title: Resveratrol derivative, trans-3,5,4'-trimethoxystilbene, exerts antiangiogenic and vascular-disrupting effects in zebrafish through the downregulation of VEGFR2 and cell-cycle modulation.
abstract: Angiogenesis plays an important role in the development of neoplastic diseases such as cancer. Resveratrol and its derivatives exert antiangiogenic effects, but the mechanisms of their actions remain unclear. The aim of this study was to evaluate the antiangiogenic activity of resveratrol and its derivative trans-3,5,4'-trimethoxystilbene in vitro using human umbilical vein endothelial cells (HUVECs) and in vivo using transgenic zebrafish, and to clarify their mechanisms of action in zebrafish by gene expression analysis of the vascular endothelial growth factor (VEGF) receptor (VEGFR2/KDR) and cell-cycle analysis. trans-3,5,4'-Trimethoxystilbene showed significantly more potent antiangiogenic activity than that of resveratrol in both assays. In zebrafish, trans-3,5,4'-trimethoxystilbene caused intersegmental vessel regression and downregulated VEGFR2 mRNA expression. Trans-3,5,4'-trimethoxystilbene also induced G2/M cell-cycle arrest, most specifically in endothelial cells of zebrafish embryos. We propose that the antiangiogenic and vascular-targeting activities of trans-3,5,4'-trimethoxystilbene result from the downregulation of VEGFR2 expression and cell-cycle arrest at G2/M phase.
authors.affiliation: Institute of Chinese Medical Sciences, University of Macau, Av. Padre Tomás Pereira S.J., Taipa, Macao SAR, China.
authors.forename: Deepa
authors.initials: D
authors.lastname: Alex
authors.forename: Emilia Conceição
authors.initials: EC
authors.lastname: Leong
authors.forename: Zai-Jun
authors.initials: ZJ
authors.lastname: Zhang
authors.forename: Gloria Tse Ho
authors.initials: GT
authors.lastname: Yan
authors.forename: Shuk-Han
authors.initials: SH
authors.lastname: Cheng
authors.forename: Chi-Weng
authors.initials: CW
authors.lastname: Leong
authors.forename: Zhen-Hua
authors.initials: ZH
authors.lastname: Li
authors.forename: Kai-Heng
authors.initials: KH
authors.lastname: Lam
authors.forename: Shun-Wan
authors.initials: SW
authors.lastname: Chan
authors.forename: Simon Ming-Yuen
authors.initials: SM
authors.lastname: Lee
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014471:Umbilical Veins / Q000166:cytology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics* / Q000378:metabolism
chemical_list: C497286:3,4',5-trimethoxystilbene; D013267:Stilbenes; D040301:Vascular Endothelial Growth Factor Receptor-2