BML-111, the lipoxin A4 agonist, modulates VEGF or CoCl2-induced migration, angiogenesis and permeability in tumor-derived endothelial cells.

Tumor angiogenesis plays a vital role in carcinogenesis, cancer progression, and metastasis. Lipoxin A4 (LXA4) is an endogenously-produced family of effective anti-inflammatory with a potent inhibitory effect on angiogenesis. However, BML-111, a LXA4 agonist, its governing tumor-derived endothelial cells (Td-EC) mechanisms remain unknown. In the present study, we utilized VEGF or CoCl2 to mimic tumor microenvironment in vitro to study the effect of BML-111 on angiogenesis and permeability of Td-EC, and preliminarily explore its specific mechanism. Data suggested that BML-111 inhibited viability, migration and angiogenesis in VEGF or CoCl2-treated Td-EC by modulating MMP2/9-TIMP1, and decreasing the production of HIF-1α and COX-2 level. In addition, we observed that BML-111 inhibited Td-EC permeability induced by VEGF or CoCl2, through the stabilization of VE-cadherin/β-catenin-dependent adherens junctions and TRPC1 pathway. Nevertheless, these effects could be blocked by BOC-2 which was the specific inhibitor of FPR2/ALX (the receptor of LXA4).These results suggest that BML-111 may have inhibitory effects on VEGF or CoCl2-induced migration, angiogenesis and permeability in tumor-derived endothelial cells.