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Carcinogenesis Advance Access published online on April 21, 2005
Carcinogenesis, doi:10.1093/carcin/bgi097
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received February 8, 2004
Revised March 31, 2005
Accepted April 10, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

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

Jeong-Eun Huh 1, Eun-Ok Lee 1, Kyung-Sun Kang 2, Young-Joon Surh 3, and Sung-Hoon Kim 1*

1 Graduate School of East-West Medical Science, KyungHee University, Yongin 449-701, South Korea
2 Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea
3 College of Pharmacy, Seoul National University, Seoul 151-742, South Korea

* To whom correspondence should be addressed.
Sung-Hoon Kim, E-mail: sungkim7{at}khu.ac.kr


  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 anti-angiogenic and anti-tumor 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 noncytotoxic concentrations. PGG effectively disrupted the bFGF-induced neovascularization in chick chorioallantoic membrane (CAM) and in Matrigel plugs in the mice. When given by i.p. injection to mice, 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 mg/kg 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 as well as reduced the secretion of VEGF and prostaglandin E2 in bFGF-treated HUVECs. Furthermore, the COX-2 inhibitor NS398 significantly inhibited tube formation and neovascularization 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 NH(2)-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 and VEGF and the anti-proliferative activity by PGG. Taken together, our data demonstrate that PGG exerts anti-tumor activity primarily via inhibition of angiogenesis through COX-2 and MAPK dependent pathways.


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