Identify a Blood-Brain Barrier Penetrating Drug-TNB using Zebrafish Orthotopic Glioblastoma Xenograft Model

Zeng, Anqi; Ye, Tinghong; Cao, Dan; Huang, Xi; Yu, Yang; Chen, Xiuli; Xie, Yongmei; Yao, Su; Zhao, Chengjian

doi:10.1038/s41598-017-14766-2

Cited by 39 publications

(43 citation statements)

References 43 publications

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“…Another group reports the presence of tight junctions in the BBB as the brain endothelial cells show immunoreactivity to Claudin-5 and Zona Occludens-1 190 . Recently a group of researchers suggested an orthotopic glioblastoma model of zebrafish, which could be used as an efficient assay system for visualising the BBB penetrating efficiency of anti-GBM drugs 191 . Given the feasibility of high-throughput screening and the advantage of similarity with mammals, it is reasonable to say that zebrafish offers an excellent opportunity for screening neurospecific compounds.…”

Section: Neurospecific Drug Discovery Using Zebrafish Modelmentioning

confidence: 99%

Zebrafish: an emerging real-time model system to study Alzheimer’s disease and neurospecific drug discovery

2018

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Zebrafish (Danio rerio) is emerging as an increasingly successful model for translational research on human neurological disorders. In this review, we appraise the high degree of neurological and behavioural resemblance of zebrafish with humans. It is highly validated as a powerful vertebrate model for investigating human neurodegenerative diseases. The neuroanatomic and neurochemical pathways of zebrafish brain exhibit a profound resemblance with the human brain. Physiological, emotional and social behavioural pattern similarities between them have also been well established. Interestingly, zebrafish models have been used successfully to simulate the pathology of Alzheimer’s disease (AD) as well as Tauopathy. Their relatively simple nervous system and the optical transparency of the embryos permit real-time neurological imaging. Here, we further elaborate on the use of recent real-time imaging techniques to obtain vital insights into the neurodegeneration that occurs in AD. Zebrafish is adeptly suitable for Ca2+ imaging, which provides a better understanding of neuronal activity and axonal dystrophy in a non-invasive manner. Three-dimensional imaging in zebrafish is a rapidly evolving technique, which allows the visualisation of the whole organism for an elaborate in vivo functional and neurophysiological analysis in disease condition. Suitability to high-throughput screening and similarity with humans makes zebrafish an excellent model for screening neurospecific compounds. Thus, the zebrafish model can be pivotal in bridging the gap from the bench to the bedside. This fish is becoming an increasingly successful model to understand AD with further scope for investigation in neurodevelopment and neurodegeneration, which promises exciting research opportunities in the future.

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Section: Neurospecific Drug Discovery Using Zebrafish Modelmentioning

confidence: 99%

Zebrafish: an emerging real-time model system to study Alzheimer’s disease and neurospecific drug discovery

2018

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“…Transplantation-based methods address some of these issues: tumors can be dissected from a transgenic tumor-bearing animal or from patient-derived xenografts (PDXs), and then serially transplanted into recipient animals such as the casper recipient strain to allow detailed in vivo imaging ( Fior et al, 2017 ; Heilmann et al, 2015 ; Hoffman, 2015 ; Siolas and Hannon, 2013 ; Tang et al, 2016 ; White et al, 2008 ; Zeng et al, 2017 ). Alternatively, stable cell lines can be generated from a transgenic animal, such as the ZMEL1 melanoma line, which can similarly be used for transplantation studies ( Heilmann et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Cancer modeling by Transgene Electroporation in Adult Zebrafish (TEAZ)

Callahan

Tepan

Zhang

et al. 2018

Disease Models &Amp; Mechanisms

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Transgenic animals are invaluable for modeling cancer genomics, but often require complex crosses of multiple germline alleles to obtain the desired combinations. Zebrafish models have advantages in that transgenes can be rapidly tested by mosaic expression, but typically lack spatial and temporal control of tumor onset, which limits their utility for the study of tumor progression and metastasis. To overcome these limitations, we have developed a method referred to as Transgene Electroporation in Adult Zebrafish (TEAZ). TEAZ can deliver DNA constructs with promoter elements of interest to drive fluorophores, oncogenes or CRISPR-Cas9-based mutagenic cassettes in specific cell types. Using TEAZ, we created a highly aggressive melanoma model via Cas9-mediated inactivation of Rb1 in the context of BRAFV600E in spatially constrained melanocytes. Unlike prior models that take ∼4 months to develop, we found that TEAZ leads to tumor onset in ∼7 weeks, and these tumors develop in fully immunocompetent animals. As the resulting tumors initiated at highly defined locations, we could track their progression via fluorescence, and documented deep invasion into tissues and metastatic deposits. TEAZ can be deployed to other tissues and cell types, such as the heart, with the use of suitable transgenic promoters. The versatility of TEAZ makes it widely accessible for rapid modeling of somatic gene alterations and cancer progression at a scale not achievable in other in vivo systems.

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“…For further validation of the hits, an in vivo disease model in zebrafish was established using atp13a2 mutant larvae exposed to Mn 2+ . In addition to this in vivo evaluation of compound efficacy, zebrafish larvae allow to concomitantly address drug safety and drug delivery through the blood-brain barrier, which is a major challenge in drug discovery for neurodegenerative disorders ( Eliceiri et al , 2011 ; Kanungo et al , 2014 ; Zeng et al , 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Phenotypic assays in yeast and zebrafish reveal drugs that rescue ATP13A2 deficiency

Heins-Marroquin

Jung

Cordero-Maldonado

et al. 2019

Brain Communications

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Mutations in ATP13A2 (PARK9) are causally linked to the rare neurodegenerative disorders Kufor-Rakeb syndrome, hereditary spastic paraplegia and neuronal ceroid lipofuscinosis. This suggests that ATP13A2, a lysosomal cation-transporting ATPase, plays a crucial role in neuronal cells. The heterogeneity of the clinical spectrum of ATP13A2-associated disorders is not yet well understood and currently, these diseases remain without effective treatment. Interestingly, ATP13A2 is widely conserved among eukaryotes, and the yeast model for ATP13A2 deficiency was the first to indicate a role in heavy metal homeostasis, which was later confirmed in human cells. In this study, we show that the deletion of YPK9 (the yeast orthologue of ATP13A2) in Saccharomyces cerevisiae leads to growth impairment in the presence of Zn2+, Mn2+, Co2+ and Ni2+, with the strongest phenotype being observed in the presence of zinc. Using the ypk9Δ mutant, we developed a high-throughput growth rescue screen based on the Zn2+ sensitivity phenotype. Screening of two libraries of Food and Drug Administration-approved drugs identified 11 compounds that rescued growth. Subsequently, we generated a zebrafish model for ATP13A2 deficiency and found that both partial and complete loss of atp13a2 function led to increased sensitivity to Mn2+. Based on this phenotype, we confirmed two of the drugs found in the yeast screen to also exert a rescue effect in zebrafish—N-acetylcysteine, a potent antioxidant, and furaltadone, a nitrofuran antibiotic. This study further supports that combining the high-throughput screening capacity of yeast with rapid in vivo drug testing in zebrafish can represent an efficient drug repurposing strategy in the context of rare inherited disorders involving conserved genes. This work also deepens the understanding of the role of ATP13A2 in heavy metal detoxification and provides a new in vivo model for investigating ATP13A2 deficiency.

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Identify a Blood-Brain Barrier Penetrating Drug-TNB using Zebrafish Orthotopic Glioblastoma Xenograft Model

Cited by 39 publications

References 43 publications

Zebrafish: an emerging real-time model system to study Alzheimer’s disease and neurospecific drug discovery

Zebrafish: an emerging real-time model system to study Alzheimer’s disease and neurospecific drug discovery

Cancer modeling by Transgene Electroporation in Adult Zebrafish (TEAZ)

Phenotypic assays in yeast and zebrafish reveal drugs that rescue ATP13A2 deficiency

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