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Sci Rep. 2016 Oct 14;6:34523. doi: 10.1038/srep34523.

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

Author information

1
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.

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.

PMID:
27739445
PMCID:
PMC5064353
DOI:
10.1038/srep34523
[Indexed for MEDLINE]
Free PMC Article

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