PUBLICATION
Zebrafish phenotypic screen identifies novel notch antagonists
- Authors
- Velaithan, V., Okuda, K.S., Ng, M.F., Samat, N., Leong, S.W., Faudzi, S.M., Abas, F., Shaari, K., Cheong, S.C., Tan, P.J., Patel, V.
- ID
- ZDB-PUB-170108-12
- Date
- 2017
- Source
- Investigational new drugs 35(2): 166-179 (Journal)
- Registered Authors
- Okuda, Kazuhide Shaun
- Keywords
- Human oral cancer, Natural products, Notch signaling, Phenotypic assay, Zebrafish
- MeSH Terms
-
- Animals
- Antineoplastic Agents/pharmacology*
- Cell Cycle/drug effects
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Cell Survival/drug effects
- Curcumin/analogs & derivatives*
- Curcumin/pharmacology*
- Embryo, Nonmammalian/abnormalities
- Embryo, Nonmammalian/drug effects
- HEK293 Cells
- Humans
- Phenotype
- Receptors, Notch/antagonists & inhibitors*
- Receptors, Notch/metabolism
- Triterpenes/pharmacology*
- Zebrafish
- Zebrafish Proteins/antagonists & inhibitors
- Zebrafish Proteins/metabolism
- PubMed
- 28058624 Full text @ Invest New Drugs
Citation
Velaithan, V., Okuda, K.S., Ng, M.F., Samat, N., Leong, S.W., Faudzi, S.M., Abas, F., Shaari, K., Cheong, S.C., Tan, P.J., Patel, V. (2017) Zebrafish phenotypic screen identifies novel notch antagonists. Investigational new drugs. 35(2):166-179.
Abstract
Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27KIP1. Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.
Errata / Notes
Erratum: Erratum to: Zebrafish phenotypic screen identifies novel Notch antagonists.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping