A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions.

Persistent Link:
http://hdl.handle.net/10150/605272
Title:
A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions.
Author:
Kraft, Robert; Kahn, Allon; Medina-Franco, José L.; Orlowski, Mikayla L.; Baynes, Cayla; López-Vallejo, Fabian; Barnard, Kobus; Maggiora, Gerald M.; Restifo, Linda L.
Affiliation:
Department of Neuroscience, University of Arizona, Tucson, AZ; Torrey Pines Institute for Molecular Studies, Port St Lucie, FL; Department of Computer Science, University of Arizona, Tucson, AZ; BIO5 Interdisciplinary Research Institute, University of Arizona, Tucson, AZ; Translational Genomics Research Institute, Phoenix, AZ; Department of Pharmacology and Toxicology, Arizona Health Sciences Center, Tucson, AZ; Departments of Neurology and Cellular & Molecular Medicine, Arizona Health Sciences Center, Tucson, AZ; Center for Insect Science, Arizona Research Laboratories, University of Arizona, Tucson, AZ
Issue Date:
2013-01
Publisher:
The Company of Biologists
Citation:
Kraft et al. (2013). A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions. Dis Model Mech 6(1):217-35
Journal:
Disease Models & Mechanisms
Rights:
Archived with thanks to Disease models & mechanisms
Abstract:
The actin-bundling protein fascin is a key mediator of tumor invasion and metastasis and its activity drives filopodia formation, cell-shape changes and cell migration. Small-molecule inhibitors of fascin block tumor metastasis in animal models. Conversely, fascin deficiency might underlie the pathogenesis of some developmental brain disorders. To identify fascin-pathway modulators we devised a cell-based assay for fascin function and used it in a bidirectional drug screen. The screen utilized cultured fascin-deficient mutant Drosophila neurons, whose neurite arbors manifest the 'filagree' phenotype. Taking a repurposing approach, we screened a library of 1040 known compounds, many of them FDA-approved drugs, for filagree modifiers. Based on scaffold distribution, molecular-fingerprint similarities, and chemical-space distribution, this library has high structural diversity, supporting its utility as a screening tool. We identified 34 fascin-pathway blockers (with potential anti-metastasis activity) and 48 fascin-pathway enhancers (with potential cognitive-enhancer activity). The structural diversity of the active compounds suggests multiple molecular targets. Comparisons of active and inactive compounds provided preliminary structure-activity relationship information. The screen also revealed diverse neurotoxic effects of other drugs, notably the 'beads-on-a-string' defect, which is induced solely by statins. Statin-induced neurotoxicity is enhanced by fascin deficiency. In summary, we provide evidence that primary neuron culture using a genetic model organism can be valuable for early-stage drug discovery and developmental neurotoxicity testing. Furthermore, we propose that, given an appropriate assay for target-pathway function, bidirectional screening for brain-development disorders and invasive cancers represents an efficient, multipurpose strategy for drug discovery.
Description:
A first-of-its-kind, proof-of-concept drug screen with implications for two unmet medical needs.
ISSN:
1754-8411
PubMed ID:
22917928
DOI:
10.1242/dmm.008243
Keywords:
Drug screen; fruit flies; primary neuronal culture; intellectual disability
Sponsors:
NIH/NINDS: NS055774; U. of Arizona Center for Insect Science; State of Florida and the Menopause & Women’s Health Research Center (Port St Lucie, FL); NIGMS (Minority Access to Research Careers): T34 GM08718
Additional Links:
http://dmm.biologists.org/content/6/1/217.long

Full metadata record

DC FieldValue Language
dc.contributor.authorKraft, Roberten
dc.contributor.authorKahn, Allonen
dc.contributor.authorMedina-Franco, José L.en
dc.contributor.authorOrlowski, Mikayla L.en
dc.contributor.authorBaynes, Caylaen
dc.contributor.authorLópez-Vallejo, Fabianen
dc.contributor.authorBarnard, Kobusen
dc.contributor.authorMaggiora, Gerald M.en
dc.contributor.authorRestifo, Linda L.en
dc.date.accessioned2016-04-14T16:01:27Zen
dc.date.available2016-04-14T16:01:27Zen
dc.date.issued2013-01en
dc.identifier.citationKraft et al. (2013). A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions. Dis Model Mech 6(1):217-35en
dc.identifier.issn1754-8411en
dc.identifier.pmid22917928en
dc.identifier.doi10.1242/dmm.008243en
dc.identifier.urihttp://hdl.handle.net/10150/605272en
dc.descriptionA first-of-its-kind, proof-of-concept drug screen with implications for two unmet medical needs.en
dc.description.abstractThe actin-bundling protein fascin is a key mediator of tumor invasion and metastasis and its activity drives filopodia formation, cell-shape changes and cell migration. Small-molecule inhibitors of fascin block tumor metastasis in animal models. Conversely, fascin deficiency might underlie the pathogenesis of some developmental brain disorders. To identify fascin-pathway modulators we devised a cell-based assay for fascin function and used it in a bidirectional drug screen. The screen utilized cultured fascin-deficient mutant Drosophila neurons, whose neurite arbors manifest the 'filagree' phenotype. Taking a repurposing approach, we screened a library of 1040 known compounds, many of them FDA-approved drugs, for filagree modifiers. Based on scaffold distribution, molecular-fingerprint similarities, and chemical-space distribution, this library has high structural diversity, supporting its utility as a screening tool. We identified 34 fascin-pathway blockers (with potential anti-metastasis activity) and 48 fascin-pathway enhancers (with potential cognitive-enhancer activity). The structural diversity of the active compounds suggests multiple molecular targets. Comparisons of active and inactive compounds provided preliminary structure-activity relationship information. The screen also revealed diverse neurotoxic effects of other drugs, notably the 'beads-on-a-string' defect, which is induced solely by statins. Statin-induced neurotoxicity is enhanced by fascin deficiency. In summary, we provide evidence that primary neuron culture using a genetic model organism can be valuable for early-stage drug discovery and developmental neurotoxicity testing. Furthermore, we propose that, given an appropriate assay for target-pathway function, bidirectional screening for brain-development disorders and invasive cancers represents an efficient, multipurpose strategy for drug discovery.en
dc.description.sponsorshipNIH/NINDS: NS055774; U. of Arizona Center for Insect Science; State of Florida and the Menopause & Women’s Health Research Center (Port St Lucie, FL); NIGMS (Minority Access to Research Careers): T34 GM08718en
dc.language.isoenen
dc.publisherThe Company of Biologistsen
dc.relation.urlhttp://dmm.biologists.org/content/6/1/217.longen
dc.rightsArchived with thanks to Disease models & mechanismsen
dc.subjectDrug screenen
dc.subjectfruit fliesen
dc.subjectprimary neuronal cultureen
dc.subjectintellectual disabilityen
dc.subject.meshAnimalsen
dc.subject.meshAnimals, Genetically Modifieden
dc.subject.meshAntineoplastic Agentsen
dc.subject.meshBiological Assayen
dc.subject.meshBrainen
dc.subject.meshBrain Neoplasmsen
dc.subject.meshCarrier Proteinsen
dc.subject.meshCells, Cultureden
dc.subject.meshDrosophilaen
dc.subject.meshDrug Discoveryen
dc.subject.meshDrug Evaluation, Preclinicalen
dc.subject.meshDrug Screening Assays, Antitumoren
dc.subject.meshHydroxymethylglutaryl-CoA Reductase Inhibitorsen
dc.subject.meshMicrofilament Proteinsen
dc.subject.meshModels, Neurologicalen
dc.subject.meshNeoplasm Metastasisen
dc.subject.meshNeuronal Plasticityen
dc.subject.meshNeuronsen
dc.subject.meshNootropic Agentsen
dc.subject.meshSignal Transductionen
dc.subject.meshStructure-Activity Relationshipen
dc.titleA cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions.en
dc.typeArticleen
dc.contributor.departmentDepartment of Neuroscience, University of Arizona, Tucson, AZen
dc.contributor.departmentTorrey Pines Institute for Molecular Studies, Port St Lucie, FLen
dc.contributor.departmentDepartment of Computer Science, University of Arizona, Tucson, AZen
dc.contributor.departmentBIO5 Interdisciplinary Research Institute, University of Arizona, Tucson, AZen
dc.contributor.departmentTranslational Genomics Research Institute, Phoenix, AZen
dc.contributor.departmentDepartment of Pharmacology and Toxicology, Arizona Health Sciences Center, Tucson, AZen
dc.contributor.departmentDepartments of Neurology and Cellular & Molecular Medicine, Arizona Health Sciences Center, Tucson, AZen
dc.contributor.departmentCenter for Insect Science, Arizona Research Laboratories, University of Arizona, Tucson, AZen
dc.identifier.journalDisease Models & Mechanismsen

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