A new zebrafish study identifies compounds that shield ears and kidneys against an anticancer drug.
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, 1990; Einhorn, 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.
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.
Drug-induced ototoxicity: mechanisms, pharmacogenetics, and protective strategiesClinical Pharmacology & Therapeutics 101:491–500.https://doi.org/10.1002/cpt.603
Cisplatin nephrotoxicity: mechanisms and renoprotective strategiesKidney International 73:994–1007.https://doi.org/10.1038/sj.ki.5002786
Beyond the zebrafish: diverse fish species for modeling human diseaseDisease Models & Mechanisms 7:181–192.https://doi.org/10.1242/dmm.012245
Zebrafish kidney development: basic science to translational researchBirth Defects Research Part C: Embryo Today: Reviews 93:141–156.https://doi.org/10.1002/bdrc.20209
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)
Lysine 27-to-methionine (K27M) mutations in the H3.1 or H3.3 histone genes are characteristic of pediatric diffuse midline gliomas (DMGs). These oncohistone mutations dominantly inhibit histone H3K27 trimethylation and silencing, but it is unknown how oncohistone type affects gliomagenesis. We show that the genomic distributions of H3.1 and H3.3 oncohistones in human patient-derived DMG cells are consistent with the DNAreplication-coupled deposition of histone H3.1 and the predominant replication-independent deposition of histone H3.3. Although H3K27 trimethylation is reduced for both oncohistone types, H3.3K27M-bearing cells retain some domains, and only H3.1K27M-bearing cells lack H3K27 trimethylation. Neither oncohistone interferes with PRC2 binding. Using Drosophila as a model, we demonstrate that inhibition of H3K27 trimethylation occurs only when H3K27M oncohistones are deposited into chromatin and only when expressed in cycling cells. We propose that oncohistones inhibit the H3K27 methyltransferase as chromatin patterns are being duplicated in proliferating cells, predisposing them to tumorigenesis.
SOX11 is an embryonic mammary epithelial marker that is normally silenced prior to birth. High SOX11 levels in breast tumours are significantly associated with distant metastasis and poor outcome in breast cancer patients. Here, we show that SOX11 confers distinct features to ER-negative DCIS.com breast cancer cells, leading to populations enriched with highly plastic hybrid epithelial/mesenchymal cells, which display invasive features and alterations in metastatic tropism when xenografted into mice. We found that SOX11+DCIS tumour cells metastasize to brain and bone at greater frequency and to lungs at lower frequency compared to cells with lower SOX11 levels. High levels of SOX11 leads to the expression of markers associated with mesenchymal state and embryonic cellular phenotypes. Our results suggest that SOX11 may be a potential biomarker for breast tumours with elevated risk of developing metastases and may require more aggressive therapies.