title: A Quininib Analogue and Cysteinyl Leukotriene Receptor Antagonist Inhibits Vascular Endothelial Growth Factor (VEGF)-independent Angiogenesis and Exerts an Additive Antiangiogenic Response with Bevacizumab.
abstract: Excess blood vessel growth contributes to the pathology of metastatic cancers and age-related retinopathies. Despite development of improved treatments, these conditions are associated with high economic costs and drug resistance. Bevacizumab (Avastin®), a monoclonal antibody against vascular endothelial growth factor (VEGF), is used clinically to treat certain types of metastatic cancers. Unfortunately, many patients do not respond or inevitably become resistant to bevacizumab, highlighting the need for more effective antiangiogenic drugs with novel mechanisms of action. Previous studies discovered quininib, an antiangiogenic small molecule antagonist of cysteinyl leukotriene receptors 1 and 2 (CysLT1and CysLT2). Here, we screened a series of quininib analogues and identified a more potent antiangiogenic novel chemical entity (IUPAC name (E)-2-(2-quinolin-2-yl-vinyl)-benzene-1,4-diol HCl) hereafter designated Q8. Q8 inhibits developmental angiogenesis in Tg(fli1:EGFP) zebrafish and inhibits human microvascular endothelial cell (HMEC-1) proliferation, tubule formation, and migration. Q8 elicits antiangiogenic effects in a VEGF-independentin vitromodel of angiogenesis and exerts an additive antiangiogenic response with the anti-VEGF biologic bevacizumab. Cell-based receptor binding assays confirm that Q8 is a CysLT1antagonist and is sufficient to reduce cellular levels of NF-κB and calpain-2 and secreted levels of the proangiogenic proteins intercellular adhesion molecule-1, vascular cell adhesion protein-1, and VEGF. Distinct reductions of VEGF by bevacizumab explain the additive antiangiogenic effects observed in combination with Q8. In summary, Q8 is a more effective antiangiogenic drug compared with quininib. The VEGF-independent activity coupled with the additive antiangiogenic response observed in combination with bevacizumab demonstrates that Q8 offers an alternative therapeutic strategy to combat resistance associated with conventional anti-VEGF therapies.
authors.affiliation: From the UCD School of Biomolecular and Biomedical Science, UCD Conway Institute and.
authors.forename: Clare T
authors.initials: CT
authors.lastname: Butler
authors.affiliation: From the UCD School of Biomolecular and Biomedical Science, UCD Conway Institute and.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Reynolds
authors.affiliation: Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin 4, Ireland, and.
authors.forename: Miriam
authors.initials: M
authors.lastname: Tosetto
authors.affiliation: From the UCD School of Biomolecular and Biomedical Science, UCD Conway Institute and.
authors.forename: Eugene T
authors.initials: ET
authors.lastname: Dillon
authors.affiliation: UCD School of Chemistry, UCD Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Guiry
authors.affiliation: From the UCD School of Biomolecular and Biomedical Science, UCD Conway Institute and.
authors.forename: Gerard
authors.initials: G
authors.lastname: Cagney
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
authors.affiliation: From the UCD School of Biomolecular and Biomedical Science, UCD Conway Institute and brendan.kennedy@ucd.ie.
authors.forename: Breandán N
authors.initials: BN
authors.lastname: Kennedy
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D001555:Benzene Derivatives / Q000494:pharmacology*; D000068258:Bevacizumab / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement; D002470:Cell Survival; D003545:Cysteine / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010636:Phenols / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015027:Zebrafish
chemical_list: D020533:Angiogenesis Inhibitors; D001555:Benzene Derivatives; D020024:Leukotriene Antagonists; D010636:Phenols; D011804:Quinolines; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C000620980:quininib; D049452:Green Fluorescent Proteins; D000068258:Bevacizumab; D003545:Cysteine
keywords: G protein-coupled receptor (GPCR); angiogenesis; calpain; cell migration; colorectal cancer; drug development; endothelial cell; leukotriene; pharmacology; vascular endothelial growth factor (VEGF)