ABSTRACT
Tumor angiogenesis and lymphangiogenesis are important processes in tumor progression and metastasis. The inhibitory effects of 3-O-acetyloleanolic acid (3AOA), a pentacyclic triterpenoid compound isolated from Vigna sinensis K., on tumor-induced angiogenesis and lymphangiogenesis in vitro and in vivo were studied. Angiopoietin-1 is an important angiogenic and lymphangiogenic factor secreted from colon carcinoma CT-26 cells under hypoxia conditions. 3AOA inhibited proliferation, migration, and tube formation of angiopoietin-1-treated human umbilical vein endothelial cells (HUVEC) and human lymphatic microvascular endothelial cells (HLMEC). 3AOA reduced angiogenesis and lymphangiogenesis in angiopoietin-1-stimulated Matrigel plugs. Also, 3AOA inhibited tumor growth and tumor-induced angiogenesis and lymphangiogenesis in an angiopoietin-1-induced CT-26 allograft colon carcinoma animal model. 3AOA inhibited activation of the angiopoietin-1 receptor Tie-2 and activation of the downstream signaling factors FAK, AKT, and ERK1/2 that are involved in the angiopoietin-1/Tie-2-signaling pathway. Thus, 3AOA has an inhibitory effect on angiogenesis and lymphangiogenesis induced by angiopoietin-1 both in vitro and in vivo, and the inhibitory effect of 3AOA is probably due to suppression of angiopoietin-1/Tie-2 signaling in HUVEC and HLMEC.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Angiopoietin-1/metabolism , Lymphangiogenesis/drug effects , Neovascularization, Pathologic/drug therapy , Receptor, TIE-2/metabolism , Triterpenes/pharmacology , Animals , Apoptosis/drug effects , Cell Line, Tumor , Female , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Mice , Mice, Inbred BALB C , Neoplasms, Experimental/drug therapy , Signal Transduction/drug effectsABSTRACT
We describe the anti-angiogenic and anti-lymphangiogenic effects of corosolic acid, a pentacyclic triterpenoid isolated from Cornus kousa Burg. A mouse colon carcinoma CT-26 animal model was employed to determine the in vivo anti-angiogenic and anti-lymphangiogenic effects of corosolic acid. Corosolic acid induced apoptosis in CT-26 cells, mediated by the activation of caspase-3. In addition, it reduced the final tumor volume and the blood and lymphatic vessel densities of tumors, indicating that it suppresses in vivo angiogenesis and lymphangiogenesis. Corosolic acid inhibited the proliferation and tube formation of human umbilical vein endothelial cells and human dermal lymphatic microvascular endothelial cells. In addition, corosolic acid decreased the proliferation and migration of human umbilical vein endothelial cells stimulated by angiopoietin-1. Pretreatment with corosolic acid decreased the phosphorylation of focal adhesion kinase (FAK) and ERK1/2, suggesting that corosolic acid contains anti-angiogenic activity that can suppress FAK signaling induced by angiopoietin-1.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Colonic Neoplasms/drug therapy , Extracellular Signal-Regulated MAP Kinases/metabolism , Human Umbilical Vein Endothelial Cells/drug effects , Lymphangiogenesis/drug effects , Triterpenes/pharmacology , Angiopoietin-1 , Animals , Apoptosis/drug effects , Carcinoma/drug therapy , Caspase 3/metabolism , Cell Line, Tumor , Cells, Cultured , Colon/pathology , Endothelial Cells/drug effects , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Humans , Mice , Neoplasms, Experimental/drug therapy , Neovascularization, PathologicABSTRACT
The cytotoxic effect of 3-O-acetyloleanolic acid, an oleanolic acid derivative isolated from the seeds of Vigna sinensis K., was investigated in human colon carcinoma HCT-116 cells. 3-O-acetyloleanolic acid dose-dependently inhibited the viability of HCT-116 cells. Apoptosis was characterized by detection of cell surface annexin V and sub-G1 apoptotic cell populations. The number of immunostained cells with annexin V-FITC was increased after treatment with 3-O-acetyloleanolic acid. The sub-G1 cell population was also increased. Expression of TRAIL-mediated apoptosis signaling-related death receptor DR5 was increased in 3-O-acetyloleanolic acid-treated HCT-116 cells. Activation of caspase-8 and caspase-3, critical mediators of extrinsic apoptosis signaling, was also increased by 3-O-acetyloleanolic acid. The results indicate that 3-O-acetyloleanolic acid induces apoptosis in HCT-116 cells mediated by an extrinsic apoptosis signaling cascade via up-regulation of DR5.