Esculetin suppresses tumor growth and metastasis by targeting Axin2/E-cadherin axis in colorectal cancer

Kim, Won Kyung; Byun, Woong Sub; Chung, Hwa‐Jin; Oh, Jedo; Park, Hyen Joo; Choi, Jae Sue; Lee, Sang Kook

doi:10.1016/j.bcp.2018.03.009

Cited by 55 publications

(51 citation statements)

References 37 publications

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“…As an essential class of natural chemicals, coumarins were reported to exhibit immense anticancer potential with minimum side effects. Esculetin, a coumarin derivative, is recognized to exhibit anti-proliferative and pro-apoptotic effects on multiple tumor types including human colorectal carcinoma, gastric carcinoma, pancreatic cancer, and prostate cancer (Arora et al 2016;Wang et al 2017;Kim et al 2018). Results from mechanistic studies also suggested that esculetin exerts its antitumor effects through the involvement of a large number of cellular pathways, including Wnt/β-catenin, Axin2/ Fig.…”

Section: Discussionmentioning

confidence: 99%

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Fraxetin Suppresses Proliferation of Non-Small-Cell Lung Cancer Cells via Preventing Activation of Signal Transducer and Activator of Transcription 3

Zhang

Wang

Deng

et al. 2019

Tohoku J. Exp. Med.

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Lung cancer represents the leading cause of cancer-associated mortality, and non-small-cell lung cancer (NSCLC) is the most frequent histologic sub-type. It is therefore urgent to develop novel agents for the treatment of NSCLC. Fraxetin (FXT) is a potent plant-derived product and has been recognized as a promising anticancer agent for breast cancer and osteosarcoma. However, the anti-cancer potential of FXT for NSCLC remains to be elucidated. Accordingly, in the present study, we evaluated the inhibitory effect of FXT on the proliferation and growth of NSCLC cells using six human NSCLC cell lines: A549, H460, HCC827, H1650, PC-9 and H1975. FXT exhibited significant inhibitory effects on the proliferation of these cancer cell lines. By contrast, no inhibitory effect was observed on the viability of non-cancer lung cell lines even at the highest concentration of FXT (100 μM). Among the NSCLC cell lines, HCC827 and H1650 cells showed the most sensitive to FXT. Accordingly, HCC827 and H1650 cells were used for the subsequent experiments. Flow cytometric analysis revealed that FXT caused a significant cell cycle arrest and pro-apoptotic effects. Mechanistically, FXT suppressed the IL-6-induced phosphorylation of tyrosine residue (Tyr705) of signal transducer and activator of transcription 3 (STAT3) probably by binding to STAT3. Molecular docking and molecular dynamic simulations studies indicated that FXT interacts with STAT3 through hydrogen bond and hydrophobic interaction. In conclusion, these findings suggest that FXT could be a promising lead compound to be used as a novel STAT3 inhibitor and potential antitumor agent for the treatment of NSCLC.

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Section: Discussionmentioning

confidence: 99%

“…Kd, dissociation constant; Ka, association constant; KD, equilibrium dissociation constant. E-cadherin, and IGF-1/PI3K/Akt signaling cascades (Lee et al 2013;Wang et al 2017;Kim et al 2018). Moreover, osthole, another well-known coumarin-derivative, exerts significant tumor-suppressing activities.…”

Section: Discussionmentioning

confidence: 99%

Fraxetin Suppresses Proliferation of Non-Small-Cell Lung Cancer Cells via Preventing Activation of Signal Transducer and Activator of Transcription 3

Zhang

Wang

Deng

et al. 2019

Tohoku J. Exp. Med.

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“…After 24 h of incubation, the cells that had invaded the outer surface of the lower chambers were fixed and stained using a Diff-Quik Staining Kit (Sysmex, Kobe, Japan) and imaged. Representative images from 3 separate experiments are shown, and the number of invaded cells was counted in 5 randomly selected microscopic fields (200 × magnification) (Kim et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

Coculture of Marine Streptomyces sp. With Bacillus sp. Produces a New Piperazic Acid-Bearing Cyclic Peptide

et al. 2018

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Microbial culture conditions in the laboratory, which conventionally involve the cultivation of one strain in one culture vessel, are vastly different from natural microbial environments. Even though perfectly mimicking natural microbial interactions is virtually impossible, the cocultivation of multiple microbial strains is a reasonable strategy to induce the production of secondary metabolites, which enables the discovery of new bioactive natural products. Our coculture of marine Streptomyces and Bacillus strains isolated together from an intertidal mudflat led to discover a new metabolite, dentigerumycin E (1). Dentigerumycin E was determined to be a new cyclic hexapeptide incorporating three piperazic acids, N-OH-Thr, N-OH-Gly, β-OH-Leu, and a pyran-bearing polyketide acyl chain mainly by analysis of its NMR and MS spectroscopic data. The putative PKS-NRPS biosynthetic gene cluster for dentigerumycin E was found in the Streptomyces strain, providing clear evidence that this cyclic peptide is produced by the Streptomyces strain. The absolute configuration of dentigerumycin E was established based on the advanced Marfey's method, ROESY NMR correlations, and analysis of the amino acid sequence of the ketoreductase domain in the biosynthetic gene cluster. In biological evaluation of dentigerumycin E (1) and its chemical derivatives [2-N,16-N-deoxydenteigerumycin E (2) and dentigerumycin methyl ester (3)], only dentigerumycin E exhibited antiproliferative and antimetastatic activities against human cancer cells, indicating that N-OH and carboxylic acid functional groups are essential for the biological activity.

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“…Esculetin, 6, 7-dihydroxycoumarin, is an active ingredient originally isolated from the bark of some natural plants, including Fraxinus rhynchophylla Hance, Fraxinus chinensis Roxb, and Fraxinus aboana Lingelsh ( 14 , 15 ). It has been shown that esculetin has some biological and pharmacological activities, including anti-oxidative ( 16 , 17 ), anti-inflammatory ( 18 ), anti-viral ( 19 ), anti-asthmatic ( 20 ), and anti-tumor effects ( 21 , 22 ). As an anti-inflammatory drug, esculetin can exert therapeutic effects on several inflammatory diseases, such as hepatic fibrosis ( 23 ), arthritis ( 24 ), and atopic dermatitis ( 25 ).…”

Section: Introductionmentioning

confidence: 99%

Esculetin Ameliorates Psoriasis-Like Skin Disease in Mice by Inducing CD4+Foxp3+ Regulatory T Cells

et al. 2018

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Psoriasis is an autoimmune and inflammatory skin disease affecting around 2–3% of the world's population. Patients with psoriasis need extensive treatments with global immunosuppressive agents that may cause severe side effects. Esculetin, a type of coumarins, is an active ingredient extracted mainly from the bark of Fraxinus rhynchophylla, which has been used to treat inflammatory and autoimmune diseases in China. However, the antipsoriatic effects of esculetin have not been reported. In this study, we aimed to investigate the effects of esculetin on psoriatic skin inflammation in a mouse model and explored the potential molecular mechanisms underlying its action. We found that esculetin ameliorated the skin lesion and reduced PASI scores as well as weight loss in imiquimod-induced psoriasis-like mice, accompanied with weakened proliferation and differentiation of keratinocytes and T cell infiltration in esculetin-treated psoriatic mice. In addition, esculetin reduced the frequency of CD8+CD44highCD62Llow effector T cells in psoriatic mice. In contrast, it increased the frequency of CD4+Foxp3+ Tregs in both lymph nodes and spleens of the psoriatic mice while promoting the differentiation of CD4+CD25− T cells into CD4+Foxp3+ Tregs in vitro. Interestingly, depleting CD4+Foxp3+ Tregs largely reversed esculetin-mediated reduction in PASI scores, indicating that esculetin attenuates murine psoriasis mainly by inducing CD4+Foxp3+ Tregs. Furthermore, the mRNA levels of proinflammatory cytokines in the psoriatic mouse skin, including IL-6, IL-17A, IL-22, IL-23, TNF-α, and IFN-γ, were dramatically decreased by the treatment with esculetin. Finally, we found that esculetin inhibited the phosphorylation of IKKα and P65 in the psoriatic skin, suggesting that it inhibits the activation of NF-κB signaling. Thus, we have demonstrated that esculetin attenuates psoriasis-like skin lesion in mice and may be a potential therapeutic candidate for the treatment of psoriasis in clinic.

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Esculetin suppresses tumor growth and metastasis by targeting Axin2/E-cadherin axis in colorectal cancer

Cited by 55 publications

References 37 publications

Fraxetin Suppresses Proliferation of Non-Small-Cell Lung Cancer Cells via Preventing Activation of Signal Transducer and Activator of Transcription 3

Fraxetin Suppresses Proliferation of Non-Small-Cell Lung Cancer Cells via Preventing Activation of Signal Transducer and Activator of Transcription 3

Coculture of Marine Streptomyces sp. With Bacillus sp. Produces a New Piperazic Acid-Bearing Cyclic Peptide

Esculetin Ameliorates Psoriasis-Like Skin Disease in Mice by Inducing CD4+Foxp3+ Regulatory T Cells

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