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The identification of dual protective agents against cisplatin-induced oto- and nephrotoxicity using the zebrafish model

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 la...

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Autores principales: Wertman, Jaime N, Melong, Nicole, Stoyek, Matthew R, Piccolo, Olivia, Langley, Stewart, Orr, Benno, Steele, Shelby L, Razaghi, Babak, Berman, Jason N
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470826/
https://www.ncbi.nlm.nih.gov/pubmed/32720645
http://dx.doi.org/10.7554/eLife.56235
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author Wertman, Jaime N
Melong, Nicole
Stoyek, Matthew R
Piccolo, Olivia
Langley, Stewart
Orr, Benno
Steele, Shelby L
Razaghi, Babak
Berman, Jason N
author_facet Wertman, Jaime N
Melong, Nicole
Stoyek, Matthew R
Piccolo, Olivia
Langley, Stewart
Orr, Benno
Steele, Shelby L
Razaghi, Babak
Berman, Jason N
author_sort Wertman, Jaime N
collection PubMed
description 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.
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spelling pubmed-74708262020-09-04 The identification of dual protective agents against cisplatin-induced oto- and nephrotoxicity using the zebrafish model Wertman, Jaime N Melong, Nicole Stoyek, Matthew R Piccolo, Olivia Langley, Stewart Orr, Benno Steele, Shelby L Razaghi, Babak Berman, Jason N eLife Cancer Biology 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. eLife Sciences Publications, Ltd 2020-07-28 /pmc/articles/PMC7470826/ /pubmed/32720645 http://dx.doi.org/10.7554/eLife.56235 Text en © 2020, Wertman et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Wertman, Jaime N
Melong, Nicole
Stoyek, Matthew R
Piccolo, Olivia
Langley, Stewart
Orr, Benno
Steele, Shelby L
Razaghi, Babak
Berman, Jason N
The identification of dual protective agents against cisplatin-induced oto- and nephrotoxicity using the zebrafish model
title The identification of dual protective agents against cisplatin-induced oto- and nephrotoxicity using the zebrafish model
title_full The identification of dual protective agents against cisplatin-induced oto- and nephrotoxicity using the zebrafish model
title_fullStr The identification of dual protective agents against cisplatin-induced oto- and nephrotoxicity using the zebrafish model
title_full_unstemmed The identification of dual protective agents against cisplatin-induced oto- and nephrotoxicity using the zebrafish model
title_short The identification of dual protective agents against cisplatin-induced oto- and nephrotoxicity using the zebrafish model
title_sort identification of dual protective agents against cisplatin-induced oto- and nephrotoxicity using the zebrafish model
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470826/
https://www.ncbi.nlm.nih.gov/pubmed/32720645
http://dx.doi.org/10.7554/eLife.56235
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