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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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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. |
format | Online Article Text |
id | pubmed-7470826 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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