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

Adrian G. Murphy, Rory Casey, Aoife Maguire, Miriam Tosetto, Clare T. Butler, Emer Conroy, Alison L. Reynolds, Kieran Sheahan, Diarmuid O'Donoghue, William M. Gallagher, David Fennelly, Breandán N. Kennedy, Jacintha O'Sullivan

Research output: Contribution to journalArticlepeer-review

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 v β 3 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.

Original languageEnglish (US)
Article number34523
JournalScientific reports
Volume6
DOIs
StatePublished - Oct 14 2016
Externally publishedYes

ASJC Scopus subject areas

  • General

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