Academic Journal
Anticancer Activity and In Vitro to In Vivo Mechanistic Recapitulation of Novel Ruthenium-Based Metallodrugs in the Zebrafish Model
| Title: | Anticancer Activity and In Vitro to In Vivo Mechanistic Recapitulation of Novel Ruthenium-Based Metallodrugs in the Zebrafish Model |
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| Authors: | Karas, Brittany F, Hotz, Jordan M, Gural, Brian M, Terez, Kristin R, DiBona, Victoria L, Côrte-Real, Leonor, Valente, Andreia, Buckley, Brian T, Cooper, Keith R |
| Contributors: | New Jersey Agricultural Experiment Station, National Institute of Environmental Health Sciences, NIEHS, Fulbright Research, Portuguese Foundation for Science and Technology, Fundação para a Ciência e Tecnologia, National Institutes of Health |
| Source: | Toxicological Sciences ; volume 182, issue 1, page 29-43 ; ISSN 1096-6080 1096-0929 |
| Publisher Information: | Oxford University Press (OUP) |
| Publication Year: | 2021 |
| Description: | Ruthenium is popular as a metal core for chemotherapeutics, due to versatile molecular coordination. Because new metallodrugs are synthesized at high rates, our studies included assays in zebrafish to expedite the initial evaluation as anticancer agents. Here we evaluated novel metallodrugs (PMC79 and LCR134), and cisplatin, a widely used platinum-based chemotherapeutic. We hypothesized that this model could characterize anticancer properties and recapitulate previous in vitro results in vivo. Our findings suggest anticancer properties of PMC79 and LCR134 were similar with less toxicity than cisplatin. Exposures from 24 to 72 h at or below the LOAELs of PMC79 and LCR134 (3.9 µM and 13.5 µm, respectively), impaired blood vessel development and tailfin regeneration. Blood vessel examination through live imaging of larvae revealed distinct regional antiangiogenic impacts. The significant decrease in gene expression of the VEGF-HIF pathway and beta-actin could explain the morphological effects observed in the whole organism following exposure. Tailfin amputation in larvae exposed to PMC79 or LCR134 inhibited tissue regrowth and cell division, but did not impact normal cell proliferation unlike cisplatin. This suggests Ru drugs may be more selective in targeting cancerous cells than cisplatin. Additionally, in vitro mechanisms were confirmed. PMC79 disrupted cytoskeleton formation in larvae and P-glycoprotein transporters in vivo was inhibited at low doses which could limit off-target effects of chemotherapeutics. Our results demonstrate the value for using the zebrafish in metallodrug research to evaluate mechanisms and off-target effects. In light of the findings reported in this article, future investigation of PMC79 and LCR134 are warranted in higher vertebrate models. |
| Document Type: | article in journal/newspaper |
| Language: | English |
| DOI: | 10.1093/toxsci/kfab041 |
| DOI: | 10.1093/toxsci/kfab041/38273183/kfab041.pdf |
| Availability: | https://doi.org/10.1093/toxsci/kfab041 http://academic.oup.com/toxsci/advance-article-pdf/doi/10.1093/toxsci/kfab041/38273183/kfab041.pdf http://academic.oup.com/toxsci/article-pdf/182/1/29/39072352/kfab041.pdf |
| Rights: | https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model |
| Accession Number: | edsbas.9D7FF5FB |
| Database: | BASE |
| DOI: | 10.1093/toxsci/kfab041 |
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