Resveratrol derivative, trans-3,5,4'-trimethoxystilbene, exerts antiangiogenic and vascular-disrupting effects in zebrafish through the downregulation of VEGFR2 and cell-cycle modulation.
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.
Alex
Deepa
D
Institute of Chinese Medical Sciences, University of Macau, Av. Padre Tomás Pereira S.J., Taipa, Macao SAR, China.
Leong
Emilia Conceição
EC
Zhang
Zai-Jun
ZJ
Yan
Gloria Tse Ho
GT
Cheng
Shuk-Han
SH
Leong
Chi-Weng
CW
Li
Zhen-Hua
ZH
Lam
Kai-Heng
KH
Chan
Shun-Wan
SW
Lee
Simon Ming-Yuen
SM
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
C497286:3,4',5-trimethoxystilbene; D013267:Stilbenes; D040301:Vascular Endothelial Growth Factor Receptor-2