Two Chinese Traditional Medicine Monomers Inhibit Tumor Angiogenesis

Angiogenesis is a complex, multistep process which starts with vascular endothelial growth factor (VEGF) A-induced vasodilatation and increased vascular permeability of pre-existing capillaries. The vascular permeability allows the extravasation of plasma proteins such as fibrinogen, which is subsequently converted to fibrin serving as a provisional matrix for migrating endothelial cells. To allow endothelial cells to migrate towards angiogenic stimuli, the vascular basement membrane and extracellular matrix surrounding pre-existing capillaries are degraded by proteases secreted by tumor cells and supporting cells. Subsequently, endothelial cells proliferate, invade the surrounding extracellular matrix and adhere to each other to form hollow tubes. Algire and chalkley were the first to suggest that tumor growth is closely connected to the development of an intrinsic vascular network. Angiogenesis is necessary to provide oxygen and nutrients to the tumor cells and also to remove waste products. Antiangiogenic therapy is now considered to be a prospective strategy.Hispidulin, extracted from Artemisia vestita, a traditional Tibetan medicinal plant, has been used traditionally in China for treating various inflammatory diseases. It has been reported that hispidulin shows anti-inflammatory, antiproliferative, antifungal, antioxidant, and anticonvulsant properties. In this study, we found that hispidulin significantly inhibited human pancreatic tumor growth in xenograft mice when subcutaneously treated at dosage of 20 mg/kg daily (P<0.001), and this effect is accompanied with a potent inhibition on angiogenesis. In vivo and ex vivo angiogenesis assays, we further demonstrated that hispidulin suppressed VEGF-induced corneal neovascularization in C57/BL6 mice and microvessel sprouting of rat aortic rings. These suggests hispidulin could be a potential angiogenesis inhibitor. Our results further showed that hispidulin inhibited vascular endothelial growth factor (VEGF)-induced cell migration, invasion and capillary-like structure formation of HUVECs in a dose-dependent manner. To understand the underlying molecular basis, we next examined the effects of hispidulin on different molecular components in treated HUVECs, and found that 10μM hispidulin suppressed the VEGF-triggered the activation of VEGF receptor 2 (VEGFR2) and its downstream signaling pathway Phosphoinositide 3-kinase-AKT-Mammalian Target of Rapamycin (PI3K-AKT-mTOR), but had little effect on Focal Adhesion Kinase (FAK) and (Extracellular Signal-regulated Kinase) ERK at effective concentration. Taken together, our results indicate that hispidulin targets VEGFR2-mediated PI3K7AKT/mTOR signaling pathway in endothelial cells, leading to the suppression of angiogenesis and pancreatic tumor growth.Isodeoxyelephantopin, a compound of sesquterpenoids, has been extracted from Elephantopus scaber L. in recent years. In this study, we found isodeoxyelephantopin could inhibit HUVECs proliferation, migration and tube formation in vitro. But, whether it could inhibit angiogenesis in vivo, and whether it could inhibit tumor growth still need further studies.In summary, we found hispidulin and Isodeoxyelephantopin could be two angiogenic inhibitors, which provides some clues for anti-tumor therapy.