Tank water-administered dabrafenib in BRAF-mutant zebrafish melanoma model
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Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.
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DOI
Tiivistelmä
Melanoma is an aggressive skin cancer which incidence and mortality rates are increasing worldwide. The cancer often involves mutations in the BRAF gene, especially a V600E variant. Dabrafenib is a small-molecule BRAF inhibitor, which mechanism of action is based on the inhibition of mitogen-activated protein kinase (MAPK) signalling pathway. The aim of this study was to characterize the pharmacological properties of dabrafenib administered to the tank water using a zebrafish (Danio rerio) melanoma model.
Pharmacokinetics and pharmacodynamics were successfully assessed and described in healthy and BRAF V600E-mutated zebrafish and ZMEL1-GFP zebrafish melanoma cells. Mass spectrometry analysis of blood samples revealed that dabrafenib was absorbed and eliminated relatively fast. The drug and its metabolites were distributed into several abdominal organs which was seen in mass spectrometry imaging. During a two-week long treatment experiment, dabrafenib reduced tumour size significantly proving its efficacy in zebrafish. The changes after the drug administration could also be seen on a histological level with H&E staining. With immunohistochemistry and Western blotting, we were able to confirm dabrafenib’s mechanism of action affecting extracellular signal-regulated kinase (ERK) phosphorylation of MAPK pathway. In addition, the drug had a dose-dependent effect on melanoma cell viability.
The need for translational models to study melanoma resistance, drug responses and therapies is increasing. Even though the BRAF V600E model has its limitations, this research provides a foundation to use tank-administered dabrafenib to study melanoma and melanoma therapies in zebrafish melanoma models. The study also supports the overall use of zebrafish as translational preclinical models.