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Preclinical validation of the small molecule drug quininib as a novel therapeutic for colorectal cancer.
Murphy, Adrian G Casey, Rory Maguire, Aoife Tosetto, Miriam Butler, Clare T Conroy, Emer Reynolds, Alison L Sheahan, Kieran O'donoghue, Diarmuid Gallagher, William M
Murphy, Adrian G
Casey, Rory
Maguire, Aoife
Tosetto, Miriam
Butler, Clare T
Conroy, Emer
Reynolds, Alison L
Sheahan, Kieran
O'donoghue, Diarmuid
Gallagher, William M
Advisors
Editors
Other Contributors
Date
2016-10-14
Date Submitted
Keywords
cancer
CANCER, COLORECTAL
CANCER, COLORECTAL
Other Subjects
Subject Mesh
Planned Date
Start Date
Collaborators
Principal Investigators
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OA Article
Adobe PDF, 1.43 MB
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Abstract
Colorectal cancer (CRC) is a leading cause of cancer deaths. Molecularly targeted therapies (e.g. bevacizumab) have improved survival rates but drug resistance ultimately develops and newer therapies are required. We identified quininib as a small molecule drug with anti-angiogenic activity using in vitro, ex vivo and in vivo screening models. Quininib (2-[(E)-2-(Quinolin-2-yl) vinyl] phenol), is a small molecule drug (molecular weight 283.75 g/mol), which significantly inhibited blood vessel development in zebrafish embryos (p < 0.001). In vitro, quininib reduced endothelial tubule formation (p < 0.001), cell migration was unaffected by quininib and cell survival was reduced by quininib (p < 0.001). Using ex vivo human CRC explants, quininib significantly reduced the secretions of IL-6, IL-8, VEGF, ENA-78, GRO-α, TNF, IL-1β and MCP-1 ex vivo (all values p < 0.01). Quininib is well tolerated in mice when administered at 50 mg/kg intraperitoneally every 3 days and significantly reduced tumour growth of HT-29-luc2 CRC tumour xenografts compared to vehicle control. In addition, quininib reduced the signal from a α
Language
en
ISSN
2045-2322
eISSN
ISBN
DOI
10.1038/srep34523
PMID
27739445
PMCID
Sponsorships
Adrian Murphy was funded by a Newman Fellowship from the University College Dublin Newman Foundation
to conduct this work. This work was also funded by a Science Foundation Ireland TIDA grant 11/TIDA/B1966