Anti-angiogenesis Research Of Small Molecules On Tumor Growth And Mechanisms

Angiogenesis, the process of generating new capillary blood vessels, plays a critical role in the growth of solid tumors by supplying nutrients and oxygen to and removal of waste from the tumor bed. Angiogenesis also plays essential roles in tumor invasion and metastasis. The angiogenic signaling pathway is mediated by a variety of pro-and anti-angiogenic factors that ultimately lead to the development of neovascular blood. It is well known that vascular endothelial factor (VEGF) plays a pivotal role in this process. VEGF acts its biologic effect mainly through VEGF receptor2(VEGFR-2, also named KDR/Flk-1)-mediated signaling pathways. For these reasons, VEGF and its receptor signaling system are attractive targets for therapeutic intervention.Activation of VEGFR-2leads to the activation of various downstream signal transduction proteins, including extracellular signal-regulated kinase (ERK)、AKT、 FAK、Src family kinase. The serine/threonine kinase AKT/PKB signaling pathway regulates endothelial cell functions such as migration, proliferation, and apoptosis. Moreover, ERK1/2activity has been implicated in diverse cellular activities including cell proliferation, differention, migration and cell death.In this study, using abundant Chinese herbal medicine resources and reforming nature small molecules to the effective structure, we select small molecules which could inhibit tumor angiogenesis obviously through in vitro and in vivo model and further study its molecular mechanisms.Previously studies had shown that usnic acid exhibited anti-inflammatory、 antiproliferative activities and its effect against cancer cells. However, the role of usnic acid in angiogenesis and the related mechanism in endothelial cell has not been reported.In this study, we investigated the functional roles of usnic acid on angiogenesis and breast tumor growth as well as potential mechanism. We found that usnic acid suppressed angiogenesis in CAM assay and corneal micropocket model in vivo and demonstrated that usnic acid significantly inhibited Bcap-37breast tumor growth and angiogenesis in xenograft tumor model. We also found that usnic acid inhibited HUVECs proliferation, migration, and tube formation in in vitro assays. Finally, we showed that usnic acid inhibited angiogenesis and Bcap-37tumor growth via VEGFR2mediated AKT and ERK1/2signaling pathways.Cell movement plays an important role in cell proliferation and migration, and actin involved in a variety of important cellular processes as maintenance cell shape and movements. Actin related protein2/3(Arp2/3) complex plays an important role in cytoskeleton associated processes and Arp2/3complex polymer filaments are directed to maintain many types of cell movement, such as cell-cell adhesion and the lamellipodia formation. Arp2/3complex activation is mainly by its upstream protein N-WASP. N-WASP protein is over expression in tumor cells and expression level is increased with the enhancement of the degree of malignancy, so, the Arp2/3complex inhibitors have potential activities in inhibiting tumor cell proliferation and migration. Previous study revealed that CK-636binded between Arp2and Arp3, where it appeared to block movement of Arp2and Arp3into their active conformation and inhibited its ability to nucleate actin filaments. So, our laboratory designed a series small molecule according to CK-636and found YR290through in vitro, in vivo studies. This study established mouse xenograft tumor model with C57BL/6and focused on detection the effect of YR290on lewis lung cancer growth, this study is under going.Over all, we found a herbal monomer usnic acid, could effectively suppress tumor growth and tumor angiogenesis. Usnic acid inhibited tumor growth and tumor angiogenesis through suppressing VEGFR-2-mediated AKT and ERK1/2signaling pathways. In addition, we performed a xenograft tumor model using C57BL/6mice and evaluated the inhibition activity of YR290, which is a small molecule, on lewis lung cancer tumor by this model.