1. Cancer Biology
  2. Human Biology and Medicine
Download icon

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

  1. Jaime N Wertman
  2. Nicole Melong
  3. Matthew R Stoyek
  4. Olivia Piccolo
  5. Stewart Langley
  6. Benno Orr
  7. Shelby L Steele
  8. Babak Razaghi
  9. Jason N Berman  Is a corresponding author
  1. Dalhousie University, Canada
  2. Children's Hospital of Eastern Ontario Research Institute, Canada
  3. IWK Health Centre, Canada
  4. University of Toronto, Canada
  5. Appili Therapeutics, Canada
Research Article
  • Cited 0
  • Views 380
  • Annotations
Cite this article as: eLife 2020;9:e56235 doi: 10.7554/eLife.56235

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.

Article and author information

Author details

  1. Jaime N Wertman

    Microbiology & Immunology, Dalhousie University, Halifax, Canada
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6029-3376
  2. Nicole Melong

    Pediatrics, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada
    Competing interests
    No competing interests declared.
  3. Matthew R Stoyek

    Department of Physiology & Biophysics, Dalhousie University, Halifax, Canada
    Competing interests
    No competing interests declared.
  4. Olivia Piccolo

    Pediatrics, IWK Health Centre, Halifax, Canada
    Competing interests
    No competing interests declared.
  5. Stewart Langley

    Pediatrics, IWK Health Centre, Halifax, Canada
    Competing interests
    No competing interests declared.
  6. Benno Orr

    Department of Molecular Genetics, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  7. Shelby L Steele

    Drug Development, Appili Therapeutics, Halifax, Canada
    Competing interests
    Shelby L Steele, Shelby L. Steele is affiliated with Appili Therapeutics Inc. The author has no financial interests to declare.
  8. Babak Razaghi

    Faculty of Dentistry, Dalhousie University, Halifax, Canada
    Competing interests
    No competing interests declared.
  9. Jason N Berman

    Hematology/Oncology, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada
    For correspondence
    jberman@cheo.on.ca
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4053-6067

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.

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).

Reviewing Editor

  1. Arduino A Mangoni, Flinders Medical Centre, Australia

Publication history

  1. Received: February 21, 2020
  2. Accepted: July 20, 2020
  3. Accepted Manuscript published: July 28, 2020 (version 1)

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.

Metrics

  • 380
    Page views
  • 55
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cancer Biology
    2. Immunology and Inflammation
    Biancamaria Ricci et al.
    Research Article

    Cancer-associated fibroblasts (CAFs) are a heterogeneous population of mesenchymal cells supporting tumor progression, whose origin remains to be fully elucidated. Osterix (Osx) is a marker of osteogenic differentiation, expressed in skeletal progenitor stem cells and bone-forming osteoblasts. We report Osx expression in CAFs and by using Osx-cre;TdTomato reporter mice we confirm the presence and pro-tumorigenic function of TdTOSX+ cells in extra-skeletal tumors. Surprisingly, only a minority of TdTOSX+ cells expresses fibroblast and osteogenic markers. The majority of TdTOSX+ cells express the hematopoietic marker CD45, have a genetic and phenotypic profile resembling that of tumor infiltrating myeloid and lymphoid populations, but with higher expression of lymphocytic immune suppressive genes. We find Osx transcript and Osx protein expression early during hematopoiesis, in subsets of hematopoietic stem cells and multipotent progenitor populations. Our results indicate that Osx marks distinct tumor promoting CD45- and CD45+ populations and challenge the dogma that Osx is expressed exclusively in cells of mesenchymal origin.

    1. Cancer Biology
    Joana G Marques et al.
    Research Article

    The NuRD complex subunit CHD4 is essential for fusion-positive rhabdomyosarcoma (FP-RMS) survival, but the mechanisms underlying this dependency are not understood. Here, a NuRD-specific CRISPR screen demonstrates that FP-RMS is particularly sensitive to CHD4 amongst the NuRD members. Mechanistically, NuRD complex containing CHD4 localizes to super-enhancers where CHD4 generates a chromatin architecture permissive for the binding of the tumor driver and fusion protein PAX3-FOXO1, allowing downstream transcription of its oncogenic program. Moreover, CHD4 depletion removes HDAC2 from the chromatin, leading to an increase and spread of histone acetylation, and prevents the positioning of RNA Polymerase 2 at promoters impeding transcription initiation. Strikingly, analysis of genome-wide cancer dependency databases identifies CHD4 as a general cancer vulnerability. Our findings describe CHD4, a classically defined repressor, as positive regulator of transcription and super-enhancer accessibility as well as establish this remodeler as an unexpected broad tumor susceptibility and promising drug target for cancer therapy.