Preclinical validation of the small molecule drug quininib as a novel therapeutic for colorectal cancer

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Title: Preclinical validation of the small molecule drug quininib as a novel therapeutic for colorectal cancer
Authors: Murphy, Adrian G.
Casey, Rory
Maguire, Aoife
Butler, Clare T.
Conroy, Emer
Reynolds, Alison
Gallagher, William M.
Kennedy, Breandán
et al.
Permanent link: http://hdl.handle.net/10197/8303
Date: 14-Oct-2016
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 αvβ3 integrin fluorescence probe in tumours 10 days after treatment initiation, indicative of angiogenic inhibition. Furthermore, quininib reduced the expression of angiogenic genes in xenografted tumours. Collectively, these findings support further development of quininib as a novel therapeutic agent for CRC.
Funding Details: Science Foundation Ireland
University College Dublin
Type of material: Journal Article
Publisher: Nature Publishing Group
Copyright (published version): 2016 the Authors
Keywords: Colorectal cancer;Quininib;Small molecule inhibitors
DOI: 10.1038/srep34523
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
Biomolecular and Biomedical Science Research Collection

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