Luteolin inhibits vascular endothelial growth factor-induced angiogenesis; inhibition of endothelial cell survival and proliferation by targeting phosphatidylinositol 3'-kinase activity

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dc.contributor.authorBagli, E.en
dc.contributor.authorStefaniotou, M.en
dc.contributor.authorMorbidelli, L.en
dc.contributor.authorZiche, M.en
dc.contributor.authorPsillas, K.en
dc.contributor.authorMurphy, C.en
dc.contributor.authorFotsis, T.en
dc.date.accessioned2015-11-24T19:05:56Z
dc.date.available2015-11-24T19:05:56Z
dc.identifier.issn0008-5472-
dc.identifier.urihttps://olympias.lib.uoi.gr/jspui/handle/123456789/20273
dc.rightsDefault Licence-
dc.subjectAngiogenesis Inhibitors/*pharmacologyen
dc.subjectAnimalsen
dc.subjectCell Division/drug effectsen
dc.subjectCell Survival/drug effectsen
dc.subjectCells, Cultureden
dc.subjectEndothelial Cells/cytology/*drug effectsen
dc.subjectFemaleen
dc.subjectHumansen
dc.subjectLuteolin/*pharmacologyen
dc.subjectMiceen
dc.subjectMice, Inbred BALB Cen
dc.subjectMitogen-Activated Protein Kinases/metabolismen
dc.subjectNeoplasms, Experimental/blood supply/drug therapyen
dc.subjectPhosphatidylinositol 3-Kinases/*antagonists & inhibitorsen
dc.subjectPhosphorylationen
dc.subjectProtein-Serine-Threonine Kinases/metabolismen
dc.subjectProto-Oncogene Proteins/metabolismen
dc.subjectProto-Oncogene Proteins c-akten
dc.subjectRabbitsen
dc.subjectRibosomal Protein S6 Kinases/metabolismen
dc.subjectVascular Endothelial Growth Factor A/*antagonists & inhibitorsen
dc.subjectp38 Mitogen-Activated Protein Kinases/metabolismen
dc.titleLuteolin inhibits vascular endothelial growth factor-induced angiogenesis; inhibition of endothelial cell survival and proliferation by targeting phosphatidylinositol 3'-kinase activityen
heal.abstractIn an attempt to identify phytochemicals contributing to the well-documented preventive effect of plant-based diets on cancer incidence and mortality, we have previously shown that certain flavonoids inhibit in vitro angiogenesis. Here, we show that the flavonoid luteolin inhibited tumor growth and angiogenesis in a murine xenograft model. Furthermore, luteolin inhibited vascular endothelial growth factor (VEGF)-induced in vivo angiogenesis in the rabbit corneal assay. In agreement, luteolin inhibited both VEGF-induced survival and proliferation of human umbilical vein endothelial cells (HUVECs) with an IC(50) of about 5 mumol/L. Luteolin inhibited VEGF-induced phosphatidylinositol 3'-kinase (PI3K) activity in HUVECs, and this inhibition was critical for both the antisurvival and antimitotic affects of the compound. Indeed, luteolin abolished VEGF-induced activation of Akt, a downstream target of PI3K conveying both survival and mitotic downstream signals. Because overexpression of a constitutively active form of Akt rescued HUVECs only from the antisurvival effects of luteolin, the result indicated that luteolin targeted mainly the survival signals of the PI3K/Akt pathway. With regard to its antimitotic activity, luteolin inhibited VEGF-induced phosphorylation of p70 S6 kinase (S6K), a downstream effector of PI3K responsible for G(1) progression. Indeed, VEGF-induced proliferation of HUVECs was sensitive to rapamycin, an inhibitor of p70 S6K activation. Surprisingly, luteolin did not affect VEGF-induced phosphorylation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases, a pathway that is considered important for the mitotic effects of VEGF. Thus, blockade of PI3K by luteolin was responsible for the inhibitory effects of the compound on VEGF-induced survival and proliferation of HUVECs. The antisurvival effects of luteolin were mediated via blockage of PI3K/Akt-dependent pathways, whereas inhibition of the PI3K/p70 S6K pathway mediated the antimitotic effects of the compound.en
heal.accesscampus-
heal.fullTextAvailabilityTRUE-
heal.identifier.primary10.1158/0008-5472.CAN-03-3104-
heal.identifier.secondaryhttp://www.ncbi.nlm.nih.gov/pubmed/15520200-
heal.identifier.secondaryhttp://cancerres.aacrjournals.org/content/64/21/7936.full.pdf-
heal.journalNameCancer Resen
heal.journalTypepeer-reviewed-
heal.languageen-
heal.publicationDate2004-
heal.recordProviderΠανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικήςel
heal.typejournalArticle-
heal.type.elΆρθρο Περιοδικούel
heal.type.enJournal articleen

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