The identification of dual protective agents against cisplatin-induced oto-and nephrotoxicity using the zebrafish model
- Dalhousie University, Canada
- Children's Hospital of Eastern Ontario Research Institute, Canada
- IWK Health Centre, Canada
- University of Toronto, Canada
- Appili Therapeutics, Canada
Abstract
Dose-limiting toxicities for cisplatin administration, including ototoxicity and nephrotoxicity, impact the clinical utility of this effective chemotherapy agent and lead to lifelong complications, particularly in pediatric cancer survivors. Using a two-pronged drug screen employing the zebrafish lateral line as an in vivo readout for ototoxicity and kidney cell-based nephrotoxicity assay, we screened 1280 compounds and identified 22 that were both oto- and nephroprotective. Of these, dopamine and L-mimosine, a plant-based amino acid active in the dopamine pathway, were further investigated. Dopamine and L-mimosine protected the hair cells in the zebrafish otic vesicle from cisplatin-induced damage and preserved zebrafish larval glomerular filtration. Importantly, these compounds did not abrogate the cytotoxic effects of cisplatin on human cancer cells. This study provides insights into the mechanisms underlying cisplatin-induced oto- and nephrotoxicity and compelling preclinical evidence for the potential utility of dopamine and L-mimosine in the safer administration of cisplatin.
Data availability
The full list of hits from both the oto- and nephrotoxicity drug screens are available on Dryad, under the doi: 10.5061/dryad.zcrjdfn8n
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Results from: The identification of dual protective agents against cisplatin-induced oto-and nephrotoxicity using the zebrafish modelDryad Digital Repository, 10.5061/dryad.zcrjdfn8n.
Article and author information
Author details
Funding
No operating funds were directly associated with this work. Jaime Wertman was supported throughout the study by a Killam Predoctoral Award and an IWK Graduate Studentship.The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Arduino A Mangoni, Flinders Medical Centre, Australia
Ethics
Animal experimentation: The use of zebrafish in this study was approved by, and carried out in accordance with, the policies of the Dalhousie University Committee on Laboratory Animals (Protocols #17-131 and #17-055).
Version history
- Received: February 21, 2020
- Accepted: July 20, 2020
- Accepted Manuscript published: July 28, 2020 (version 1)
- Version of Record published: September 3, 2020 (version 2)
Copyright
© 2020, Wertman et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The identification of dual protective agents against cisplatin-induced oto-and nephrotoxicity using the zebrafish model
eLife 9:e56235.
https://doi.org/10.7554/eLife.56235
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