A Quininib Analogue and Cysteinyl Leukotreine Receptor Antagonist inhibits VEGF-Independent Angiogenesis and Exerts an Additive Anti-angiogenic Response with Bevacizumab [Cell Biology]

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 anti-angiogenic drugs with novel mechanisms of action. Previous studies discovered quininib, an anti-angiogenic small molecule antagonist of cysteinyl leukotriene receptor 1 and 2 (CysLT1-2). Here, we screened a series of quininib analogues and identified a more potent anti-angiogenic 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 anti-angiogenic effects in a VEGF-independent in vitro model of angiogenesis and exerts an additive anti-angiogenic response with the anti-VEGF biological bevacizumab. Cell-based receptor binding assays confirm Q8 is a CysLT1 antagonist and is sufficient to reduce cellular levels of NF-kB and calpain 2 and secreted levels of pro-angiogenic proteins, ICAM-1, VCAM-1 and VEGF. Distinct reductions of VEGF by bevacizumab explains the additive anti-angiogenic effects observed in combination with Q8. In summary, Q8 is a more effective anti-angiogenic drug compared to quininib. The VEGF-independent activity coupled with the additive anti-angiogenic response observed in combination with bevacizumab demonstrates that Q8 offers an alternative therapeutic strategy to combat resistance associated with conventional anti-VEGF therapies.

from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2ijB3OZ
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