Dehydrocostuslactone suppresses angiogenesis in vitro and in vivo through inhibition of Akt/GSK-3β and mTOR signaling pathways.

Abstract

The 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.

• Authors: Chih-Ya Wang, An-Chi Tsai, Chieh-Yu Peng, Ya-Ling Chang, Kuo-Hsiung Lee, Che-Ming Teng, Shiow-Lin Pan
• Journal: PloS one (PLoS One) Vol. 7 Issue 2 Pg. e31195 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22359572 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Lactones
• Sesquiterpenes
• dehydrocostus lactone
• MTOR protein, human
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Glycogen Synthase Kinase 3

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Cells, Cultured
• Glycogen Synthase Kinase 3 (antagonists & inhibitors)
• Glycogen Synthase Kinase 3 beta
• Humans
• Lactones (pharmacology, therapeutic use)
• Mice
• Neovascularization, Pathologic (drug therapy)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Sesquiterpenes (pharmacology, therapeutic use)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)