Dear Colleagues,

Our scientific and technological knowledge has grown tremendously. The number of drugs approved relative to the costs, however, has continuously decreased. Various approaches have emerged to increase the efficacy of research and the development of new drugs. It has been widely recognized that zebrafish can be powerful tools in the drug discovery field, given advantages such as high fecundity, ease of drug administration, similarity to mammals in terms of structures and functions of various tissues, and suitability for the 3Rs (replacement, reduction, and refinement). The process of drug development consists of multiple steps, including the initial discovery of drugs that can be used as therapeutics, preclinical, and clinical validation of their efficacy and toxicity, and the review, approval, and post-marketing surveillance of drugs by regulatory authorities. Using genome-editing technologies, genetic abnormalities observed in human diseases can be mimicked in zebrafish to make a disease model. The phenotypes of the disease model zebrafish can be used to identify novel compounds and/or new indications for old drugs (i.e., drug repositioning) that ameliorate the abnormal phenotypes of the zebrafish disease models. The toxicity of compounds can also be assessed using zebrafish. The International Council for Harmonization has considered including developmental toxicity testing using zebrafish in their guidelines. Zebrafish can also be integrated to validate the efficacy and toxicities of compounds that are identified as novel therapeutics by other approaches, such as computational drug discovery using big data. In this Special Issue, we invite authors to contribute articles focusing on zebrafish as powerful tools for drug discovery. This research topic will maximize the knowledge of the usefulness of zebrafish in drug development, with hopes of increasing the efficiency of the process and identifying drugs that can be used to prevent and/or treat diseases for which effective medications are currently lacking.

Prof. Dr. Yuhei Nishimura
Guest Editor

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• zebrafish
• disease model
• phenotype
• drug repositioning
• computational biology
• toxicology

1. Type: Research article
Title: Canthin-6-one inhibits developmental and tumour-associated angiogenesis in zebrafish and synergises with VEGFR inhibitors

Author(s): Mei Fong Ng, Pei Jean Tan, Denver Desmond Britto, Sy Bing Choi, Norazwana Samat, Dedrick Soon Seng Song, Satoshi Ogawa, Ishwar S.Parhar, Benjamin M Hogan, Jonathan W Astin, Vyomesh Patel, Kazuhide S Okuda
The Corresponding author(s): Kazuhide S Okuda

Affiliation(s):

Cancer Research Malaysia, Selangor, Malaysia

Instittue for Molecular Biosciences, University of Queensland, QLD, Australia

Peter MacCallum Cancer Centre, VIC, Australia

University of Melbourne, VIC, Australia

La Trobe Institute for Molecular Science, La Trobe University, VIC, Australia

University of Auckland, Auckland, New Zealand

Perdana University, Selangor, Malaysia

Monash University, Bandar Sunway, Malaysia

Abstract:

Tumor-associated angiogenesis play key roles in tumor growth and cancer metastasis. Consequently, several anti-angiogenic drugs such as sunitinib and axitinib, have been approved for use as anti-cancer therapies. However, majority of these drugs target the vascular endothelial growth factor A (VEGF-A)/vascular endothelial growth factor receptor 2 (VEGFR-2) pathway and have shown mixed outcome, largely due to side effects and development of resistances. In this study, we utilised the Tg(friend leukaemia integration 1 a (fli1a):EGFP)^y1 zebrafish transgenic line to screen for novel anti-angiogenic molecules from a library of compounds derived from natural products. From our initial analysis, we identified canthin-6-one, an indole alkaloid, which is able to inhibit zebrafish intersegmental vessel (ISV) and sub-intestinal vessel (SIV) development at concentrations of 20 µM. Further characterisation revealed that treatment of canthin-6-one reduced endothelial cell number within the ISVs at 48 hours post-fertilisation (hpf) in developing zebrafish and inhibited proliferation of human vascular endothelial cells, suggesting that canthin-6-one is likely inhibiting endothelial cell proliferation. Of note, canthin-6-one was found not to inhibit VEGF-A-induced phosphorylation of VEGFR-2 and did not inhibit VEGFA-induced Erk phosphorylation in ISV in vivo, suggesting canthin-6-one is likely inhibiting angiogenesis independent of VEGF-A/VEGFR-2 pathway. Importantly, we found that canthin-6-one was able to inhibit tumor-associated angiogenesis in a zebrafish B16F10 melanoma cell xenograft model and synergised with clinically approved anti-angiogenic therapeutic sunitinib malate. In summary, we show that canthin-6-one exhibits anti-angiogenic properties in both developmental and pathological contexts in zebrafish, independent of the VEGF-A/VEGFR-2 pathway and demonstrate that canthin-6-one may hold value for further development as a novel anti-angiogenic drug.

2. Dr. Noelia Fernandez-Castillo, etc.

RBFOX1 is gene with a pleiotropic effect on many psychiatric disorders. We have previously worked with rbfox1 knockout zebrafish and behavioural experiments showed that KO fish display a phenotype mirroring symptoms common to psychiatric disorders hyperactivity, thigmotaxis, and alterations in social behaviour.
We have now investigated whether acute exposure to Fluoxetine, a selective serotonin reuptake inhibitor, can rescue these behavioural alterations observed in rbfox1 knockout zebrafish. We tested several concentrations of fluoxetine and observed that some behaviours were rescued at the higher concentration tested, reestablishing behaviour similar to WT fish. We are currently running new batches of experiments to confirm these results.