Penta-O-galloyl-beta-D-glucose suppresses tumor growth via inhibition of angiogenesis and stimulation of apoptosis: roles of cyclooxygenase-2 and mitogen-activated protein kinase pathways.

Abstract

Recent studies have revealed that 1,2,3,4,6-penta-O-galloyl-beta-d-glucose (PGG) has anti-tumorigenic activity in vitro. In the present work, we evaluated the in vitro and in vivo antiangiogenic and antitumor activities of PGG and examined its molecular mechanisms. PGG significantly inhibited the proliferation and tube formation in basic fibroblast growth factor (bFGF)-treated human umbilical vein endothelial cells (HUVECs) at non-cytotoxic concentrations. PGG effectively disrupted the bFGF-induced neo-vascularization in chick chorioallantoic membrane (CAM) and in Matrigel plugs in the mice. When mice were intraperitoneally injected, PGG also significantly inhibited tumor angiogenesis induced by Lewis lung carcinoma (LLC) and the growth of LLC by 57 and 91% of control tumor weight at 4 and 20 mg/kg, respectively. Immunohistochemical analysis revealed decreased microvessel density, decreased expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF), reduced tumor cell proliferation and increased tumor cell apoptosis. Similarly, PGG significantly attenuated the expression of COX-2 and VEGF and reduced the secretion of VEGF and prostaglandin E2 in bFGF-treated HUVECs. Furthermore, the COX-2 inhibitor NS398 significantly inhibited tube formation and neo-vascularization in CAM, supporting the role of COX-2 in PGG inhibition of angiogenesis. PGG diminished the phosphorylation of extracellular signal regulated kinase 1/2, Jun NH2-terminal kinase and activated phospho-p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner in bFGF-treated HUVECs. In addition, p38 inhibitor SB203580 abolished the downregulation of COX-2, VEGF and the antiproliferative activity by PGG. Taken together, our data demonstrate that PGG exerts antitumor activity primarily via inhibition of angiogenesis through COX-2 and MAPK- dependent pathways.

• Authors: Jeong-Eun Huh, Eun-Ok Lee, Min-Seok Kim, Kyung-Sun Kang, Cheol-Ho Kim, Bae-Cheon Cha, Young-Joon Surh, Sung-Hoon Kim
• Journal: Carcinogenesis (Carcinogenesis) Vol. 26 Issue 8 Pg. 1436-45 (Aug 2005) ISSN: 0143-3334 [Print] England
• PMID: 15845650 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Anticarcinogenic Agents
• Hydrolyzable Tannins
• Fibroblast Growth Factor 2
• pentagalloylglucose
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases
• Mitogen-Activated Protein Kinases

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Anticarcinogenic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Division (drug effects)
• Cell Line, Tumor
• Cyclooxygenase 2
• Fibroblast Growth Factor 2 (pharmacology)
• Hydrolyzable Tannins (chemistry, pharmacology)
• Lung Neoplasms (blood supply, prevention & control)
• Medicine, East Asian Traditional
• Mice
• Mice, Inbred BALB C
• Mitogen-Activated Protein Kinases (metabolism)
• Models, Molecular
• Neovascularization, Pathologic (prevention & control)
• Prostaglandin-Endoperoxide Synthases (metabolism)