In this study, we investigated the effects of costunolide and Dehydrocostus lactone, which have been isolated from Saussurea lappa using activity-guided isolation, on three soft tissue sarcoma cell lines of various origins. The effects on cell proliferation, cell cycle distribution, apoptosis induction, and ABC transporter expression were analysed. Both compounds inhibited cell viability dose- and time-dependently. IC50 values ranged from 6.2 μg/mL to 9.8 μg/mL. Cells treated with costunolide showed no changes in cell cycle, little in caspase 3/7 activity, and low levels of cleaved caspase-3 after 24 and 48 h. Dehydrocostus lactone caused a significant reduction of cells in the G1 phase and an increase of cells in the S and G2/M phase. Moreover, it led to enhanced caspase 3/7 activity, cleaved caspase-3, and cleaved PARP indicating apoptosis induction. In addition, the influence of costunolide and Dehydrocostus lactone on the expression of ATP binding cassette transporters related to multidrug resistance (ABCB1/MDR1, ABCC1/MRP1, and ABCG2/BCRP1) was examined using real-time RT-PCR. The expressions of ABCB1/MDR1 and ABCG2/BCRP1 in liposarcoma and synovial sarcoma cells were significantly downregulated by Dehydrocostus lactone.
CONCLUSIONS:
Our data demonstrate for the first time that Dehydrocostus lactone affects cell viability, cell cycle distribution and ABC transporter expression in soft tissue sarcoma cell lines. Furthermore, it led to caspase 3/7 activity as well as caspase-3 and PARP cleavage, which are indicators of apoptosis. Therefore, this compound may be a promising lead candidate for the development of therapeutic agents against drug-resistant tumours.

Parasitol Res. 2012 Jun;110(6):2125-30.

Essential oil composition and larvicidal activity of Saussurea lappa roots against the mosquito Aedes albopictus (Diptera: Culicidae).[Pubmed: 22167373 ]

In recent years, uses of environment friendly and biodegradable natural insecticides of plant origin have received renewed attention as agents for vector control.
METHODS AND RESULTS:
The aim of this research was to determine larvicidal activity of the essential oil derived from roots of Saussurea lappa (Compositae) and the isolated constituents against the larvae of the Culicidae mosquito Aedes albopictus. Essential oil of S. lappa roots was obtained by hydrodistillation and analyzed by gas chromatography (GC) and GC-mass spectrometry (MS). A total of 39 components of the essential oil of S. lappa roots were identified. The essential oil has higher content of (79.80%) of sesquiterpenoids than monoterpenoids (13.25%). The principal compounds in S. lappa essential oil were Dehydrocostus lactone (46.75%), costunolide (9.26%), 8-cedren-13-ol (5.06%), and α-curcumene (4.33%). Based on bioactivity-directed fractionation, Dehydrocostus lactone and costunolide were isolated from S. lappa essential oil. Dehydrocostus lactone and costunolide exhibited strong larvicidal activity against A. albopictus with LC(50) values of 2.34 and 3.26 μg/ml, respectively, while the essential oil had an LC(50) value of 12.41 μg/ml.
CONCLUSIONS:
The result indicated that the essential oil of S. lappa and the two isolated constituents have potential for use in control of A. albopictus larvae and could be useful in search of newer, safer and more effective natural compounds as larvicides.

Int J Gynecol Cancer. 2015 May 25.

Dehydrocostus Lactone Inhibits Proliferation, Antiapoptosis, and Invasion of Cervical Cancer Cells Through PI3K/Akt Signaling Pathway.[Pubmed: 26017248]

Recent studies found that Dehydrocostus lactone (DHC), a traditional Chinese medicine in curing chronic ulcer and inflammation, can inhibit several type of tumor cells. The purpose of this study was to define the role of DHC on cervical cancer cells and to explore its mechanism of action.
METHODS AND RESULTS:
We used DHC alone or in combination with PI3K/Akt-specific inhibitor LY294002 (LY) to treat Hela cells [human papillomavirus (HPV)-18 positive] and C33a cells (HPV negative). The proliferation, apoptosis, and Akt activation were assessed. Cell invasive ability was assayed in transwell chambers. We found that DHC significantly inhibited proliferation, antiapoptosis, and invasion of both cells, and reduced the level of p-Akt phosphorylation in these cells, in a dose- or time-dependent manner. In addition, these inhibitions of DHC were significantly strengthened by LY.
CONCLUSIONS:
The result suggested that DHC plays a potent role in anticervical cancer in multiple biological aspects through PI3K/Akt signaling pathway, independently of HPV infection. This finding surely adds new knowledge to understand the role of DHC in fighting cancers.

Immunopharmacol Immunotoxicol. 2012 Oct;34(5):810-4.

The effects of dehydrocostus lactone on osteoblastic MC3T3-E1 cells in redox changes and PI3K/Akt/CREB.[Pubmed: 22324303]

Antimycin A (AMA) inhibits mitochondrial electron transport chain between cytochrome b and c.
METHODS AND RESULTS:
In the present study, we investigated the effects of Dehydrocostus lactone on osteoblastic MC3T3-E1 cells in the presence of AMA with a focus on redox changes and PI3K/Akt/CREB signaling. AMA increased nitrotyrosin level and decreased NADPH level, activities of thioredoxin reductase, phosphoinositide 3-kinase (PI3K), and Akt (protein kinase B [PKB]), and phosphorylated cAMP-response element-binding protein (CREB). Pretreatment with Dehydrocostus lactone prior to AMA exposure significantly prevented the loss of NADPH, production of nitrotyrosine, and thioredoxin reductase inactivation induced by AMA. Moreover, Dehydrocostus lactone increased activities of PI3K and Akt, and CREB phosphorylation inhibited by AMA.
CONCLUSIONS:
These results suggest that antioxidant activity and PI3K/Akt/CREB activation are related to the protective effect of Dehydrocostus lactone against osteoblast damage induced by AMA.

Eur J Pharmacol. 2007 Jun 22;565(1-3):37-44.

The alpha-methylene-gamma-butyrolactone moiety in dehydrocostus lactone is responsible for cytoprotective heme oxygenase-1 expression through activation of the nuclear factor E2-related factor 2 in HepG2 cells.[Pubmed: 17391667 ]

Inducible heme oxygenase (HO)-1 acts against oxidants that are thought to play a major role in the pathogenesis of several diseases. The alpha-methylene-gamma-butyrolactone (CH2-BL) structural unit, which characterizes a group of naturally occurring sesquiterpene lactones, is known to possess numerous biological activities. In the present study, we evaluated Dehydrocostus lactone possessing CH2-BL moiety, one of the bioactive constituents of the medicinal plant Saussurea lappa, as an inducer of cytoprotective HO-1.
METHODS AND RESULTS:
In HepG2 cells, treatment with Dehydrocostus lactone induced HO-1 expression and increased HO activity in a concentration-dependent manner. Similar results were also observed when the cells were incubated with CH2-BL, a parent structure of Dehydrocostus lactone. In contrast, mokko lactone, a reduced product of Dehydrocostus lactone, and alpha-methyl-gamma-butyrolactone (CH3-BL), a parent structure of mokko lactone, did not induce HO-1 expression. Pretreatment with either Dehydrocostus lactone or CH2-BL for 6 h protected the cells from hydrogen peroxide-mediated toxicity, whereas mokko lactone or CH3-BL failed to exert a cytoprotective action. Inhibition of HO-1 expression by HO-1 small interfering RNA (siRNA) abrogated cellular protection afforded by Dehydrocostus lactone or CH2-BL. In addition, Dehydrocostus lactone caused the nuclear accumulation of the nuclear factor E2-related factor 2 (Nrf2) and increased the promoter activity of antioxidant response element (ARE). Using Nrf2 siRNA, Nrf2 activation was confirmed to contribute to cytoprotective HO-1 expression by Dehydrocostus lactone or CH2-BL.
CONCLUSIONS:
Collectively, our findings suggest that CH2-BL moiety in Dehydrocostus lactone increases cellular resistance to oxidant injury in HepG2 cells, presumably through Nrf2/ARE-dependent HO-1 expression.