Chemical screening in zebrafish for novel biological and therapeutic discovery

Wiley, David M.; Redfield, Shelby E.; Zon, Leonard I.

doi:10.1016/bs.mcb.2016.10.004

Cited by 99 publications

(92 citation statements)

References 90 publications

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“…Despite higher animals have been for many year models of excellence used to evaluate drugs toxicity, the zebrafish presents itself as a reliable vertebrate model to determine, developmental toxicity, general toxicity and to perform an initial drug screening. Derived from its use, have been reported comparable results to the data obtained with higher models [14][15][16] . This manuscript surveys recent studies testing the cardiotoxicity of drugs used to treat pathologies in different animal models, identifying as early as feasibly possible potential safety liabilities of drugs selected for human evaluation [17] .…”

Section: Introductionsupporting

confidence: 71%

Zebrafish as Toxicological model for screening and recapitulate human diseases

Caballero¹,

Candiracci²

2018

JUMD

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Embryonic and larval Danio rerio (zebrafish) is increasingly used as a toxicological model to conduct rapid in vivo tests and developmental toxicity assays; the zebrafish features high genetic homology to mammals, robust, phenotypes, highthroughput genetic and chemical screening have made it a powerful tool to evaluate in vivo toxicity. New methodologies of genome editing as CRISPR/Cas9; ZFN and TALEN make it a suitable model to perform studies to pair human genetic diseases as well. This review surveys recent studies employing zebrafish as experimental model, comparing it with other in vivo and in vitro models, presenting zebrafish as a potent vertebrate tool to evaluate drug toxicity and efficacy in order to facilitate more extensive, easy and comprehensive knowledge of new generation drugs.

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Section: Introductionsupporting

confidence: 71%

Zebrafish as Toxicological model for screening and recapitulate human diseases

Caballero¹,

Candiracci²

2018

JUMD

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“…Zebrafish larvae are a powerful tool for small molecule screening in disease models(Wiley et al, 2017). Current therapeutic options for FLC patients are limited.…”

Section: Resultsmentioning

confidence: 99%

DNAJB1-PRKACA fusion induces liver inflammation in zebrafish model of Fibrolamellar Hepatocellular Carcinoma

Oliveira¹,

Houseright²,

Korte³

et al. 2019

Preprint

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Fibrolamellar Hepatocellular Carcinoma (FLC) is a rare liver cancer that primarily affects adolescents and young adults. Up to now there is only one identified molecular target responsible for driving the disease, the chimeric protein encoded by DNAJB1-PRKACA (J-PKAca). Immune cells have been identified as key players in liver cancer biology, however the effect of J-PKAca on inflammation in the liver microenvironment is not known. Here we report a new zebrafish model of FLC with non-invasive live imaging capabilities that allows the study of the interactions between immune cells and transformed hepatocytes. We found that overexpression of the dnajb1a-prkcaaa fusion gene specifically in hepatocytes induces early malignancy features in FLC transgenic larvae, such as increased liver and hepatocyte size. In addition, this aberrant form of PKA promotes a pro-inflammatory liver microenvironment by increasing the number of neutrophils and macrophages in the liver area and inducing macrophage polarization to a pro-inflammatory phenotype. Increased caspase-a activity was also found in the liver of FLC transgenic larvae. Importantly, pharmacological inhibition of TNFα secretion and caspase-a activity decreased liver size and inflammation. Overall, these findings suggest that inflammation may be an early feature of FLC involved in progression, and that targeting TNFαand caspase-1 may be beneficial in treating FLC.

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“…Meanwhile, the application of zebrafish model in the high-throughput screening of small molecules has also become a rapid and effective approach for the study of specific biological processes, especially in the research on highly conserved developmental regulation, disease genes and signal transduction pathways [14][15][16]. As such, we aimed to engineer a transgenic zebrafish model expressing drug efflux transporter P-gp promoter driven fluorescent reporter gene by using Tol2-meidated approach and investigate the potential regulatory mechanism.…”

Section: Introductionmentioning

confidence: 99%

An engineered Abcb4 expressing model reveals the central role of NF-κB in the regulation of drug resistance in zebrafish

Sun

et al. 2020

Preprint

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Multidrug resistance (MDR) represents the major cause of unsatisfaction in the application of chemotherapy for cancer treatment. So far, an in vivo robust high-throughput screening system for anti-tumor drug MDR is still lacking and the molecular mechanisms for MDR still remain elusive. Given a myriad of merits of zebrafish relative to other animal models, we aimed to establish MDR system in zebrafish stably expressing ATP-binding cassette (ATP-cassette) superfamily transporters and study the potential regulatory mechanism. We first constructed a Tg(abcb4:EGFP) transgenic zebrafish stably expressing both Abcb4 and EGFP using Tol2mediated approach. The expression level of Abcb4 and EGFP was significantly induced when Tg(abcb4:EGFP) transgenic zebrafish embryos were exposed to doxorubicin (DOX) or vincristine (VCR), accompany with a marked decrease in rhodamine B (RhB) accumulation in embryos, which indicates a remarkable increase in drug efflux upon the exposure to DOX or VCR. Mechanistically, AKT and ERK signaling were activated when treated with DOX or VCR.With the application of AKT and ERK inhibitors, the drug resistance phenomena could be reversed with differential responsive effects. Of note, downstream NF-κB played a central role in the regulation of Abcb4-mediated drug resistance. Taken together, the engineered Tg(abcb4:EGFP) transgenic zebrafish model provides a new platform for drug resistance screening in vivo, which could facilitate and accelerate the process of drug development.

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Chemical screening in zebrafish for novel biological and therapeutic discovery

Cited by 99 publications

References 90 publications

Zebrafish as Toxicological model for screening and recapitulate human diseases

Zebrafish as Toxicological model for screening and recapitulate human diseases

DNAJB1-PRKACA fusion induces liver inflammation in zebrafish model of Fibrolamellar Hepatocellular Carcinoma

An engineered Abcb4 expressing model reveals the central role of NF-κB in the regulation of drug resistance in zebrafish

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