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Related Concept Videos

Genetic Screens02:46

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Genetic screens are tools used to identify genes and mutations responsible for phenotypes of interest. Genetic screens help identify individuals or a group of people at risk of developing  genetic diseases and help them with early intervention, targeted therapy, and reproductive options.
Forward genetic screens
Forward or “classical” genetic screens involve creating random mutations in an organism’s DNA using radiation, mutagens, or insertion of additional bases, which...
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Related Experiment Video

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A Manual Small Molecule Screen Approaching High-throughput Using Zebrafish Embryos
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Zebrafish phenotypic screen identifies novel Notch antagonists.

Vithya Velaithan1, Kazuhide Shaun Okuda1, Mei Fong Ng1

  • 1Cancer Research Malaysia, 12A, Jalan TP5, Taman Perindustrian UEP, 47600, Subang Jaya, Malaysia.

Investigational New Drugs
|January 7, 2017
PubMed
Summary

Zebrafish screens identified EDD3, a natural compound, as a promising Notch antagonist. EDD3 shows potential for treating human cancers by inhibiting Notch signaling and cell proliferation.

Keywords:
Human oral cancerNatural productsNotch signalingPhenotypic assayZebrafish

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Area of Science:

  • * Pharmacology
  • * Molecular Biology
  • * Cancer Research

Background:

  • * Notch signaling is crucial for embryonic development and implicated in human cancers.
  • * Natural products offer a rich source for novel therapeutic agents.
  • * Zebrafish embryos serve as an effective in vivo model for drug discovery.

Purpose of the Study:

  • * To identify novel small molecules modulating Notch signaling using a zebrafish phenotypic screen.
  • * To evaluate potential natural product-derived compounds as Notch antagonists.
  • * To investigate the therapeutic potential of identified compounds in human cancer models.

Main Methods:

  • * High-throughput screening of 234 natural compounds in zebrafish embryos.
  • * Secondary screening using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE).
  • * Analysis of Notch target gene and protein expression, cell proliferation, and cell cycle arrest in cancer cell lines.

Main Results:

  • * Three compounds induced phenotypes similar to known Notch inhibitors in zebrafish embryos.
  • * EDD3 and 3H4MB were identified as potential Notch antagonists in HEK293TΔE cells.
  • * EDD3 reduced Notch target proteins (NOTCH1, NICD, HES1), inhibited proliferation, and induced G0/G1 cell cycle arrest in human oral cancer cells.

Conclusions:

  • * Zebrafish phenotypic screening is a valuable tool for identifying drug candidates.
  • * EDD3 demonstrates significant potential as a Notch antagonist for cancer therapy.
  • * Further development of EDD3 as a therapeutic agent is warranted.