The Acyclic Retinoid Peretinoin Inhibits Hepatitis C Virus Replication and Infectious Virus Release in Vitro

Shimakami, Tetsuro; Honda, Masao; Shirasaki, Takayoshi; Takabatake, Riuta; Liu, Fanwei; Murai, Kazuhisa; Shiomoto, Takayuki; Funaki, Masaya; Yamane, Daisuke; Murakami, Seishi; Lemon, Stanley M.

doi:10.1038/srep04688

Cited by 13 publications

(15 citation statements)

References 42 publications

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“…Recently, a new target of ACR was elucidated in an in vitro study by using Huh-7.5 cells infected with HCV-RNA [76]. This study revealed that ACR inhibits HCV-RNA replication and infectious virus release by modulating several aspects of lipid metabolism, such as triglyceride abundance and the expression of mature sterol regulatory element-binding protein 1c (SREBP1c).…”

Section: Molecular Mechanism Of Acr In Chemoprevention Of Hepatocellumentioning

confidence: 99%

A Role for Acyclic Retinoid in the Chemoprevention of Hepatocellular Carcinoma: Therapeutic Strategy Targeting Phosphorylated Retinoid X Receptor-α

2014

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Hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis due to its high rate of recurrence after the initial curative treatment. Therefore, development of effective therapeutic strategies that can prevent recurrence and secondary tumor formation is required to improve the clinical outcomes of HCC patients. Malfunctioning of the retinoid X receptors (RXRs) of HCC patient by activation of the Ras-mitogen-activated protein kinase (MAPK) signaling pathway is strongly associated with hepatocarcinogenesis. Acyclic retinoid (ACR), a synthetic retinoid, prevents HCC recurrence by inhibiting Ras-MAPK activation and the subsequent RXRα phosphorylation, thereby improving patient prognosis. Here, we have reviewed the detailed effects of ACR on the prevention of HCC development, with particular references to the results of our previous basic and clinical research.

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Section: Molecular Mechanism Of Acr In Chemoprevention Of Hepatocellumentioning

confidence: 99%

A Role for Acyclic Retinoid in the Chemoprevention of Hepatocellular Carcinoma: Therapeutic Strategy Targeting Phosphorylated Retinoid X Receptor-α

2014

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“…Our group and others have observed that ACR may suppress cell growth or inhibit hepatitis C virus replication by altering energy production and lipid metabolism in hepatocellular carcinoma cell lines (18,19). However, in vitro study in malignant cells provides limited information to understand the mechanism of tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Metabolome Analyses Uncovered a Novel Inhibitory Effect of Acyclic Retinoid on Aberrant Lipogenesis in a Mouse Diethylnitrosamine-Induced Hepatic Tumorigenesis Model

Qin¹,

Tatsukawa

Hitomi

et al. 2016

Cancer Prevention Research

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Acyclic retinoid (ACR) is a promising drug under clinical trials for preventing recurrence of hepatocellular carcinoma. The objective of this study was to gain insights into molecular basis of the antitumorigenic action of ACR from a metabolic point of view. To achieve this, comprehensive cationic and lipophilic liver metabolic profiling was performed in mouse diethylnitrosamine (DEN)-induced hepatic tumorigenesis model using both capillary electrophoresis time-of-flight mass spectrometry and liquid chromatography time-of-flight mass spectrometry. ACR significantly counteracted against acceleration of lipogenesis but not glucose metabolism in DEN-treated mice liver, suggesting an important role of lipid metabolic reprogramming in the initiation step of hepatic tumorigenesis. Knowledge-based pathway analysis suggested that inhibition of linoleic acid metabolites such as arachidonic acid, a proinflammatory precursor, played a crucial role in the prevention by ACR of DEN-induced chronic inflammationmediated tumorigenesis of the liver. As a molecular mechanism of the ACR's effect to prevent the aberrant lipogenesis, microarray analysis identified that a key transcription regulator of both embryogenesis and tumorigenesis, COUP transcription factor 2, also known as NR2F2, was associated with the metabolic effect of ACR in human hepatocellular carcinoma cells. Our study provided potential therapeutic targets for the chemoprevention of hepatocellular carcinoma as well as new insights into the mechanisms underlying prevention of hepatic tumorigenesis.

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“…Retinoid acids have been implicated in clinical applications, both as a potential antitumor agent and for the treatment of skin diseases (15). In addition, there have been a number of studies suggest that the retinoic acid or its analogues exhibit antiviral activities against a variety of pathogens, including human immunodeficiency virus type 1 (HIV-1) (16,17), measles virus (18), human herpesvirus 8 (HHV-8) (19), hepatitis C virus (HCV) (20)(21)(22), and adenovirus (23). Particularly, acitretin has been used to treat patients with HIV who have psoriasis (17,24), and the drug is well tolerated.…”

Section: Discussionmentioning

confidence: 99%

Identification of Retinoic Acid Receptor Agonists as Potent Hepatitis B Virus Inhibitors via a Drug Repurposing Screen

Wang

Shen

et al. 2018

Antimicrob Agents Chemother

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Currently available therapies for chronic hepatitis B virus (HBV) infection can efficiently reduce viremia but induce hepatitis B surface antigen (HBsAg) loss in very few patients; also, these therapies do not greatly affect the viral covalently closed circular DNA (cccDNA). To discover new agents with complementary anti-HBV effects, we performed a drug repurposing screen of 1,018 Food and Drug Administration (FDA)-approved compounds using HBV-infected primary human hepatocytes (PHH). Several compounds belonging to the family of retinoic acid receptor (RAR) agonists were identified that reduced HBsAg levels in a dose-dependent manner without significant cytotoxicity. Among them, tazarotene exhibited the most potent anti-HBV effect, with a half-maximal inhibitory concentration (IC) for HBsAg of less than 30 nM in PHH. The inhibitory effect was also observed in HBV-infected differentiated HepaRG (dHepaRG) models, but not in HepG2.215 cells, and HBV genotypes A to D were similarly inhibited. Tazarotene was further demonstrated to repress HBV cccDNA transcription, as determined by the levels of HBV cccDNA and RNAs and the activation of HBV promoters. Moreover, RNA sequence analysis showed that tazarotene did not induce an interferon response but altered the expression of a number of genes associated with RAR and metabolic pathways. Inhibition of RARβ, but not RARα, by a specific antagonist significantly attenuated the anti-HBV activity of tazarotene, suggesting that tazarotene inhibits HBV in part through RARβ. Finally, a synergistic effect of tazarotene and entecavir on HBV DNA levels was observed. Therefore, RAR agonists as represented by tazarotene were identified as potential novel anti-HBV agents.

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The Acyclic Retinoid Peretinoin Inhibits Hepatitis C Virus Replication and Infectious Virus Release in Vitro

Cited by 13 publications

References 42 publications

A Role for Acyclic Retinoid in the Chemoprevention of Hepatocellular Carcinoma: Therapeutic Strategy Targeting Phosphorylated Retinoid X Receptor-α

A Role for Acyclic Retinoid in the Chemoprevention of Hepatocellular Carcinoma: Therapeutic Strategy Targeting Phosphorylated Retinoid X Receptor-α

Metabolome Analyses Uncovered a Novel Inhibitory Effect of Acyclic Retinoid on Aberrant Lipogenesis in a Mouse Diethylnitrosamine-Induced Hepatic Tumorigenesis Model

Identification of Retinoic Acid Receptor Agonists as Potent Hepatitis B Virus Inhibitors via a Drug Repurposing Screen

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