Hydroxygenkwanin Inhibits Class I HDAC Expression and Synergistically Enhances the Antitumor Activity of Sorafenib in Liver Cancer Cells

Chen, Chi-Yuan; Chuang, Wen-Yu; Leu, Yann‐Lii; Ueng, Shir-Hwa; Hsueh, Chuen; Yeh, Chih-Ting; Wang, Tong Hong

doi:10.3389/fonc.2020.00216

Cited by 13 publications

(18 citation statements)

References 71 publications

(70 reference statements)

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“…Qualitative and quantitative UPLC-ESI-MS/MS analyses show that 352 metabolites including 11 terpenoids, 35 alkaloids, 80 phenolic acids, 25 coumarins, 7 lignans, 184 flavonoids and 10 other compounds were detected and identified, among which 15 metabolites are unique to DHP and 16 metabolites are unique to BZH. Among these unique compounds, phlorizin was studied as a potential pharmaceutical treatment for type 2 diabetes [33]; Hydroxygenkwanin has antitussive, expectorant and antiasthmatic effects [34]; Cosmosiin has anti-tumor, antiinflammatory and anti-virus effects [35]; Avicularin has antihypertensive, antitussive and expectorant effects [36]. Those active ingredients could all be used as potential biomarkers for identifying the two cultivars.…”

Section: Plos Onementioning

confidence: 99%

Characterization of two closely related citrus cultivars using UPLC-ESI-MS/MS-based widely targeted metabolomics

Wang

Chen

et al. 2021

PLoS ONE

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Citrus cultivars are widely spread worldwide, and some of them only differ by specific mutations along the genome. It is difficult to distinguish them by traditional morphological identification. To accurately identify such similar cultivars, the subtle differences between them must be detected. In this study, UPLC-ESI-MS/MS-based widely targeted metabolomics analysis was conducted to study the chemical differences between two closely related citrus cultivars, Citrus reticulata ‘DHP’ and C. reticulata ‘BZH’. Totally 352 metabolites including 11 terpenoids, 35 alkaloids, 80 phenolic acids, 25 coumarins, 7 lignans, 184 flavonoids and 10 other compounds were detected and identified; Among them, 15 metabolites are unique to DHP and 16 metabolites are unique to BZH. Hierarchical cluster analysis (HCA), principal component analysis (PCA), and orthogonal signal correction and partial least squares-discriminant analysis (OPLS-DA) can be used to clearly discriminate between DHP and BZH. 93 metabolites including 36 down-regulated and 57 up-regulated are significantly different in DHP and BZH. They are mainly involved in the biosynthesis of flavonoids, flavones, flavonols, and isoflavonoids. In addition, the relative content levels of flavonoids, alkaloids, and terpenoids are much higher in the peel of DHP than that of BZH, the presence of which may correlate with the quality difference of the peels. The results reported herein indicate that metabolite analysis based on UPLC-ESI-MS/MS is an effective means of identifying cultivars with different genotypes, especially those that cannot be distinguished based on traditional identification methods.

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Section: Plos Onementioning

confidence: 99%

Characterization of two closely related citrus cultivars using UPLC-ESI-MS/MS-based widely targeted metabolomics

Wang

Chen

et al. 2021

PLoS ONE

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“…Moreover, previous studies suggest that the p53 protein can regulate the expression of RAD51 by binding to the p53 response element on the RAD51 promoter and inhibiting the transcription of the RAD51 gene [ 55 ]. Our previous study has shown that HGK can improve the binding ability of p53 to the target gene promoter by stimulating the acetylation of p53 [ 46 ]. Therefore, we hypothesized that the acetylation of p53 due to HGK can promote the binding of p53 to the RAD51 promoter, thereby negatively regulating the expression of RAD51.…”

Section: Discussionmentioning

confidence: 99%

“…Hydroxygenkwanin (HGK) is a flavonoid extracted from Daphne genkwa , which not only has anti-inflammatory properties, but also induces mitochondrial damage and DNA breaks in glioma cells, leading to cell cycle arrest and apoptosis [ 44 , 45 ]. In addition, our previous research has shown that by inhibiting the expression of the transcription factor, FOXM1, and Class I histone deacetylase (HDAC), HGK can inhibit the growth, migration, and invasion of liver cancer cells, thereby promoting cellular apoptosis [ 46 , 47 ]. In this study, we aimed to identify a natural compound that could inhibit DDR, using a single-strand annealing (SSA) yeast-cell analysis system.…”

Section: Introductionmentioning

confidence: 99%

Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models

Chen

Cheng

Shieh

et al. 2021

IJMS

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Molecules involved in DNA damage response (DDR) are often overexpressed in cancer cells, resulting in poor responses to chemotherapy and radiotherapy. Although treatment efficacy can be improved with the concomitant use of DNA repair inhibitors, the accompanying side effects can compromise the quality of life of patients. Therefore, in this study, we identified a natural compound that could inhibit DDR, using the single-strand annealing yeast-cell analysis system, and explored its mechanisms of action and potential as a chemotherapy adjuvant in hepatocellular carcinoma (HCC) cell lines using comet assay, flow cytometry, Western blotting, immunofluorescence staining, and functional analyses. We developed a mouse model to verify the in vitro findings. We found that hydroxygenkwanin (HGK) inhibited the expression of RAD51 and progression of homologous recombination, thereby suppressing the ability of the HCC cell lines to repair DNA damage and enhancing their sensitivity to doxorubicin. HGK inhibited the phosphorylation of DNA damage checkpoint proteins, leading to apoptosis in the HCC cell lines. In the mouse xenograft model, HGK enhanced the sensitivity of liver cancer cells to doxorubicin without any physiological toxicity. Thus, HGK can inhibit DDR in liver cancer cells and mouse models, making it suitable for use as a chemotherapy adjuvant.

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“…Viability was assayed by staining with trypan blue and/or MTT, as described previously [ 19 ]. Combination index (CI) values were calculated to define the synergistic or additive effects of treatment as previously described [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

Growth Suppression in Lung Cancer Cells Harboring EGFR-C797S Mutation by Quercetin

et al. 2021

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are approved treatments for non-small-cell lung cancer (NSCLC) patients harboring activating EGFR mutations. The EGFR C797S mutation is one of the known acquired-resistance mutations to the latest third-generation TKIs. At present, there are no clear options for treating patients who acquire resistance to third-generation TKIs. The acquisition of the EGFR C797S mutation was shown to upregulate the expression of AXL, a receptor tyrosine kinase of the TAM (TYRO3-AXL-MER) family, and the suppression of AXL is effective in reducing the growth of NSCLC cells harboring EGFR C797S. As quercetin was recently shown to inhibit AXL, quercetin may be effective in treating NSCLC cells harboring the EGFR C797S mutation. In this work, the cytotoxic effects of quercetin and its ability to inhibit tumor growth were examined in TKI-resistant NSCLC cells harboring the EGFR C797S mutation. We demonstrated that quercetin exhibited potent cytotoxic effects on NSCLC cells harboring the EGFR C797S mutation by inhibiting AXL and inducing apoptosis. Quercetin inhibited the tumor growth of xenografted NSCLC cells harboring the EGFR C797S mutation and appeared to act synergistically with brigatinib to inhibit of tumor growth in vivo. In summary, herein, we revealed that quercetin is an effective inhibitor for the treatment of non-small-cell lung cancer harboring the EGFR C797S mutation.

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Hydroxygenkwanin Inhibits Class I HDAC Expression and Synergistically Enhances the Antitumor Activity of Sorafenib in Liver Cancer Cells

Cited by 13 publications

References 71 publications

Characterization of two closely related citrus cultivars using UPLC-ESI-MS/MS-based widely targeted metabolomics

Characterization of two closely related citrus cultivars using UPLC-ESI-MS/MS-based widely targeted metabolomics

Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models

Growth Suppression in Lung Cancer Cells Harboring EGFR-C797S Mutation by Quercetin

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