PUBLICATION
Screening for Chemical Suppressors of the Wnt/β-catenin Signaling Pathway
- Authors
- Nishiya, N.
- ID
- ZDB-PUB-170206-14
- Date
- 2017
- Source
- Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 137: 133-136 (Review)
- Registered Authors
- Nishiya, Naoyuki
- Keywords
- none
- MeSH Terms
-
- Animals
- Antineoplastic Agents/pharmacology*
- Antineoplastic Agents/therapeutic use*
- Depression, Chemical
- Dose-Response Relationship, Drug
- Drug Screening Assays, Antitumor*
- Embryonic Development/drug effects
- Humans
- Mice
- Molecular Targeted Therapy*
- Neoplasms/drug therapy*
- Neoplasms/genetics*
- Neoplasms/pathology
- Stem Cells/cytology
- Stem Cells/drug effects
- Wnt Signaling Pathway/drug effects*
- Wnt Signaling Pathway/physiology*
- Zebrafish/embryology
- PubMed
- 28154320 Full text @ Yakugaku Zasshi
Citation
Nishiya, N. (2017) Screening for Chemical Suppressors of the Wnt/β-catenin Signaling Pathway. Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. 137:133-136.
Abstract
Aberrant activation of Wnt/β-catenin canonical signaling is observed in multiple malignant tumors, and is recognized as an attractive therapeutic target for molecular targeted drugs. This signaling pathway is also involved in maintaining pluripotency in adult stem cells. Therefore, lowering potential stem cell toxicity is a key factor for the development of a Wnt/β-catenin signaling inhibitor. Here, we show Wnt/β-catenin pathway inhibitors with low toxicity, identified through phenotype-based screening using zebrafish embryos. Artificial activation of the Wnt/β-catenin pathway in fertilized eggs, which are often considered the "ultimate stem cells", results in an "eyeless" phenotype in zebrafish embryos. Screening for compounds that rescue this "eyeless" phenotype and have no effects on normal embryogenesis could help us identify Wnt/β-catenin pathway inhibitors with minimal stem cell toxicities, at least at a concentration that suppresses aberrant signaling. Chemical suppressors of the "eyeless" phenotype include novel and known compounds with different modes of action. Some of these compounds diminish the activation of crosstalk between other signaling pathways and the Wnt/β-catenin pathway. These inhibitors reduced tumor growth in ApcMin/+ mice and did not show apparent toxicities. Thus, our screening for chemical suppressors of the "eyeless" phenotype allowed us to successfully identify inhibitors for the Wnt/β-catenin pathway with low toxicity.
Errata / Notes
Article in Japanese.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping