title: Developing a Novel Embryo-Larval Zebrafish Xenograft Assay to Prioritize Human Glioblastoma Therapeutics.
abstract: Glioblastoma is an aggressive brain cancer requiring improved treatments. Existing methods of drug discovery and development require years before new therapeutics become available to patients. Zebrafish xenograft models hold promise for prioritizing drug development. We have developed an embryo-larval zebrafish xenograft assay in which cancer cells are implanted in a brain microenvironment to discover and prioritize compounds that impact glioblastoma proliferation, migration, and invasion. We illustrate the utility of our assay by evaluating the well-studied, phosphatidylinositide 3-kinase inhibitor LY294002 and zinc oxide nanoparticles (ZnO NPs), which demonstrate selective cancer cytotoxicity in cell culture, but the in vivo effectiveness has not been established. Exposures of 3.125-6.25 μM LY294002 significantly decreased proliferation up to 34% with concentration-dependent trends. Exposure to 6.25 μM LY294002 significantly inhibited migration/invasion by ∼27% within the glioblastoma cell mass (0-80 μm) and by ∼32% in the next distance region (81-160 μm). Unexpectedly, ZnO enhanced glioblastoma proliferation by ∼19% and migration/invasion by ∼35% at the periphery of the cell mass (161+ μm); however, dissolution of these NPs make it difficult to discern whether this was a nano or ionic effect. These results demonstrate that we have a short, relevant, and sensitive zebrafish-based assay to aid glioblastoma therapeutic development.
authors.affiliation: 1 Department of Environmental and Molecular Toxicology, Oregon State University , Corvallis, Oregon.
authors.forename: Leah Christine
authors.initials: LC
authors.lastname: Wehmas
authors.affiliation: 1 Department of Environmental and Molecular Toxicology, Oregon State University , Corvallis, Oregon.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Tanguay
authors.affiliation: 2 Department of Physics, Boise State University , Boise, Idaho.
authors.forename: Alex
authors.initials: A
authors.lastname: Punnoose
authors.affiliation: 3 Department of Biochemistry and Biophysics, Oregon State University , Corvallis, Oregon.
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Greenwood
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000175:diagnosis* / Q000188:drug therapy*; D064593:Heterografts / Q000187:drug effects; D006801:Humans; D053768:Metal Nanoparticles / Q000008:administration & dosage; D009025:Morpholines / Q000494:pharmacology; D014183:Transplantation, Heterologous; D015027:Zebrafish / Q000196:embryology / Q000254:growth & development / Q000378:metabolism* / Q000601:surgery*; D015034:Zinc Oxide / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D015034:Zinc Oxide