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

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).

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.

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)

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

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

  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
(2020)
The identification of dual protective agents against cisplatin-induced oto-and nephrotoxicity using the zebrafish model
eLife 9:e56235.
https://doi.org/10.7554/eLife.56235

Share this article

https://doi.org/10.7554/eLife.56235

Further reading

    1. Biochemistry and Chemical Biology
    2. Cancer Biology
    Flavie Coquel, Sing-Zong Ho ... Philippe Pasero
    Research Article

    Cancer cells display high levels of oncogene-induced replication stress (RS) and rely on DNA damage checkpoint for viability. This feature is exploited by cancer therapies to either increase RS to unbearable levels or inhibit checkpoint kinases involved in the DNA damage response. Thus far, treatments that combine these two strategies have shown promise but also have severe adverse effects. To identify novel, better-tolerated anticancer combinations, we screened a collection of plant extracts and found two natural compounds from the plant, Psoralea corylifolia, that synergistically inhibit cancer cell proliferation. Bakuchiol inhibited DNA replication and activated the checkpoint kinase CHK1 by targeting DNA polymerases. Isobavachalcone interfered with DNA double-strand break repair by inhibiting the checkpoint kinase CHK2 and DNA end resection. The combination of bakuchiol and isobavachalcone synergistically inhibited cancer cell proliferation in vitro. Importantly, it also prevented tumor development in xenografted NOD/SCID mice. The synergistic effect of inhibiting DNA replication and CHK2 signaling identifies a vulnerability of cancer cells that might be exploited by using clinically approved inhibitors in novel combination therapies.

    1. Cancer Biology
    2. Immunology and Inflammation
    Sofia V Krasik, Ekaterina A Bryushkova ... Ekaterina O Serebrovskaya
    Research Article

    The current understanding of humoral immune response in cancer patients suggests that tumors may be infiltrated with diffuse B cells of extra-tumoral origin or may develop organized lymphoid structures, where somatic hypermutation and antigen-driven selection occur locally. These processes are believed to be significantly influenced by the tumor microenvironment through secretory factors and biased cell-cell interactions. To explore the manifestation of this influence, we used deep unbiased immunoglobulin profiling and systematically characterized the relationships between B cells in circulation, draining lymph nodes (draining LNs), and tumors in 14 patients with three human cancers. We demonstrated that draining LNs are differentially involved in the interaction with the tumor site, and that significant heterogeneity exists even between different parts of a single lymph node (LN). Next, we confirmed and elaborated upon previous observations regarding intratumoral immunoglobulin heterogeneity. We identified B cell receptor (BCR) clonotypes that were expanded in tumors relative to draining LNs and blood and observed that these tumor-expanded clonotypes were less hypermutated than non-expanded (ubiquitous) clonotypes. Furthermore, we observed a shift in the properties of complementarity-determining region 3 of the BCR heavy chain (CDR-H3) towards less mature and less specific BCR repertoire in tumor-infiltrating B-cells compared to circulating B-cells, which may indicate less stringent control for antibody-producing B cell development in tumor microenvironment (TME). In addition, we found repertoire-level evidence that B-cells may be selected according to their CDR-H3 physicochemical properties before they activate somatic hypermutation (SHM). Altogether, our work outlines a broad picture of the differences in the tumor BCR repertoire relative to non-tumor tissues and points to the unexpected features of the SHM process.