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Cell Cycle Inhibition by the Anti-Angiogenic Agent TNP-470 Is Mediated by p53 and p21WAF1/CIP1
Yi Zhang, Eric C. Griffith, Julien Sage, Tyler Jacks and Jun O. Liu
Proceedings of the National Academy of Sciences of the United States of America
Vol. 97, No. 12 (Jun. 6, 2000), pp. 6427-6432
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/122653
Page Count: 6
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Angiogenesis has been demonstrated to be essential for tumor growth and metastasis, and inhibition of angiogenesis is emerging as a promising strategy for treating cancer. Among the most potent inhibitors of angiogenesis is the fumagillin family of natural products. An analog of fumagillin, known as TNP-470 or AGM-1470, has been undergoing clinical trials for treating a variety of cancers. TNP-470 has been shown to block endothelial cell cycle progression in the late G1 phase. Although the direct molecular target for TNP-470 has been identified as the type 2 methionine aminopeptidase (MetAP2), how inhibition of this enzyme leads to cell cycle arrest has remained unclear. We report that treatment of endothelial and other drug-sensitive cell types leads to the activation of the p53 pathway, causing an accumulation of the G1 cyclin-dependent kinase inhibitor p21WAF1/CIP1. The requirement of p53 and p21WAF1/CIP1 for the cell cycle inhibition by TNP-470 is underscored by the observation that cells deficient in p53 and p21WAF1/CIP1 are resistant to TNP-470. These results shed significant light on the mechanism of cell cycle inhibition by TNP-470 and suggest an alternative method of activating p53 in endothelial cells to halt angiogenesis and tumor progression.
Proceedings of the National Academy of Sciences of the United States of America © 2000 National Academy of Sciences