title: Quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR- 2 regulated AKT/mTOR/P70S6K signaling pathways.
abstract: Angiogenesis is a crucial step in the growth and metastasis of cancers, since it enables the growing tumor to receive oxygen and nutrients. Cancer prevention using natural products has become an integral part of cancer control. We studied the antiangiogenic activity of quercetin using ex vivo, in vivo and in vitro models. Rat aortic ring assay showed that quercetin at non-toxic concentrations significantly inhibited microvessel sprouting and exhibited a significant inhibition in the proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Most importantly, quercetin treatment inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay. Western blot analysis showed that quercetin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, mTOR, and ribosomal protein S6 kinase in HUVECs. Quercetin (20 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that quercetin inhibited tumorigenesis by targeting angiogenesis. Furthermore, quercetin reduced the cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.
authors.affiliation: Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Poyil
authors.initials: P
authors.lastname: Pratheeshkumar
authors.forename: Amit
authors.initials: A
authors.lastname: Budhraja
authors.forename: Young-Ok
authors.initials: YO
authors.lastname: Son
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Songze
authors.initials: S
authors.lastname: Ding
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Andrew
authors.initials: A
authors.lastname: Hitron
authors.forename: Jeong-Chae
authors.initials: JC
authors.lastname: Lee
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002642:Chick Embryo; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010766:Phosphorylation; D011467:Prostate / Q000098:blood supply* / Q000187:drug effects* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D011794:Quercetin; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases