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Tytuł:
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Combination of curcumin with N-n-butyl haloperidol iodide inhibits hepatocellular carcinoma malignant proliferation by downregulating enhancer of zeste homolog 2 (EZH2) - lncRNA H19 to silence Wnt/β-catenin signaling.
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Autorzy:
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Khan H; Department of Pharmacology, Shantou University Medical College, No. 22 Xinling Road, Shantou 515041, Guangdong, China.
Ni Z; Department of Pharmacology, Shantou University Medical College, No. 22 Xinling Road, Shantou 515041, Guangdong, China.
Feng H; Shanghai Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Xing Y; Department of Pharmacology, Shantou University Medical College, No. 22 Xinling Road, Shantou 515041, Guangdong, China.
Wu X; Department of Pharmacology, Shantou University Medical College, No. 22 Xinling Road, Shantou 515041, Guangdong, China.
Huang D; Department of Pharmacology, Shantou University Medical College, No. 22 Xinling Road, Shantou 515041, Guangdong, China.
Chen L; Department of Pharmacology, Shantou University Medical College, No. 22 Xinling Road, Shantou 515041, Guangdong, China.
Niu Y; Department of Pharmacology, Shantou University Medical College, No. 22 Xinling Road, Shantou 515041, Guangdong, China. Electronic address: .
Shi G; Department of Pharmacology, Shantou University Medical College, No. 22 Xinling Road, Shantou 515041, Guangdong, China. Electronic address: .
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Źródło:
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Phytomedicine : international journal of phytotherapy and phytopharmacology [Phytomedicine] 2021 Oct; Vol. 91, pp. 153706. Date of Electronic Publication: 2021 Aug 14.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: Stuttgart : Urban & Fischer Verlag
Original Publication: Stuttgart ; New York : G. Fischer, c1994-
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MeSH Terms:
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Carcinoma, Hepatocellular*/drug therapy
Carcinoma, Hepatocellular*/genetics
Curcumin*/pharmacology
Liver Neoplasms*/drug therapy
Liver Neoplasms*/genetics
RNA, Long Noncoding*/genetics
Haloperidol/*analogs & derivatives
Wnt Signaling Pathway/*drug effects
Animals ; Cell Line, Tumor ; Cell Proliferation ; Enhancer of Zeste Homolog 2 Protein/genetics ; Enhancer of Zeste Homolog 2 Protein/metabolism ; Gene Expression Regulation, Neoplastic ; Haloperidol/pharmacology ; Humans ; Mice, Nude ; Xenograft Model Antitumor Assays ; Mice
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Contributed Indexing:
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Keywords: H19; N-n-butyl haloperidol iodide; curcumin; enhancer of zeste homolog 2; hepatocellular carcinoma; β-catenin
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Substance Nomenclature:
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0 (N-n-butyl haloperidol iodide)
0 (RNA, Long Noncoding)
EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein)
IT942ZTH98 (Curcumin)
J6292F8L3D (Haloperidol)
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Entry Date(s):
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Date Created: 20210913 Date Completed: 20211006 Latest Revision: 20240226
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Update Code:
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20240226
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DOI:
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10.1016/j.phymed.2021.153706
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PMID:
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34517264
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Background: Hepatocellular carcinoma (HCC) is one of the most common cause of cancer-related death worldwide. Curcumin (C) has been extensively investigated in different types of malignancies, including hepatocellular carcinoma, but its physicochemical properties have significantly influenced its clinical use. Several approaches are being explored to enhance curcumin's therapeutic response, including its combination with various drugs.
Purpose: This study aimed to evaluate the anti-tumor effect of curcumin (C) in combination with F2 (N-n-butyl haloperidol iodide) on hepatocellular carcinoma and its potential underlying mechanism in vitro and in vivo.
Methods: Cell proliferation was evaluated by CCK-8 and colony formation assays, and apoptosis was measured by flow cytometry. The migratory and invasive abilities of Hep3B and SMMC-7721 cells were measured by wound-healing and matrigel transwell assays. In order to investigate the molecular pathways, various experiments such as western blotting, qPCR, RNA-seq, immunostaining and transfection were performed. To evaluate the anti-HCC effects in vivo, a xenograft tumor model was used.
Results: Our findings showed that the combination of curcumin (C) & F2 (F2C) strongly inhibited malignant proliferation and migration in SMMC-7721 and Hep3B cells. The F2C treatment downregulates enhancer of zeste homolog 2 (EZH2) transcription and protein expression, which is key epigenetic regulator responsible for HCC development. Moreover, the inhibition of EZH2 by F2C led to Wnt/β-catenin signaling inhibition by decreasing tri-methylation of histone H3 at lysine 27 (H3K27me3) and long non-coding RNA H19 expression. The inhibition of F2C was associated with the suppression of tumorigenicity in xenograft HCC models.
Conclusion: These findings suggested that, F2C inhibited HCC formation, migration and its modulatory mechanism seemed to be associated with downregulation of EZH2, silencing Wnt/β-catenin signaling by interacting with H19, suggesting that F2C may be a promising drug in the clinical treatment of HCC.
(Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
