Toxicity: Fishing for protective compounds

A new zebrafish study identifies compounds that shield ears and kidneys against an anticancer drug.
  1. Giuliano Ciarimboli  Is a corresponding author
  1. Experimental Nephrology, Med. Clinic D, Muenster University Hospital, Germany

Cancer treatments have become increasingly effective over the past few decades, but the chemotherapy drugs that kill tumour cells also damage healthy tissues. This can lead to serious side effects that go on to impair the quality of life of patients after recovery. For instance, cisplatin, a drug used to treat testicular cancer, is toxic to kidneys and hair cells in the ear that are necessary for hearing processes (Daugaard, 1990Einhorn, 2002; Rybak and Ramkumar, 2007; Pabla and Dong, 2008; Lanvers-Kaminsky et al., 2017). Now, in eLife, Jason Berman and colleagues in institutions across Canada – including Jamie Wertman as first author – report the results of a study screening for compounds that reduce the toxicity of cisplatin (Wertman et al., 2020).

To do so, the team enlisted the zebrafish Danio rerio, a tiny freshwater tropical fish similar to humans at the molecular level, but can be bred cheaply and quickly (Schartl, 2014). It has become an exceptionally important in vivo model for biomedical research, especially to test the toxicity of drugs such as cisplatin or the antibiotics gentamicin (Rocha-Sanchez et al., 2018; Swanhart et al., 2011). Indeed, even at the larval stage, the fish has easily accessible hair cells in its lateral line (a sensory organ under the skin), and a primitive, anatomically simple kidney (Swanhart et al., 2011).

Wertman et al. examined whether 1200 compounds could protect the kidneys and lateral line hair cells of zebrafish larvae against the toxic effects of cisplatin. The screening highlighted 22 molecules, including two that offered the highest levels of protection: dopamine, a compound that nerve cells use to communicate, and L-mimosine, a rare plant non-protein amino acid similar to the amino acid tyrosine (Figure 1). Their protective potential was confirmed in vivo in the primitive kidney and another population of hair cells in zebrafish larvae. In addition, dopamine and L-mimosine did not keep cisplatin from killing cancer cells grown in the laboratory.

Protective effects of dopamine and L-mimosine against the cancer drug cisplatin.

Treatment of zebrafish larvae with cisplatin (panel A) impairs the function (lightning bolt icon) of the fish's primitive kidney (pronephros), and of its anterior and posterior lateral line – the organs that display hair cells similar to the ones found in ears. Application of dopamine or L-mimosine (panel B) suppresses the toxic effects of cisplatin.

The next step would be to investigate how dopamine and L-mimosine perform this protective role. Organic cation transporters are a family of proteins that help to carry molecules – including dopamine – into cells. In their absence, cisplatin is less toxic for ears and kidneys (Hucke et al., 2019). It is therefore possible that dopamine and L-mimosine compete with cisplatin for access to the transporters: this would result in fewer cisplatin molecules accessing kidney and ear hair cells, ultimately protecting the organs against the cancer drug.

Finally, it is essential to demonstrate that dopamine and L-mimosine do not impair the anticancer activity of cisplatin in vivo, which could also be done in zebrafish larvae. In addition, this animal model could be useful to study neurotoxicity, another potential side effect of the drug. This would allow scientists to investigate whether the two compounds only protect specific organs, or globally interfere with cisplatin activity.

Confirming that dopamine and L-mimosine preserve the anticancer properties of cisplatin in vivo, together with fully understanding how they shield ears and kidneys from the drug’s toxicity should help to develop protective therapies. Ultimately, this would allow more aggressive cancer chemotherapy to be performed, and improve the quality of life of cancer survivors.

References

    1. Daugaard G
    (1990)
    Cisplatin nephrotoxicity: experimental and clinical studies
    Danish Medical Bulletin 37:1–12.

Article and author information

Author details

  1. Giuliano Ciarimboli

    Giuliano Ciarimboli is in the Experimental Nephrology, Med. Clinic D, Muenster University Hospital, Muenster, Germany

    For correspondence
    gciari@uni-muenster.de
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4365-3656

Publication history

  1. Version of Record published: September 3, 2020 (version 1)

Copyright

© 2020, Ciarimboli

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 586
    views
  • 32
    downloads
  • 0
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Giuliano Ciarimboli
(2020)
Toxicity: Fishing for protective compounds
eLife 9:e61547.
https://doi.org/10.7554/eLife.61547

Further reading

    1. Cancer Biology
    Pirunthan Perampalam, James I MacDonald ... Frederick A Dick
    Research Article

    Dormancy in cancer is a clinical state in which residual disease remains undetectable for a prolonged duration. At a cellular level, rare cancer cells cease proliferation and survive chemotherapy and disseminate disease. We created a suspension culture model of high-grade serous ovarian cancer (HGSOC) dormancy and devised a novel CRISPR screening approach to identify survival genes in this context. In combination with RNA-seq, we discovered the Netrin signaling pathway as critical to dormant HGSOC cell survival. We demonstrate that Netrin-1, –3, and its receptors are essential for low level ERK activation to promote survival, and that Netrin activation of ERK is unable to induce proliferation. Deletion of all UNC5 family receptors blocks Netrin signaling in HGSOC cells and compromises viability during the dormancy step of dissemination in xenograft assays. Furthermore, we demonstrate that Netrin-1 and –3 overexpression in HGSOC correlates with poor outcome. Specifically, our experiments reveal that Netrin overexpression elevates cell survival in dormant culture conditions and contributes to greater spread of disease in a xenograft model of abdominal dissemination. This study highlights Netrin signaling as a key mediator HGSOC cancer cell dormancy and metastasis.

    1. Cancer Biology
    2. Cell Biology
    Camille Dantzer, Justine Vaché ... Violaine Moreau
    Research Article

    Immune checkpoint inhibitors have produced encouraging results in cancer patients. However, the majority of ß-catenin-mutated tumors have been described as lacking immune infiltrates and resistant to immunotherapy. The mechanisms by which oncogenic ß-catenin affects immune surveillance remain unclear. Herein, we highlighted the involvement of ß-catenin in the regulation of the exosomal pathway and, by extension, in immune/cancer cell communication in hepatocellular carcinoma (HCC). We showed that mutated ß-catenin represses expression of SDC4 and RAB27A, two main actors in exosome biogenesis, in both liver cancer cell lines and HCC patient samples. Using nanoparticle tracking analysis and live-cell imaging, we further demonstrated that activated ß-catenin represses exosome release. Then, we demonstrated in 3D spheroid models that activation of β-catenin promotes a decrease in immune cell infiltration through a defect in exosome secretion. Taken together, our results provide the first evidence that oncogenic ß-catenin plays a key role in exosome biogenesis. Our study gives new insight into the impact of ß-catenin mutations on tumor microenvironment remodeling, which could lead to the development of new strategies to enhance immunotherapeutic response.