Tumor angiogenesis plays an essential role in carcinogenesis, cancer progression, and metastasis. The inflammation is a key feature of the environment within and around tumors. Some studies indicate that the lipoxins, endogenous anti-inflammatory lipid mediators, might be involved in tumor angiogenesis. Lipoxins (LXs) are trihydroxytetraene-containing eicosanoids. The transcellular biosynthetic pathways, involving either 5- and 15-lipoxygenases or 5- and 12-lipoxygenases, generate LXs. A growing list of inflammation-related disease models extensively studies LXs. LXA4 is an important anti-inflammatory and proresolving lipid-based autacoids in inflammation. LXs have important properties. They include the ability to attenuate reactive oxygen species. es generation in lipopolysaccharide-stimulated macrophages, the influence on stored-operated channels in erythroleukemia cells, and the capability to attenuate acute lung injury in lipopolysaccharide-treated mice. In addition, LXs has involved in tumor angiogenesis. In this study, BML-111, a lipoxin A4 analog, is a lipoxin A4 receptor agonist.
BML-111 is a lipoxin A4 receptor agonist with antiangiogenic, antitumor, and anti-inflammatory properties.
BML-111 represses the activity of angiotensin converting enzyme (ACE) and increases the activity of ACE2. In H22 cells, BML-111 inhibits the production of vascular endothelial growth factor and reduces hypoxia-inducible factor-1α level. It also inhibits leukotriene B4-induced cellular migration with an IC50 of 5 nM. Furthermore, BML-111 treatment suppresses tumor-related angiogenesis and tumor growth in vivo. BML-111 also enhances the in situ apoptosis while inhibiting macrophage infiltration in tumor tissue. Furthermore, BML-111 protects LPS-induced acute lung injury and LPS/D-GalN-induced acute liver injury. BML-111 represses the activity of ACE but increases the activity of ACE2. BML-111 decreases the expression levels of ACE, AngII, and AngII type 1 receptor (AT1R), meanwhile increases the levels of ACE2, angiotensin-(1-7) (Ang-1-7), and Mas.
In summary, BML-111 has antiangiogenic, antitumor, and anti-inflammatory properties. Meanwhile, LXs and their analogs are potential angiogenesis inhibitors and antitumor agents.