Blockade of TNF-α-induced NF-κB signaling pathway and anti-cancer therapeutic response of dihydrotanshinone I

Wang, Fei; Ma, Juan; Wang, Ke Si; Mi, Chunliu; Lee, Jun Young; Jin, Xuejun

doi:10.1016/j.intimp.2015.08.003

Cited by 38 publications

(32 citation statements)

References 34 publications

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“…Cells (5×10 4 /well) were seeded in the 24-well plates, and then co-transfected with the promoter reporter constructs encoding NF-κB-TATA-Luc (0.5 μg/well) and pEFRenilla-Luc (10 ng/well) as previously described 12, 23. Twenty-four hours after transfection, the cells were exposed to serum-free medium with or without niclosamide for 16 h, followed by treatment with TNFα (20 ng/mL) for 8 h. The cells were harvested for luciferase activity using the dual-luciferase assay kits 12.…”

Section: Methodsmentioning

confidence: 99%

The antihelminthic drug niclosamide effectively inhibits the malignant phenotypes of uveal melanoma in vitro and in vivo

Zhou

Jin

et al. 2017

Theranostics

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Uveal melanoma (UM) is a lethal intraocular malignancy with an average survival of only 2~8 months in patients with hepatic metastasis. Currently, there is no effective therapy for metastatic UM. Here, we reported that niclosamide, an effective repellence of tapeworm that has been approved for use in patients for approximately 50 years, exhibited strong antitumor activity in UM cells in vitro and in vivo. We showed that niclosamide potently inhibited UM cell proliferation, induced apoptosis and reduced migration and invasion. p-Niclosamide, a water-soluble niclosamide, exerted potent in vivo antitumor activity in a UM xenograft mouse model. Mechanistically, niclosamide abrogated the activation of the NF-κB pathway induced by tumor necrosis factor α (TNFα) in UM cells, while niclosamide elevated the levels of intracellullar and mitochondrial reactive oxygen species (ROS) in UM cells. Quenching ROS by N-acetylcysteine (NAC) weakened the ability of niclosamide-mediated apoptosis. Matrix metalloproteinase 9 (MMP-9) knockdown by shRNA potentiated, while ectopic expression of MMP-9 rescued, the niclosamide-attenuated invasion, implying that MMP-9 is pivotal for invasion blockage by niclosamide in UM cells. Furthermore, our results showed that niclosamide eliminated cancer stem-like cells (CSCs) as reflected by a decrease in the Aldefluor+ percentage and serial re-plating melanosphere formation, and these phenotypes were associated with the suppressed Wnt/β-catenin pathway by niclosamide in UM. Niclosamide caused a dose- and time-dependent reduction of β-catenin and the key components [e.g., DVLs, phospho-GSK3β (S9), c-Myc and Cyclin D1] in the canonical Wnt/β-catenin pathway. Additionally, niclosamide treatment in UM cells reduced ATP and cAMP contents, and decreased PKA-dependent phosphorylation of β-catenin at S552 and S675 which determine the stability of β-catenin protein, suggesting that niclosamide may work as a mitochondrial un-coupler. Taken together, our results shed light on the mechanism of antitumor action of niclosamide and warrant clinical trial for treatment of UM patients.

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Section: Methodsmentioning

confidence: 99%

The antihelminthic drug niclosamide effectively inhibits the malignant phenotypes of uveal melanoma in vitro and in vivo

Zhou

Jin

et al. 2017

Theranostics

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“…[7][8][9][10] The tanshinones consist of four major constituents, such as tanshinone Ⅰ (Tan-Ⅰ), tanshinone IIA, crytotanshinone and dihydrotanshinone Ⅰ, and their biological effects have been a prime research focus. [11][12][13][14] The major constituents of Dan-shen have been recently shown to possess some activities against human cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Tanshinone I attenuates the malignant biological properties of ovarian cancer by inducing apoptosis and autophagy via the inactivation of PI3K/AKT/mTOR pathway

et al. 2019

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Objectives Tanshinone I (Tan‐I) is one of the vital fatsoluble monomer components, which extracted from Chinese medicinal herb Salvia miltiorrhiza Bunge. It has been shown that Tan‐I exhibited anti‐tumour activities on different types of cancers. However, the underlying mechanisms by which Tan‐Ⅰ regulates apoptosis and autophagy in ovarian cancer remain unclear. Thus, this study aimed to access the therapy effect of Tan‐Ⅰ and the underlying mechanisms. Methods Ovarian cancer cells A2780 and ID‐8 were treated with different concentrations of Tan‐Ⅰ (0, 1.2, 2.4, 4.8 and 9.6 μg/mL) for 24 hours. The cell proliferation was analysed by CCK8 assay, EdU staining and clone formation assay. Apoptosis was assessed by the TUNEL assay and flow cytometry. The protein levels of apoptosis protein (Caspase‐3), autophagy protein (Beclin1, ATG7, p62 and LC3II/LC3I) and PI3K/AKT/mTOR pathway were determined by Western blot. Autophagic vacuoles in cells were observed with LC3 dyeing using confocal fluorescent microscopy. Anti‐tumour activity of Tan‐Ⅰ was accessed by subcutaneous xeno‐transplanted tumour model of human ovarian cancer in nude mice. The Ki67, Caspase‐3 level and apoptosis level were analysed by immunohistochemistry and TUNEL staining. Results Tan‐Ⅰ inhibited the proliferation of ovarian cancer cells A2780 and ID‐8 in a dose‐dependent manner, based on CCK8 assay, EdU staining and clone formation assay. In additional, Tan‐Ⅰ induced cancer cell apoptosis and autophagy in a dose‐dependent manner in ovarian cancer cells by TUNEL assay, flow cytometry and Western blot. Tan‐Ⅰ significantly inhibited tumour growth by inducing cell apoptosis and autophagy. Mechanistically, Tan‐Ⅰ activated apoptosis‐associated protein Caspase‐3 cleavage to promote cell apoptosis and inhibited PI3K/AKT/mTOR pathway to induce autophagy. Conclusions This is the first evidence that Tan‐Ⅰ induced apoptosis and promoted autophagy via the inactivation of PI3K/AKT/mTOR pathway on ovarian cancer and further inhibited tumour growth, which might be considered as effective strategy.

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“…DHT (Supplementary Figure S2), a tanshinone isolated from Danshen, is structurally similar to that of tanshinone IIA and cryptotanshinone. For a long time, investigation to its bioactivities was mainly focused on its cytotoxicity to a variety of tumor cells (Liu et al, 2015; Wang et al, 2015). Although increasing evidence suggested that DHT has beneficial potentials for the treatment of cardiovascular diseases (Zhang et al, 2009; Liu et al, 2010), its anti-atherosclerotic effect, either in vivo or in vitro , has not been fully established.…”

Section: Introductionmentioning

confidence: 99%

Dihydrotanshinone I Attenuates Atherosclerosis in ApoE-Deficient Mice: Role of NOX4/NF-κB Mediated Lectin-Like Oxidized LDL Receptor-1 (LOX-1) of the Endothelium

Zhao

Gao

et al. 2016

Front. Pharmacol.

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Dihydrotanshinone I (DHT) is a natural compound extracted from Salvia miltiorrhiza Bunge which has been widely used for treating cardiovascular diseases. However, its role in atherosclerosis remains unclear. In this study, the effect of DHT on atherosclerosis were investigated using apolipoprotein E-deficient (ApoE-/-) mice and endothelial cells. In lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), DHT (10 nM) decreased lectin-like ox-LDL receptor-1 (LOX-1) and NADPH oxidase 4 (NOX4) expression, reactive oxygen species (ROS) production, NF-κB nuclear translocation, ox-LDL endocytosis and monocytes adhesion. Silence NOX4 inhibited LPS-induced LOX-1 expression, NF-κB nuclear translocation, ox-LDL endocytosis and monocytes adhesion. In ApoE-/- mice fed with an atherogenic diet, DHT (10 and 25 mg kg-1) significantly attenuated atherosclerotic plaque formation, altered serum lipid profile, decreased oxidative stress and shrunk necrotic core areas. The enhanced expression of LOX-1, NOX4, and NF-κB in aorta was also dramatically inhibited by DHT. In conclusion, these results suggested that DHT showed anti-atherosclerotic activity through inhibition of LOX-1 mediated by NOX4/NF-κB signaling pathways both in vitro and in vivo. This finding suggested that DHT might be used as a potential vascular protective candidate for the treatment of atherosclerosis.

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Blockade of TNF-α-induced NF-κB signaling pathway and anti-cancer therapeutic response of dihydrotanshinone I

Cited by 38 publications

References 34 publications

The antihelminthic drug niclosamide effectively inhibits the malignant phenotypes of uveal melanoma in vitro and in vivo

The antihelminthic drug niclosamide effectively inhibits the malignant phenotypes of uveal melanoma in vitro and in vivo

Tanshinone I attenuates the malignant biological properties of ovarian cancer by inducing apoptosis and autophagy via the inactivation of PI3K/AKT/mTOR pathway

Dihydrotanshinone I Attenuates Atherosclerosis in ApoE-Deficient Mice: Role of NOX4/NF-κB Mediated Lectin-Like Oxidized LDL Receptor-1 (LOX-1) of the Endothelium

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