Preclinical validation of the small molecule drug quininib as a novel therapeutic for colorectal cancer.
AuthorsMurphy, Adrian G
Butler, Clare T
Reynolds, Alison L
Gallagher, William M
Kennedy, Breandán N
Affiliation1 Centre for Colorectal Disease, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland. 2 UCD School of Biomolecular and Biomedical Science Conway Institute, University College Dublin, Dublin 4, Ireland. 3 Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland. 4 Department of Histopathology, St. James's Hospital, Dublin 8, Ireland.
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CitationMurphy, A. G. et al. Preclinical validation of the small molecule drug quininib as a novel therapeutic for colorectal cancer. Sci. Rep. 6, 34523; doi: 10.1038/srep34523 (2016)
PublisherNature Publishing Group
AbstractColorectal 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
SponsorsAdrian 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
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