A novel screening method for transition metal‐based anticancer compounds using zebrafish embryo‐larval assay and inductively coupled plasma‐mass spectrometry analysis

As novel metallodrugs continue to emerge, they are evaluated using models, including zebrafish, that offer unique sublethal endpoints. Testing metal‐based anticancer compounds with high‐throughput zebrafish toxicological assays requires analytical methods with the sensitivity to detect these subleth...

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Bibliographic Details
Published in:Journal of applied toxicology 2019-08, Vol.39 (8), p.1173-1180
Main Authors: Karas, Brittany F., Côrte‐Real, Leonor, Doherty, Cathleen L., Valente, Andreia, Cooper, Keith R., Buckley, Brian T.
Format: Article
Language:English
Subjects:
analytical
Analytical methods
Animals
anticancer agents
Antineoplastic Agents - chemistry
Antineoplastic Agents - toxicity
Apoptosis
Apoptosis - drug effects
Assaying
Biological Assay
Cancer
Chemotherapy
Chorion
Cisplatin
Cisplatin - chemistry
Cisplatin - toxicity
Danio rerio
Dose-Response Relationship, Drug
dose‐response
Embryo, Nonmammalian - drug effects
Embryo, Nonmammalian - pathology
Embryonic Development - drug effects
Embryos
Exposure
Hatching
ICPMS
Inductively coupled plasma mass spectrometry
Larva - drug effects
Lesions
Lethality
Mass spectrometry
Mass spectroscopy
Metallodrugs
Metals
Organometallic Compounds - chemistry
Organometallic Compounds - toxicity
Platinum
Quantitation
Ruthenium
Ruthenium - chemistry
Ruthenium - toxicity
ruthenium organometallic compounds
Scientific imaging
Screening
Sensitivity analysis
Spectrophotometry, Atomic
Spectroscopy
sublethal
Toxicity
Toxicology
Transition metals
Zebrafish
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Summary:As novel metallodrugs continue to emerge, they are evaluated using models, including zebrafish, that offer unique sublethal endpoints. Testing metal‐based anticancer compounds with high‐throughput zebrafish toxicological assays requires analytical methods with the sensitivity to detect these sublethal tissue doses in very small sample masses (e.g., egg mass 100 μg). A robust bioanalytical model, zebrafish embryos coupled with inductively coupled plasma‐mass spectrometry (ICPMS) for measurement of delivered dose, creates a very effective means for screening metal‐based chemotherapeutic agents. In this study, we used ICPMS quantitation with the zebrafish embryo assays to detect metal equivalents at multiple response endpoints for two compounds, the chemotherapeutic agent cisplatin and ruthenium (Ru)‐based prospective metallodrug, PMC79. We hypothesized that cisplatin and PMC79 have different mechanisms for inducing apoptosis and result in similar lesions but different potencies following water‐borne exposure. An ICPMS method was developed to detect the metal in waterborne solution and tissue (detection limit: 5 parts per trillion for Ru or platinum [Pt]). The Ru‐based compound was more potent (LC50: 7.8 μm) than cisplatin (LC50: 158 μm) and induced disparate lesions. Lethality from cisplatin exposure exhibited a threshold (values >15 mg/L) while no threshold was observed for delayed hatching (lowest observed adverse effect level 3.75 mg/L cisplatin; 8.7 Pt (ng)/organism). The Ru organometallic did not have a threshold for lethality. Cisplatin‐induced delayed hatching was investigated further by larval‐Pt distribution and preferentially distributed to the chorion. We propose that zebrafish embryo‐larval assays coupled with ICPMS serve as a powerful platform to evaluate relative potency and toxic effects of metallodrug candidates. Anticancer metallodrug evaluation requires a high‐throughput model, testing potency and toxicity. This study evaluated inductively coupled plasma‐mass spectrometry metal equivalent detection coupled with a zebrafish embryo‐larval assay. We evaluated a popular chemotherapeutic, cisplatin, with a novel ruthenium‐based anticancer compound, PMC79. This method allowed comparison of the two compounds showing different uptake, distribution, potency and lesions. We believe this bioanalytical model will serve as a platform for metallodrug evaluation.
ISSN:0260-437X
1099-1263
1099-1263
DOI:10.1002/jat.3802