3,4-Dimethoxystilbene, a resveratrol derivative with anti-angiogenic effect, induces both macroautophagy and apoptosis in endothelial cells.
Angiogenesis plays an important role in many pathological processes. Identification of novel anti-angiogenic agents will provide new insights into the mechanisms for angiogenesis as well as potential lead compounds for developing new drugs. In the present study, a series of resveratrol methylated derivatives have been synthesized and screened. We found trans-3,4-dimethoxystilbene (3,4-DMS) with the fullest potential to develop as an anti-angiogenic agent. In vitro and in vivo analyses suggested that 3,4-DMS could effectively inhibit endothelial cell proliferation, migration, tube formation, and endogenous neovascularization. Our results showed that 3,4-DMS exerted its anti-angiogenic effect likely through induction of endothelial cell apoptosis via a pathway involving p53, Bax, cytochrome c, and caspase proteases. Moreover, 3,4-DMS also induced macroautophagy in endothelial cells through activation of AMPK and the downstream inhibition of mTOR signaling pathway. Further studies indicated that intracellular calcium ([Ca(2+)](i)) might bridge the 3,4-DMS-induced apoptosis and macroautophagy through modulating reactive oxygen species (ROS) levels in endothelial cells. Combination of 3,4-DMS with inhibitor of autophagy, such as 3-methyladenine (3-MA) and autophagy-related gene (ATG) 5 small interfering RNA (siRNA), potentiated the pro-apoptotic and anti-angiogenic effects of 3,4-DMS. Our study provides a novel angiogenic inhibitor and a useful tool in exploring the molecular mechanisms for the crosstalk between apoptosis and macroautophagy in endothelial cells. 3,4-DMS could be served as a potential lead compound for developing a class of new drugs targeting angiogenesis-related diseases.
College of Bioengineering, Henan University of Technology, Zhengzhou 450001, China. chaperones@163.com
Lu
L
Zhang
HongJuan
H
Jing
LiuQing
L
Cui
HuanQing
H
Li
Bo
B
Zhou
GuangZhou
G
Zhou
Fang
F
Dai
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D020533:Angiogenesis Inhibitors; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C582097:3,4-dimethoxystilbene; C502778:ATG5 protein, human; D020533:Angiogenesis Inhibitors; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C025946:3-methyladenine; D045304:Cytochromes c; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D053148:Caspase 3; D053453:Caspase 9; D000225:Adenine; D000077185:Resveratrol; D002118:Calcium