title: Preclinical validation of the small molecule drug quininib as a novel therapeutic for colorectal cancer.
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 αvβ3integrin 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.
authors.affiliation: Centre for Colorectal Disease, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland.|UCD School of Biomolecular and Biomedical Science Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: Adrian G
authors.initials: AG
authors.lastname: Murphy
authors.affiliation: Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland.
authors.forename: Rory
authors.initials: R
authors.lastname: Casey
authors.affiliation: Department of Histopathology, St. James's Hospital, Dublin 8, Ireland.
authors.forename: Aoife
authors.initials: A
authors.lastname: Maguire
authors.affiliation: Centre for Colorectal Disease, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland.
authors.forename: Miriam
authors.initials: M
authors.lastname: Tosetto
authors.affiliation: UCD School of Biomolecular and Biomedical Science Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: Clare T
authors.initials: CT
authors.lastname: Butler
authors.affiliation: UCD School of Biomolecular and Biomedical Science Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: Emer
authors.initials: E
authors.lastname: Conroy
authors.affiliation: UCD School of Biomolecular and Biomedical Science Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Reynolds
authors.affiliation: Centre for Colorectal Disease, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland.
authors.forename: Kieran
authors.initials: K
authors.lastname: Sheahan
authors.affiliation: Centre for Colorectal Disease, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland.
authors.forename: Diarmuid
authors.initials: D
authors.lastname: O'Donoghue
authors.affiliation: UCD School of Biomolecular and Biomedical Science Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: William M
authors.initials: WM
authors.lastname: Gallagher
authors.affiliation: Centre for Colorectal Disease, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland.
authors.forename: David
authors.initials: D
authors.lastname: Fennelly
authors.affiliation: UCD School of Biomolecular and Biomedical Science Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: Breandán N
authors.initials: BN
authors.lastname: Kennedy
authors.affiliation: Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland.
authors.forename: Jacintha
authors.initials: J
authors.lastname: O'Sullivan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001808:Blood Vessels / Q000187:drug effects; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects; D015870:Gene Expression; D019073:HT29 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000150:complications / Q000378:metabolism*; D010636:Phenols / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D010636:Phenols; D011804:Quinolines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000620980:quininib