1. Cancer Biology
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 7
  • Views 1,946
  • 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.

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

The following data sets were generated

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)
  4. 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.

Metrics

  • 1,946
    Page views
  • 262
    Downloads
  • 7
    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)

  1. Further reading

Further reading

    1. Cancer Biology
    2. Cell Biology
    Maxim I Maron et al.
    Research Article Updated

    Protein arginine methyltransferases (PRMTs) are required for the regulation of RNA processing factors. Type I PRMT enzymes catalyze mono- and asymmetric dimethylation; Type II enzymes catalyze mono- and symmetric dimethylation. To understand the specific mechanisms of PRMT activity in splicing regulation, we inhibited Type I and II PRMTs and probed their transcriptomic consequences. Using the newly developed Splicing Kinetics and Transcript Elongation Rates by Sequencing (SKaTER-seq) method, analysis of co-transcriptional splicing demonstrated that PRMT inhibition resulted in altered splicing rates. Surprisingly, co-transcriptional splicing kinetics did not correlate with final changes in splicing of polyadenylated RNA. This was particularly true for retained introns (RI). By using actinomycin D to inhibit ongoing transcription, we determined that PRMTs post-transcriptionally regulate RI. Subsequent proteomic analysis of both PRMT-inhibited chromatin and chromatin-associated polyadenylated RNA identified altered binding of many proteins, including the Type I substrate, CHTOP, and the Type II substrate, SmB. Targeted mutagenesis of all methylarginine sites in SmD3, SmB, and SmD1 recapitulated splicing changes seen with Type II PRMT inhibition, without disrupting snRNP assembly. Similarly, mutagenesis of all methylarginine sites in CHTOP recapitulated the splicing changes seen with Type I PRMT inhibition. Examination of subcellular fractions further revealed that RI were enriched in the nucleoplasm and chromatin. Taken together, these data demonstrate that, through Sm and CHTOP arginine methylation, PRMTs regulate the post-transcriptional processing of nuclear, detained introns.

    1. Cancer Biology
    2. Ecology
    Daniel Garcia-Souto et al.
    Short Report

    Clonally transmissible cancers are tumour lineages that are transmitted between individuals via the transfer of living cancer cells. In marine bivalves, leukaemia-like transmissible cancers, called hemic neoplasia (HN), have demonstrated the ability to infect individuals from different species. We performed whole-genome sequencing in eight warty venus clams that were diagnosed with HN, from two sampling points located more than 1000 nautical miles away in the Atlantic Ocean and the Mediterranean Sea Coasts of Spain. Mitochondrial genome sequencing analysis from neoplastic animals revealed the coexistence of haplotypes from two different clam species. Phylogenies estimated from mitochondrial and nuclear markers confirmed this leukaemia originated in striped venus clams and later transmitted to clams of the species warty venus, in which it survives as a contagious cancer. The analysis of mitochondrial and nuclear gene sequences supports all studied tumours belong to a single neoplastic lineage that spreads in the Seas of Southern Europe.