Options
Preclinical validation of the small molecule drug quininib as a novel therapeutic for colorectal cancer
Date Issued
2016-10-14
Date Available
2017-01-30T15:35:44Z
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.
Sponsorship
Science Foundation Ireland
University College Dublin
Type of Material
Journal Article
Publisher
Nature Publishing Group
Journal
Scientific Reports
Volume
6
Copyright (Published Version)
2016 the Authors
Language
English
Status of Item
Peer reviewed
This item is made available under a Creative Commons License
File(s)
Owning collection
Scopus© citations
15
Acquisition Date
Mar 28, 2024
Mar 28, 2024
Views
1607
Acquisition Date
Mar 28, 2024
Mar 28, 2024
Downloads
419
Last Week
1
1
Last Month
11
11
Acquisition Date
Mar 28, 2024
Mar 28, 2024