Using a zebrafish xenograft tumor model to compare the efficacy and safety of VEGFR-TKIs

Hou, Wanting; Zhong, Jian; Xiao, Chaoxin; Yi, Cheng; Zhao, Chengjian; Zhang, Lin; Cao, Dan

doi:10.1007/s00432-022-04560-7

Cited by 2 publications

(1 citation statement)

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“…The impact of the inhibitor treatment increased in a dose-dependent manner and the embryos developed severe bradycardia, blood congestion, pericardial edema and loss of ventricular beating. A dose-dependent increase in toxicity was expected and has been described for other SMIs as well ( Cassar et al, 2020 ; Wanting et al, 2023 ). G2-2 and G2-3 were demonstrated to be highly toxic and the most potent compounds from this set.…”

Section: Discussionsupporting

confidence: 57%

Zebrafish as model system for the biological characterization of CK1 inhibitors

Meier,

Gahr,

Roth

et al. 2023

Front. Pharmacol.

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Introduction: The CK1 family is involved in a variety of physiological processes by regulating different signaling pathways, including the Wnt/β-catenin, the Hedgehog and the p53 signaling pathways. Mutations or dysregulation of kinases in general and of CK1 in particular are known to promote the development of cancer, neurodegenerative diseases and inflammation. There is increasing evidence that CK1 isoform specific small molecule inhibitors, including CK1δ- and CK1ε-specific inhibitors of Wnt production (IWP)-based small molecules with structural similarity to benzimidazole compounds, have promising therapeutic potential.Methods: In this study, we investigated the suitability of the zebrafish model system for the evaluation of such CK1 inhibitors. To this end, the kinetic parameters of human CK1 isoforms were compared with those of zebrafish orthologues. Furthermore, the effects of selective CK1δ inhibition during zebrafish embryonic development were analyzed in vivo.Results: The results revealed that zebrafish CK1δA and CK1δB were inhibited as effectively as human CK1δ by compounds G2-2 with IC50 values of 345 and 270 nM for CK1δA and CK1δB versus 503 nM for human CK1δ and G2-3 exhibiting IC50 values of 514 and 561 nM for zebrafish CK1δA and B, and 562 nM for human CK1δ. Furthermore, the effects of selective CK1δ inhibition on zebrafish embryonic development in vivo revealed phenotypic abnormalities indicative of downregulation of CK1δ. Treatment of zebrafish embryos with selected inhibitors resulted in marked phenotypic changes including blood stasis, heart failure, and tail malformations.Conclusion: The results suggest that the zebrafish is a suitable in vivo assay model system for initial studies of the biological relevance of CK1δ inhibition.

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Section: Discussionsupporting

confidence: 57%