PUBLICATION

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

Authors
Wertman, J.N., Melong, N., Stoyek, M.R., Piccolo, O., Langley, S., Orr, B., Steele, S.L., Razaghi, B., Berman, J.N.
ID
ZDB-PUB-200729-6
Date
2020
Source
eLIFE   9: (Journal)
Registered Authors
Berman, Jason, Langley, Stewart, Melong, Nicole, Piccolo, Olivia, Razaghi, Babak, Stoyek, Matthew, Wertman, Jaime
Keywords
cancer biology, human, human biology, medicine, zebrafish
MeSH Terms
  • Animals
  • Antineoplastic Agents/pharmacology
  • Antineoplastic Agents/toxicity
  • Cell Line, Tumor
  • Cisplatin*/pharmacology
  • Cisplatin*/toxicity
  • Dopamine/pharmacology
  • Drug Combinations
  • Hair Cells, Auditory/drug effects
  • Hair Cells, Auditory/pathology
  • Humans
  • Kidney/drug effects
  • Kidney/pathology
  • Lateral Line System/drug effects
  • Lateral Line System/pathology
  • Mimosine/pharmacology
  • Models, Animal
  • Protective Agents/pharmacology*
  • Zebrafish
PubMed
32720645 Full text @ Elife
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.
Genes / Markers
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Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes