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Cytotoxicity and Activation of the Wnt/beta-catenin Pathway in Mouse Embryonic Stem Cells Treated With Four GSK3 Inhibitors

Cytotoxicity and Activation of the Wnt/beta-catenin Pathway in Mouse Embryonic Stem Cells Treated With Four GSK3 Inhibitors

Ortwin Naujok, Jana Lentes, Ulf Diekmann, Claudia Davenport, Sigurd Lenzen

BMC Res Notes. 2014 Apr 29;7:273.

PMID: 24779365

Abstract:

Background:
Small membrane-permeable molecules are now widely used during maintenance and differentiation of embryonic stem cells of different species. In particular the glycogen synthase kinase 3 (GSK3) is an interesting target, since its chemical inhibition activates the Wnt/beta-catenin pathway. In the present comparative study four GSK3 inhibitors were characterized.
Methods:
Cytotoxicity and potential to activate the Wnt/beta-catenin pathway were tested using the commonly used GSK3 inhibitors BIO, SB-216763, CHIR-99021, and CHIR-98014. Wnt/beta-catenin-dependent target genes were measured by quantitative PCR to confirm the Wnt-reporter assay and finally EC50-values were calculated.
Results:
CHIR-99021 and SB-216763 had the lowest toxicities in mouse embryonic stem cells and CHIR-98014 and BIO the highest toxicities. Only CHIR-99021 and CHIR-98014 lead to a strong induction of the Wnt/beta-catenin pathway, whereas BIO and SB-216763 showed a minor or no increase in activation of the Wnt/beta-catenin pathway over the natural ligand Wnt3a. The data from the Wnt-reporter assay were confirmed by gene expression analysis of the TCF/LEF regulated gene T.
Conclusions:
Out of the four tested GSK3 inhibitors, only CHIR-99021 and CHIR-98014 proved to be potent pharmacological activators of the Wnt/beta-catenin signaling pathway. But only in the case of CHIR-99021 high potency was combined with very low toxicity.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP252935947	CHIR 98014		252935-94-7	Price

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