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  • EphB promotes tumor growth by stimulating angiogenesis throu


    EphB4 promotes tumor growth by stimulating angiogenesis through EphrinB2 [18]. However, the distinct and specifically involvement of Sitagliptin phosphate monohydrate and veins in the tumor angiogenesis of all tumor grades is unclear. Our results indicate that the relation between EphrinB2 and EphB4 stained blood vessels was also unchanged in all tumor grades. These data support the suggestion that EphrinB2 and EphB4 mediate reciprocal interactions of all tumor grades with an unchanged relation between arteries and veins in the tumor angiogenesis. The relation between arteries and veins is not dependent on tumor types and tumor grades. The VEGF-mediated arteriogenesis is modulated by angiopoietins, and it was shown that angiopoietin-1 can block the decrease of venous endothelial cells mediated by VEGF [14]. Therefore, our future experiments should clear the roles of EphB4 and EphrinB2 in VEGF-mediated tumor angiogenesis in tumor tissues of the urogenital tract.
    Introduction Angiogenesis plays a significant role in the pathogenesis of a variety of disorders including cancer, proliferative retinopathies, rheumatoid arthritis or psoriasis [1]. In addition, angiogenesis is widely identified as a crucial factor in metastasis, which is a major contributor to cancer-related death. Therefore, inhibition of angiogenesis has been considered as an attractive strategy for the treatment of cancers. Many anti-angiogenesis agents have been under clinical trial, or approved for clinical use. On the opposite, many limitations have been disclosed including resistance, enhancing hypoxia, and reducing delivery of drugs. Intracellular signals for angiogenesis including cell growth, proliferation, migration, and survival are frequently triggered by receptor tyrosine kinases (RTKs). Cancer cells secrete various RTKs involved in the process of angiogenesis [2]. Interaction of vascular endothelial growth factors (VEGFs) and its receptor (VEGF Receptor-2, VEGFR-2) promotes epithelial cell (EC) survival, proliferation, and migration [3]. Angiopoietin (Ang) and its receptor (tyrosine kinase with Ig and epidermal growth factor homology domain-2, Tie-2) are essential for vessel maturation, stabilization, and remodeling of vasculature [4]. Activation of erythropoietin-producing hepatoma receptor B4 (EphB4) by its membrane-associated ligand, ephrinB2, is critical for vessel maturation, remodeling, and stabilization [5]. The possibility of inhibiting angiogenic RTK has led to development of specific RTK inhibitors as anti-angiogenesis and anticancer agents. However, acquired resistance caused by compensatory activation of multiple RTKs limit the benefit of these drugs [6]. It has been revealed that simultaneous inhibition and combinatorial targeting of multiple pro-angiogenic RTKs have been recognized as valuable strategies to maximize the therapeutic potential [7]. There are several small molecular multi-target RTK inhibitors in clinical trials as anti-angiogenesis agents. Five drugs with different inhibition profile against angiogenic RTKs have been approved including Sorafenib (Nexavar, Bayer) [8], Regorafenib (Stivarga, Bayer), Linifanib (ABT-869, Abbott) [9], Vandetanib (Caprelsa, AstraZeneca) [10], and Cabozantinib (Cabometyx, Exelixis) [11] (Fig. 1). Encouraged by previous results, we described here the discovery of a series of multiplex inhibitors of VEGFR-2/EphB4/TIE-2 as novel anti-angiogenesis agents. To the best of our knowledge, all the three RTKs contain a highly conserved catalytic site binding with ATP. The catalytic domains and ATP-binding site in the active conformation of these RTKs are notably similar. Moreover, it is reasonable to assume that all the ATP-competitive RTKIs with anti-angiogenesis potency bind to the ATP binding site of RTKs. Overlay of the crystal structures of the three RTKs is depicted in Fig. 2. Structural alignment indicated that there was no significant difference. The RMSD values for them are 0.849 Å, 0.725 Å, and 0.706 Å, respectively. As the structures display a similar two-lobed architecture and highly similar to each other, we believe that the similarity of kinase domains makes the multiplex inhibitors a feasible drug discovery strategy.