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First published on February 9, 2005; DOI: 10.1124/mol.104.009894

0026-895X/05/6705-1444-1450$20.00
Mol Pharmacol 67:1444-1450, 2005

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ORIGINAL ARTICLE

Blockade of Vascular Endothelial Growth Factor Receptor Signal Pathway and Antitumor Activity of ON-III (2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone), a Component from Chinese Herbal Medicine

Xiao-Feng Zhu, Bin-Fen Xie, Jun-Min Zhou, Gong-Kan Feng, Zong-Chao Liu, Xiao-Yi Wei, Feng-Xian Zhang, Mei-Fang Liu, and Yi-Xin Zeng

Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, China (X.-F.Z., B.-F.X., J.-M.Z., G.-K.F., Z.-C.L., Y.-X.Z.); and Southern China Institute of Botany, the Chinese Academy of Sciences, Guangzhou, China (X.-Y.W., F.-X.Z., M.-F.L.)

Abstract

Antiangiogenesis is a promising strategy of cancer treatment. Vascular endothelial growth factor receptor [fetal liver kinase/kinase-inserting domain-containing receptor (KDR)] is a tyrosine kinase receptor and has been strongly implicated in tumor angiogenesis. In this study, we report that 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (ON-III), extracted from the dried flower Cleistocalyx operculatus, used in traditional Chinese medicine, reversibly inhibited KDR tyrosine kinase phosphorylation, but epidermal growth factor receptor tyrosine kinase phosphorylation was unaffected under the same concentrations of ON-III. ON-III also inhibited mitogen-activated protein kinase (MAPK) and AKT activation of KDR signal transduction in downstream molecules without reduced total MAPK and AKT. The results in vitro showed that ON-III inhibited growth of human vascular endothelial HDMEC cells in the presence of VEGF preferentially, compared with epidermal growth factor. Systemic administration of ON-III at nontoxic doses in nude mice resulted in inhibition of subcutaneous tumor growth of human hepatocarcinoma Bel7402 and lung cancer GLC-82 xenografts. The tumor vessel density decreased, as determined by immunohistochemical staining, for CD31 after ON-III treatment. These results indicated that ON-III inhibited KDR tyrosine kinase, shut down KDR-mediated signal transduction, and inhibited tumor growth of human xenografts in vivo.

Received November 30, 2004; accepted February 8, 2005

Address correspondence to: Dr. Yi-Xin Zeng, Cancer Center, Sun Yat-sen University, 651 DongFeng Road East, GuangZhou 510060, China. E-mail: yxzeng{at}gzsums.edu.cn




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