BIBLIOS

Document type
Journal articles

Document subtype
Full paper

Title
Anti-cancer activity and in vitro to in vivo mechanistic recapitulation of novel ruthenium-based metallodrugs in the zebrafish model

Participants in the publication
B.F Karas (Author)
RUTGERS UNIVERSITY
J.M Hotz (Author)
RUTGERS UNIVERSITY
B.M Gural (Author)
RUTGERS UNIVERSITY
K.R Terez (Author)
RUTGERS UNIVERSITY
V.L DiBona (Author)
RUTGERS UNIVERSITY
L. Côrte-Real (Author)
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA
CQE
A. Valente (Author)
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA
CQE
B.T Buckley (Author)
RUTGERS UNIVERSITY
K.R Cooper (Author)
RUTGERS UNIVERSITY

Summary
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.


Institution
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA

Where published
Toxicological Sciences

Publication Identifiers

Document Identifiers
DOI - https://doi.org/10.1093/toxsci/kfab041

Rankings
SCIMAGO Q1 (2020) - 1.352 - Toxicology