CHE-MING TENG2018-09-102018-09-102012http://www.scopus.com/inward/record.url?eid=2-s2.0-84863128252&partnerID=MN8TOARShttp://scholars.lib.ntu.edu.tw/handle/123456789/368804The traditional Chinese medicine component dehydrocostuslactone (DHC) isolated from Saussurea costus (Falc.) Lipschitz, has been shown to have anti-cancer activity. Angiogenesis is an essential process in the growth and progression of cancer. In this study, we demonstrated, for the first time, the anti-angiogenic mechanism of action of DHC to be via the induction of cell cycle progression at the G0/G1 phase due to abrogation of the Akt/glycogen synthase kinase-3β (GSK-3β)/cyclin D1 and mTOR signaling pathway. First, we demonstrated that DHC has an anti-angiogenic effect in the matrigel-plug nude mice model and an inhibitory effect on human umbilical vein endothelial cell (HUVEC) proliferation and capillary-like tube formation in vitro. DHC caused G0/G1 cell cycle arrest, which was associated with the down-regulation of cyclin D1 expression, leading to the suppression of retinoblastoma protein phosphorylation and subsequent inhibition of cyclin A and cdk2 expression. With respect to the molecular mechanisms underlying the DHC-induced cyclin D1 down-regulation, this study demonstrated that DHC significantly inhibits Akt expression, resulting in the suppression of GSK-3β phosphorylation and mTOR expression. These effects are capable of regulating cyclin D1 degradation, but they were significantly reversed by constitutively active myristoylated (myr)-Akt. Furthermore, the abrogation of tube formation induced by DHC was also reversed by overexpression of Akt. And the co-treatment with LiCl and DHC significantly reversed the growth inhibition induced by DHC. Taken together, our study has identified Akt/GSK-3β and mTOR as important targets of DHC and has thus highlighted its potential application in angiogenesis-related diseases, such as cancer. ? 2012 Wang et al.[SDGs]SDG3angiogenesis inhibitor; cyclin A; cyclin D1; cyclin dependent kinase 2; dehydrocostuslactone; glycogen synthase kinase 3beta; mammalian target of rapamycin; protein kinase B; retinoblastoma protein; unclassified drug; angiogenesis inhibitor; antineoplastic agent; dehydrocostus lactone; glycogen synthase kinase 3; glycogen synthase kinase 3 beta; lactone; MTOR protein, human; protein kinase B; sesquiterpene; target of rapamycin kinase; animal experiment; antiangiogenic activity; article; cancer inhibition; capillary tube; cell cycle G0 phase; cell cycle G1 phase; cell cycle progression; cell proliferation; controlled study; down regulation; drug effect; drug mechanism; enzyme inhibition; enzyme phosphorylation; G1 phase cell cycle checkpoint; human; human cell; in vitro study; in vivo study; nonhuman; protein degradation; protein expression; protein phosphorylation; signal transduction; tumor vascularization; umbilical vein endothelial cell; animal; cell culture; drug antagonism; mouse; neovascularization (pathology); Costus; Mus musculus; Saussurea; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cells, Cultured; Glycogen Synthase Kinase 3; Humans; Lactones; Mice; Neovascularization, Pathologic; Proto-Oncogene Proteins c-akt; Sesquiterpenes; Signal Transduction; TOR Serine-Threonine Kinasesjournal article10.1371/journal.pone.0031195