Butler Clare T, Reynolds Alison L, Tosetto Miriam, Dillon Eugene T, Guiry Patrick J, Cagney Gerard, O'Sullivan Jacintha, Kennedy Breandán N
From the UCD School of Biomolecular and Biomedical Science, UCD Conway Institute and.
Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin 4, Ireland, and.
J Biol Chem. 2017 Mar 3;292(9):3552-3567. doi: 10.1074/jbc.M116.747766. Epub 2016 Dec 29.
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 (CysLT and CysLT). Here, we screened a series of quininib analogues and identified a more potent antiangiogenic novel chemical entity (IUPAC name ()-2-(2-quinolin-2-yl-vinyl)-benzene-1,4-diol HCl) hereafter designated Q8. Q8 inhibits developmental angiogenesis in Tg(:EGFP) zebrafish and inhibits human microvascular endothelial cell (HMEC-1) proliferation, tubule formation, and migration. Q8 elicits antiangiogenic effects in a VEGF-independent model of angiogenesis and exerts an additive antiangiogenic response with the anti-VEGF biologic bevacizumab. Cell-based receptor binding assays confirm that Q8 is a CysLT antagonist 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.
血管过度生长会导致转移性癌症和年龄相关性视网膜病变的病理过程。尽管已开发出改进的治疗方法，但这些病症仍伴随着高昂的经济成本和耐药性。贝伐单抗（阿瓦斯汀®）是一种抗血管内皮生长因子（VEGF）的单克隆抗体，临床上用于治疗某些类型的转移性癌症。不幸的是，许多患者对贝伐单抗无反应或不可避免地产生耐药性，这凸显了对具有新型作用机制的更有效抗血管生成药物的需求。先前的研究发现了喹尼inib，一种半胱氨酰白三烯受体1和2（CysLT1和CysLT2）的抗血管生成小分子拮抗剂。在此，我们筛选了一系列喹尼inib类似物，并鉴定出一种更有效的抗血管生成新型化学实体（IUPAC名称（）-2-（2-喹啉-2-基-乙烯基）-苯-1,4-二醇HCl），以下简称Q8。Q8抑制Tg（：EGFP）斑马鱼的发育性血管生成，并抑制人微血管内皮细胞（HMEC-1）的增殖、小管形成和迁移。Q8在不依赖VEGF 的血管生成模型中引发抗血管生成作用，并与抗VEGF生物制剂贝伐单抗产生相加的抗血管生成反应。基于细胞的受体结合试验证实Q8是一种CysLT拮抗剂，足以降低细胞内NF-κB和钙蛋白酶-2的水平以及促血管生成蛋白细胞间粘附分子-1、血管细胞粘附蛋白-1和VEGF的分泌水平。贝伐单抗对VEGF的明显降低解释了与Q8联合使用时观察到的相加抗血管生成作用。总之，与喹尼inib相比，Q8是一种更有效的抗血管生成药物。不依赖VEGF的活性以及与贝伐单抗联合观察到的相加抗血管生成反应表明，Q8提供了一种替代治疗策略，以对抗与传统抗VEGF疗法相关的耐药性。
