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 pathwayReport as inadecuate




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 - Download this document for free, or read online. Document in PDF available to download.

Molecular Cancer

, 12:147

First Online: 22 November 2013Received: 22 June 2013Accepted: 19 November 2013DOI: 10.1186-1476-4598-12-147

Cite this article as: Saraswati, S., Kumar, S. & Alhaider, A.A. Mol Cancer 2013 12: 147. doi:10.1186-1476-4598-12-147

Abstract

BackgroundVEGF 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.

MethodsWe used α-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 α-santalol.

Resultsα-santalol significantly inhibits HUVEC proliferation, migration, invasion, and tube formation. Western blot analysis indicated that α-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. α-santalol treatment inhibited ex vivo and in vivo angiogenesis as evident by rat aortic and sponge implant angiogenesis assay. α-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 α-santalol inhibited tumorigenesis by targeting angiogenesis. Furthermore, α-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 α-santalol form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR2 kinase unit.

Conclusionα-santalol inhibits angiogenesis by targeting VEGFR2 regulated AKT-mTOR-P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.

Keywordsα-santalol Angiogenesis VEGFR2 AKT-mTOR-P70S6K Molecular docking Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-12-147 contains supplementary material, which is available to authorized users.

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Author: Sarita Saraswati - Shakti Kumar - Abdulqader A Alhaider

Source: https://link.springer.com/







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