title: Luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis.
abstract: Angiogenesis, the formation of new blood vessels from pre-existing vascular beds, is essential for tumor growth, invasion, and metastasis. Luteolin is a common dietary flavonoid found in fruits and vegetables. We studied the antiangiogenic activity of luteolin using in vitro, ex vivo, and in vivo models. In vitro studies using rat aortic ring assay showed that luteolin at non-toxic concentrations significantly inhibited microvessel sprouting and proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Luteolin also inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay. Gelatin zymographic analysis demonstrated the inhibitory effect of luteolin on the activation of matrix metalloproteinases MMP-2 and MMP-9. Western blot analysis showed that luteolin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 in HUVECs. Proinflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α level were significantly reduced by the treatment of luteolin in PC-3 cells. Luteolin (10 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that luteolin inhibited tumorigenesis by targeting angiogenesis. CD31 and CD34 immunohistochemical staining further revealed that the microvessel density could be remarkably suppressed by luteolin. Moreover, luteolin reduced cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 expressions. Taken together, our findings demonstrate that luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis.
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: Young-Ok
authors.initials: YO
authors.lastname: Son
authors.forename: Amit
authors.initials: A
authors.lastname: Budhraja
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
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: Donghern
authors.initials: D
authors.lastname: Kim
authors.forename: Sasidharan Padmaja
authors.initials: SP
authors.lastname: Divya
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D047311:Luteolin / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D055806:Microvessels / Q000187:drug effects / Q000502:physiology; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; 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; D048049:Extracellular Signal-Regulated MAP Kinases; D020782:Matrix Metalloproteinases; D047311:Luteolin