α-santalol inhibits the angiogenesis and growth of human prostate tumor growth by targeting vascular endothelial growth factor receptor 2-mediated AKT/mTOR/P70S6K signaling pathway

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Abstract

Background: VEGF receptor 2 (VEGFR2) inhibitors, as efficient antiangiogenesis agents, have been applied in the cancer treatment. However, recently, most of these anticancer drugs have some adverse effects. Discovery of novel VEGFR2 inhibitors as anticancer drug candidates is still needed. Methods: We used a-santalol and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVECs) and Prostate tumor cells (PC-3 or LNCaP) in vitro. Tumor xenografts in nude mice were used to examine the in vivo activity of a-santalol. Results: a-santalol significantly inhibits HUVEC proliferation, migration, invasion, and tube formation. Western blot analysis indicated that a-santalol inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including AKT, ERK, FAK, Src, mTOR, and pS6K in HUVEC, PC-3 and LNCaP cells. a-santalol treatment inhibited ex vivo and in vivo angiogenesis as evident by rat aortic and sponge implant angiogenesis assay. a-santalol significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model. The antiangiogenic effect by CD31 immunohistochemical staining indicated that a-santalol inhibited tumorigenesis by targeting angiogenesis. Furthermore, a-santalol reduced the cell viability and induced apoptosis in PC-3 cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Molecular docking simulation indicated that a-santalol form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR2 kinase unit. Conclusion: a-santalol inhibits angiogenesis by targeting VEGFR2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.

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Saraswati, S., Kumar, S., & Alhaider, A. A. (2013). α-santalol inhibits the angiogenesis and growth of human prostate tumor growth by targeting vascular endothelial growth factor receptor 2-mediated AKT/mTOR/P70S6K signaling pathway. Molecular Cancer, 12(1). https://doi.org/10.1186/1476-4598-12-147

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